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The role of cocrystals in solid-state synthesis of imides and the development of novel crystalline forms of active pharm...

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Title:
The role of cocrystals in solid-state synthesis of imides and the development of novel crystalline forms of active pharmaceutical ingredients
Physical Description:
Book
Language:
English
Creator:
Cheney, Miranda
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
Publication Date:

Subjects

Subjects / Keywords:
Supramolecular chemistry
Pharmaceutical cocrystal
Crystal form
Crystal engineering
Lamotrigine
Meloxicam
Dissertations, Academic -- Chemistry -- Doctoral -- USF   ( lcsh )
Genre:
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: With a greater understanding of the fundamentals of crystal engineering lays the potential for the development of a vast array of novel materials for a plethora of applications. Addressed herein is the latent potential of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and primary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolated as part of the reaction pathway in three cases and is described in detail. The impact of cocrystals upon active pharmaceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable properties. Properties between crystal form and cocrystal former were also examined.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2009.
Bibliography:
Includes bibliographical references.
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Statement of Responsibility:
by Miranda Cheney.
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Title from PDF of title page.
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Includes vita.

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ABSTRACT: With a greater understanding of the fundamentals of crystal engineering lays the potential for the development of a vast array of novel materials for a plethora of applications. Addressed herein is the latent potential of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and primary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolated as part of the reaction pathway in three cases and is described in detail. The impact of cocrystals upon active pharmaceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable properties. Properties between crystal form and cocrystal former were also examined.
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Meloxicam
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The Role of Cocrystals in Solid-State Synthesis of Imides and the Development of Novel Crystalline Forms of Active Pharmaceutical Ingredients by Miranda L. Cheney A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Michael J. Zaworotko, Ph.D. Mohamed Eddaoudi, Ph.D. Wayne C. Guida, Ph.D. Joanna A. Bis, Ph.D. Date of Approval: November 9, 2009 Keywords: Supramolecular chemistry, Pharm aceutical cocrystal, Crystal form, Crystal engineering, Lamotrigine, Meloxicam Copyright 2009 Miranda L. Cheney

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Dedication For my family

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Acknowledgements I would like to thank my professor Dr Michael Zaworotko for his guidance, informative discussions, and encouragement dur ing my time as a member of his research group. I greatly appreciate the opportunity to work in his lab and in teract with all the members of the Zaworotko research group, both past and present. I would also like to thank Thar Pharmaceu ticals for providing me with the unique opportunity to conduct research in their lab while completing my Ph.D. In particular I would like to Dr. Ning Shan for many thought provoking discussions that transpired into my success. Dr. Mazen Hanna and Raymond Houck, I thank you both for taking the chance on a graduate student. Finally, I would like to thank my fam ily for their endless love and support throughout my entire educational career.

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i Table of Contents List of Tables x List of Figures xii Abstract xix Chapter 1. Introduction 1.1. Introduction 1 1.2. Supramolecular Chemistry 1 1.3. Self Assembly and Intermolecular Interactions 2 1.4. The Design of Supramolecular Solids Cr ystal Engineering 4 1.4.1. Supramolecular Synthons 5 1.5. Cocrystals – A History 7 1.5.1. Cocrystal Synthesis 13 1.6. The Cambridge Structural Database and the Supramolecular Synthon Approach 14 1.7. Solid-State Synthesis is Green Chemistry 16 1.7.1. Cocrystals and Solid-State Synthesis 18 1.8. The Impact of Crystal Form 20 1.8.1. Crystal Form Types 21 1.8.2. Pharmaceutical Cocrysta ls with Solubility Data 24

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ii 1.8.3. Pharmaceutical Cocrystals with Animal Data 34 1.8.4. Polymorphism and the Pharmaceutical Industry 38 1.9. Summary 40 1.10. References Cited 41 Chapter 2. Cocrystal Controlled Solid-State Synthesis (C3S3) of Imides 62 2.1 Preamble 62 2.2. Results and Discussion 68 2.2.1. Reaction 1 2-methyl-4-nitroaniline and NTCDA 68 2.2.1.1. Synthetic Techniques and Characterization 68 2.2.1.2. Analysis of Crystal Structures 71 2.2.2. Reaction 2 3-aminobenzoic acid and NTCDA 75 2.2.2.1. Synthetic Techniques and Characterization 75 2.2.2.2. Analysis of Crystal Structures 77 2.2.3. Reaction 3 2-methyl-4-nitroanilne and pyromellitic anhydride 81 2.2.3.1. Synthetic Techniques and Characterization 81 2.2.3.2. Analysis of Crystal Structures 83 2.2.4. Reaction 4 1-adamantylamine and phthalic anhydride 85 2.2.4.1. Synthetic Techniques and Characterization 85 2.2.4.2. Analysis of Crystal Structures 88 2.2.5. C3S3 for the General Formation of Imides 91 2.2.5.1. Imide Purity 91 2.2.5.2. Monitoring the Condensation Reaction via DSC 94

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iii 2.2.5.3. Analysis of Cocrystals and Imides via PXRD 98 2.2.5.4. Monitoring the Condensation Reaction via FT-IR 100 2.3. Conclusions 103 2.4. Materials and Methods 104 2.4.1. Materials 104 2.4.2. Synthetic Methods 104 2.4.3. Characterization Methods 114 2.5. References Cited 117 Chapter 3. Lamotrigine Crystal Form s: Synthesis, Characterization, and Evaluation 123 3.1. Preamble 123 3.2. Results and Discussion 126 3.2.1. Salt vs. Cocrystal 126 3.2.2. CSD Analysis 127 3.2.3. Motif 1 vs. Motif 2 132 3.2.4. Crystal Structure Descriptions 132 3.3. Solubility and Dissolution Study 153 3.4. Animal Pharmacokinetic (PK) Study 156 3.5. Conclusions 158 3.6. Materials and Methods 160 3.6.1. Materials 160 3.6.2. Synthesis of Compounds 1-10 160 3.6.3. Crystal Form Characterization 163

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iv 3.6.4. Solubility and Dissolution Study 165 3.6.5. Animal Pharmacokinetic (PK) Study 165 3.7. References Cited 168 Chapter 4. Meloxicam Crystal Forms: Synthesis, Characterization, and Evaluation 175 4.1. Preamble 175 4.2. Results and Discussion 177 4.2.1. Reliability of Cocrystal or Salt Formation 177 4.2.2. Cambridge Structural Database (CSD) Analysis 180 4.2.3. Crystal Structure Descriptions 186 4.2.4. Melting Point Analysis 195 4.2.5. Solubility and Dissolution Study 197 4.2.6. Animal Pharmacokinetic (PK) Study 200 4.3. Conclusions 203 4.4. Materials and Methods 204 4.4.1. Materials 204 4.4.2. Synthesis of Compounds 1-7 205 4.4.3. Crystal Form Characterization 208 4.4.4. Solubility and Dissolution Study 209 4.4.5. Animal Pharmacokinetic (PK) Study 210 4.5. References Cited 212 Chapter 5. Summary and Future Directions 218 5.1. Summary 218

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v 5.2. Future Directions 222 Appendices 224 Appendix 1. Experimental data for PA1+AA1 (2-methyl-4-nitroaniline+NTCDA) 225 Appendix 2. Experimental data for PA1+AA2 (2-methyl-4-nitroaniline+pyromellitic anhydride) 227 Appendix 3. Experimental data for PA1+AA3 (2-methyl-4-nitroaniline+maleic anhydride) 230 Appendix 4. Experimental data for PA1+AA4 (2-methyl-4-nitroaniline+phthalic anhydride) 233 Appendix 5. Experimental data for PA1+AA5 (2-methyl-4-nitroaniline+ 3, 3’, 4, 4’-biphenyl tetracarboxylic dianhydride) 236 Appendix 6. Experimental data for PA2+AA1 (3-aminobenzoic acid+NTCDA) 239 Appendix 7. Experimental data for PA2+AA2 (3-aminobenzoic acid+pyromellitic anhydride) 241 Appendix 8. Experimental data for PA2+AA3 (3-aminobenzoic acid+maleic anhydride) 244 Appendix 9. Experimental data for PA2+AA4 (3-aminobenzoic acid+phthalic anhydride) 247 Appendix 10. Experimental data for PA2+AA5 (3-aminobenzoic acid+

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vi 3, 3’, 4, 4’-biphenyl tetracarboxylic dianhydride) 250 Appendix 11. Experimental data for PA2+AA6 (3-aminobenzoic acid+1,8-naphthalic anhydride) 253 Appendix 12. Experimental data for PA3+AA2 (melamine+pyromellitic anhydride) 256 Appendix 13. Experimental data for PA3+AA3 (melamine+maleic anhydride) 259 Appendix 14. Experimental data for PA3+AA4 (melamine+phthalic anhydride) 262 Appendix 15. Experimental data for PA4+AA1 (1,4-phenylenediamine+NTCDA) 265 Appendix 16. Experimental data for PA4+AA2 (1,4-phenylenediamine+pyromellitic anhydride) 268 Appendix 17. Experimental data for PA4+AA3 (1,4-phenylenediamine+maleic anhydride) 271 Appendix 18. Experimental data for PA4+AA4 (1,4-phenylenediamine+phthalic anhydride) 274 Appendix 19. Experimental data for PA4+AA5 (1,4-phenylenediamine +3, 3’, 4, 4’-biphenyltetracarboxylic dianhydride) 277 Appendix 20. Experimental data for PA4+AA6 (1,4-phenylenediamine+1,8-naphthalic anhydride) 280 Appendix 21. Experimental data for PA5+AA1

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vii (1,5-naphthalenediamine+NTCDA) 283 Appendix 22. Experimental data for PA5+AA2 (1,5-naphthalenediamine+ pyromellitic anhydride) 286 Appendix 23. Experimental data for PA5+AA3 (1,5-naphthalenediamine+maleic anhydride) 289 Appendix 24. Experimental data for PA5+AA4 (1,5-naphthalenediamine+phthalic anhydride) 292 Appendix 25. Experimental data for PA5+AA5 (1,5-naphthalenediamine +3, 3’, 4, 4’-biphenyltetracarboxylic dianhydride) 295 Appendix 26. Experimental data for PA5+AA6 (1,5-naphthalenediamine+1,8-naphthalic anhydride) 298 Appendix 27. Experimental data for PA6+AA3 (1-adamantylamine+maleic anhydride) 301 Appendix 28. Experimental data for PA6+AA4 (1-adamantylamine+phthalic anhydride) 304 Appendix 29. Experimental data for PA7+AA2 (triphenylmethylamine+pyromellitic anhydride) 308 Appendix 30. Experimental data for PA7+AA3 (triphenylmethylamine+maleic anhydride) 311 Appendix 31. Experimental data for PA7+AA4 (triphenylmethylamine+phthalic anhydride) 314 Appendix 32. Experimental data for PA7+AA5

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viii (triphenylmethylamine +3, 3’, 4, 4’-biphenyltetracarboxylic dianhydride) 317 Appendix 33. Histograms for specified contacts between aminopyridine to carboxylic acid and aminopyridine to alcohol moieties (Com prised of entries in the CSD) 320 Appendix 34. Experimental data for lamotrigine methylparaben form I 322 Appendix 35. Experimental data for lamotrigine methylparaben form II 323 Appendix 36. Experimental data for lamotrigine nicotinamide cocrystal 324 Appendix 37. Experimental data for lamotrigine nicotinamide monohydrate 325 Appendix 38. Experimental data fo r lamotrigine saccharinate salt 327 Appendix 39. Experimental data for lamotrigine adipate salt 328 Appendix 40. Experimental data for lamotrigine malate salt 329 Appendix 41. Experimental data for lamotrigine nicotinate dimethanol solvate 330 Appendix 42. Experimental data for lamotrigine dimethanol solvate 332 Appendix 43. Experimental data for lamotrigine ethanol hydrate 334 Appendix 44. Histograms for specified contacts between carboxylic acid-azole, alcohol-azole, and primary amide-azole compiled from entries in the CSD 336

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ix Appendix 45. Experimental data for meloxicam 1-hydroxy-2-naphthoic acid cocrystal 337 Appendix 46. Experimental data for meloxicam glutaric acid cocrystal 338 Appendix 47. Experimental data for meloxicam L-malic acid cocrystal of a salt 339 Appendix 48. Experimental data fo r meloxicam aspirin cocrystal 340 Appendix 49. Experimental data for meloxicam salicylic acid cocrystal form III 341 Appendix 50. Experimental data for meloxicam salicylic acid cocrystal form I 342 Appendix 51. Experimental data for meloxicam salicylic acid cocrystal form II 343 About the Author End Page

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x List of Tables Table 1.1. Summary of intermol ecular interactions commonly exhibited in supramolecular chemistry with the covalent bond included for comparison 2 Table 1.2. Summary of hydrogen bonds and their characteristics 3 Table 1.3. Summary of the pharmacoki netic metrics for the presented pharmaceutical cocrystals 38 Table 2.1. Table of 49 reactions colo r coded to differentiate outcomes after solvent-drop grinding and heating 68 Table 2.2. Crystal structure parameters for cocrystals 1a-4a 90 Table 2.3. Summary of DSC and 1HNMR data 93 Table 2.4. Hydrogen bond dist ances and parameters 116 Table 3.1. pKa values and the resulting pKa values for the lamotrigine salts 127 Table 3.2. Comparison of supramolecula r homosynthon versus supramolecular heterosynthon with aminopyridin es and complementary moieties 130 Table 3.3. Crystallographic data and structure refinement parameters for compounds 1-2, 4-10 152 Table 3.4. Hydrogen bond dist ances and parameters 166 Table 4.1. pKa values and pKa values for meloxicam and a set

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xi of carboxylic acids 179 Table 4.2. Percent occurrence for supramolecular homosynthons and heterosynthons with amino-azole s in the presence of carboxylic acids, carboxylates, primar y amides, and alcohols 185 Table 4.3. Percent occurrence for supramolecular homosynthons and heterosynthons with azoles in the presence of carboxylic acids, carboxylates, primar y amides, and alcohols 185 Table 4.4. Crystal structure para meters for cocrystals 1-5 195 Table 4.5. Melting points for meloxicam, cocrystal formers, and there correspond ing cocrystals 196 Table 4.6. Hydrogen bond dist ances and parameters 210

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xii List of Figures Figure 1.1. (a) Supramolecular homosynthon exemplified by an amide-amide dimer (b) S upramolecular heterosynthon exemplified by an acid-amide dimer 6 Figure 1.2. (a) Alcohol-aromatic ni trogen supramolecular heterosynthon (b) Carboxylic acid-aromatic nitrogen supramolecular heterosynthon 6 Figure 1.3. Ternary cocrys tal developed by establis hing a synthon hierarchy 10 Figure 1.4. Possible supramolecular synthons from supramolecular heterosynthon competitive studies 11 Figure 1.5. Analysis of SciFinder Scholar references by year for the term “cocrystal” 12 Figure 1.6. [2+2] Photodimerization of cinnamic acid to truxillic acid 17 Figure 1.7. MacGillivray’s [2+2] Photodi meraztion utilizing a cocrystal template 19 Figure 1.8. Hydrogen bonding of itraconazo le succinic acid cocrystal with succinic acid molecule in green 25 Figure 1.9. Fluoxetine HCl succinic aci d cocrystal supramolecular synthons were the Cl is shown in dark green 26 Figure 1.10. Intermolecular and intram olecular interactions found in

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xiii the piroxicam saccharin cocrystal 27 Figure 1.11. Supramolecular synthon s present in the norfloxacin isonicotinamide cocrystal solvate highlighting the persistence of the amide dimer, solvent molecules have been deleted for clarity 28 Figure 1.12. Phosphoric acid cocrys tal of a monophosphate salt 29 Figure 1.13. Hydrogen bonding of the cel ecoxib nicotinamide cocrystal 30 Figure 1.14. Carbamazepine aspirin cocrystal 31 Figure 1.15. 2-point recognition supramol ecular synthon of AMG 517 succinic acid cocrystal 32 Figure 2.1. Reaction scheme for imide fo rmation from primary amine and 64 carboxylic acid anhydride via cocrystallization Figure 2.2. Proposed reaction mechanism for carboxylic acid anhydride and 65 primary amine producing an imide Figure 2.3. Carboxylic acid anhydrides 67 Figure 2.4. Primary amines 67 Figure 2.5. UV-Vis spectrum of DMF so lvent drop grind versus methanol grind, NTCDA, and 2-methyl-4-nitroaniline 69 Figure 2.6. DSC’s highlighting the phase tr ansitions that occur for mixtures (left) and cocrystal (right). All temp eratures are in degrees Celsius. 71 Figure 2.7 Color changes for reaction 1 71 Figure 2.8. Intermolecular interactions sustaining 1a. 1a obeys the topochemical postulate as the shortest distance between the

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xiv nitrogen atoms of the amine mo ieties and the carbon atoms of the carbonyl moieties is 3.42 72 Figure 2.9. Crystal packing of 1a viewed down the c -axis 73 Figure 2.10. Molecular structur e of diimide 1b as generate d via recrystallization of 1b from DMSO 74 Figure 2.11. Crystal packing of 1b.DMSO solvate (3:2) obtained via recrystallization from DMSO 74 Figure 2.12. Color coded crystal packing of 1b DMSO: diimide A = red, diimide B = blue, diimide C = green, DMSO = yellow 75 Figure 2.13. UV-Vis spectrum of DM F solvent-drop grind versus 3-aminobenzoic acid, methanol solvent-drop grind, and NDTCA 76 Figure 2.14. DSCs highlighting the phase transi tions that occur for cocrystal (left) and mixture (right). All temperat ures are in degrees Celsius 77 Figure 2.15. Colors of 3-aminobenzoic ac id, NTCDA, dry grinding product, DMF grinding product, and final imide 2b 77 Figure 2.16. Crystal packing of cocrystal 2a 1,4-dioxane 79 Figure 2.17. Simplified crysta l packing of the 1:2 complex of 2b with pyridine 80 Figure 2.18. Crystal packing of the pyridine solvate of the 1:2 complex of 2b with pyridine 80 Figure 2.19. DSCs highlighting the phase tran sitions that occur fo r cocrystal (left) and mixture (right). All temper atures are in degrees Celsius. 82 Figure 2.20. Stepwise reac tion of 2-methyl-4-nitoaniline and pyromellitic anhydride highlighting cocrystal formation 83

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xv Figure 2.21. Crystal structure of cocrystal 3a formed between 2-methyl-4-nitroaniline and pyromellitic anhydride 84 Figure 2.22. Molecular stru cture of diimide 3b 85 Figure 2.23. Crystal packing of 3b 85 Figure 2.24. DSC of 4a 87 Figure 2.25. DSC of 4b 87 Figure 2.26. Crystal packing of 4a 89 Figure 2.27. DSC trace of mixture of 3-aminobenzoic acid and phthalic anhydride 95 Figure 2.28. DSC trace of a mixture of 1,4-phenylenediamine and NTCDA 96 Figure 2.29. DSC trace of a mixtur e of 1,4-phenylenediamine and 1,8-naphthalic anhydride 97 Figure 2.30. DSC trace of a mixture of 1,5-naphthalenediamine and maleic anhydride 98 Figure 2.31. PXRD of eight solvent drop grinds, st arting materials, and calculated cocrystal 99 Figure 2.32. Powder diffraction patterns of solvent drop grinds after heating for ca. 2 days at 150 C 100 Figure 2.33. Infrared spectr a (FT-IR) of NTCDA and 2-methyl-4-nitroaniline DM F solvent drop grind (red) compared to anhydride (purple) and amine (blue) 101 Figure 2.34. FT-IR of imide (red ) with starting materials 101 Figure 2.35. FT-IR of intermediate (red) formed from phthalic anhydride (purple)

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xvi and 1-adamantylamine (green) 102 Figure 2.36. FT-IR of imide (red) generated from 1-adamantylamine and phthalic anhydride 103 Figure 3.1. Molecular structures of cocrystal and salt formers 127 Figure 3.2. Motif 1 involves breaking the aminopyridine dimer and motif 2 retains the aminopyridine di mer but breaks the exterior bifurcated interaction 128 Figure 3.3. Supramolecular synthons exhibited by 1 133 Figure 3.4. 1 breaks motif 1 as show n in the hydrogen bonding pattern 134 Figure 3.5. Breaking motif 2 shown in the hydrogen bonding of 2 135 Figure 3.6. Crystal packing of 2 136 Figure 3.7. Supramolecular synthons present in 4 137 Figure 3.8. Crystal packing of 4 interrupting motif 2 138 Figure 3.9. Tetrameric motif present in 5 139 Figure 3.10. Crystal packing of 5 140 Figure 3.11. Supramolecular synthon s of 6 do not form motif 1 141 Figure 3.12. Crystal packing of 6 142 Figure 3.13. Supramolecular synthons of 7 generating motif 1, breaking motif 2 143 Figure 3.14. Crystal packing of 7 highlighting a chain running perpendicular to the sheet 144 Figure 3.15. Breaking motif 1 shown in the hydrogen bonded assembly of 8 145 Figure 3.16. Crystal packing of tetrameric units of 8 146

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xvii Figure 3.17. Crystal form 9 breaking motif 2 147 Figure 3.18. Bilayers formed in crystal packing of 9 148 Figure 3.19. Crystal packing of KAD PAG in CSD highlighting the angle between the lamotrigine methanol units 149 Figure 3.20. Crystal form 10 interrupting motif 2 150 Figure 3.21. Ethanol water lamotrigine ribbons 151 Figure 3.22. Dissolution profiles in water for lamotrigine and crystal forms 2-5 153 Figure 3.23. Dissolution profiles at pH = 1 for lamotrigine and crystal forms 2-5 153 Figure 3.24. Rat serum concentrations of lamotrigine, 3, 4 and 5 157 Figure 4.1. Anionic, Cationic, and Zwitterionic forms of Meloxicam 176 Figure 4.2. Line drawings of the carboxylic acids used to form pharmaceutical cocrystals with meloxicam 179 Figure 4.3. Meloxicam chains sustai ned by sulfonyl-amide dimers and sulfathiazole-alcohol supramolecular synthons 181 Figure 4.4. Supramolecular unit of 1 187 Figure 4.5. Crystal packing of f our supramolecular units of 1 187 Figure 4.6. Meloxicam:glutaric acid cocrystal (2) supramolecular synthons highlighting the meloxi cam and glutaric acid dimers 189 Figure 4.7. Crystal packing of multiple chains of 2 189 Figure 4.8. Supramolecular synthon s in 3 showing a neutral and cationic meloxicam and an anionic L-malate 191

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xviii Figure 4.9. Stacked layers of the meloxicam L-malic acid cocrys tal of a salt (3) 191 Figure 4.10. Meloxicam aspirin cocrys tal (4) basic supramolecular unit 192 Figure 4.11. Units of the meloxicam aspirin cocrystal (4) translating along a 21 screw axis 193 Figure 4.12. Meloxicam salicylic acid cocrystal form III (5) 2-point recognition su pramolecular synthon 194 Figure 4.13. Meloxicam salicylic acid units translating along 21 screw axis 194 Figure 4.14. Plot for analysis of melting point of cocrystal versus melting point of cocrystal former 197 Figure 4.15. Dissolution profiles for me loxicam and five crystal forms in pH 8 buffer, 37 C 200 Figure 4.16. Rat plasma concentrations after single dose administration of meloxicam and six cocrystals 202 Figure 4.17. Cocrystal and meloxi cam solubility versus rat plasma concentration 202

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xix The Role of Cocrystals in Solid-State Synt hesis of Imides and the Development of Novel Crystalline Forms of Active Pharmaceutical Ingredients Miranda L. Cheney ABSTRACT With a greater understanding of the fundame ntals of crystal engineering lays the potential for the development of a vast ar ray of novel materials for a plethora of applications. Addressed herein is the latent poten tial of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal contro lled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and pr imary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolat ed as part of the r eaction pathway in three cases and is described in detail.

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xx The impact of cocrystals upon active pharm aceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal so lvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrysta llization attempts of meloxicam afforded seven novel cocrystals. Solubility and pha rmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable propert ies. Properties between crystal form and cocrystal former were also examined.

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1 Chapter 1Introduction 1.1. Introduction 1.2. Supramolecular chemistry Supramolecular chemistry,1, 2 or the chemistry of the intermolecular bond,3 has been defined by Jean Marie Lehn as “chemistry beyond the molecule”.4 Supramolecular chemistry is therefore inhe rently reliant upon the understa nding of molecules at the molecular level, i.e. the chemistry of covale nt interactions that hold atoms together, to facilitate the study of the intermolecular interactions between neighboring molecules. Initial studies of complexes once called “bermolecles” 5 or “supermolecules” were examined to gain insight into the intermolecular interactions that afforded such conglomerations. The basic concepts that developed were premised upon the reliability of molecular recognition even ts between two different bu t complementary molecules initially described as the receptor and the substr ate. Investigations into substrate-receptor binding was first examined in the context of biological processes which led to the development of the “lock and key” model described by Emil Fischer.6 The realization of Nature’s success with molecular recognition led to the deliberate design of complexes founded upon molecular recognition ev ents such as crown ethers,7 cavitands,8 and cryptands9 designed for ion selection.10-12 Further exploration in to molecular recognition

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2 devices produced functional supramolecular r eceptors for applicati ons such as catalysis13, 14 and carrier-mediated membrane transport.15, 16 1.3. Self Assembly and Intermolecular Interactions Supramolecular chemistry is reliant upon mo lecular recognition and self assembly of target molecules via weak non covalent in termolecular interactio ns such as hydrogen bonds, metal coordination bonds, CH, van der Waals forces and electrostatic interactions.2 A summary of the bond energies of a select set of intermolecular interactions with a relevant example is provided in Table 1.1.17 Table 1.1. Summary of intermolecular interactions commonly exhibited in supramolecular chemistry with the covalent bond included for comparison Interaction Strength (kJ/mol) Example Covalent 150-450 O-O to C-C bond Non Covalent 2-300 Dispersion to ion-ion Hydrogen Bond 4-120 CH to HF Dipole-Dipole 5-50 Acetone Stacking <50 Benzene van der Waals <5 Inert gas The hydrogen bond is of particular impor tance in supramolecular chemistry because of its relative st rength and directionality.18 A definition of a hydrogen bond has been suggested by many authors with the earl iest examples being the most restrictive (electronegative atom interacting with anot her electronegative atom with a hydrogen in

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3 between).19-23 However, more recent definitions include weaker interactions such as CH O as hydrogen bonds.24 For the purpose of this dissertation a hydrogen bond will include interactions between two electronegativ e atoms, typically se parated by a distance less than the sum of the van der Waals rad ii, where one atom can be defined as the hydrogen bond donor and the other atom acts as the acceptor, where hydrogen is located between the two atoms and is directional in nature. Table 1.2 summarizes strong, moderate, and weak hydrogen bonds and their characteristic bond strengths, lengths, angles, interaction type, and the position of the hydrogen (c loser to the donor (D) or acceptor (A)) relative to the strength of the bond.18 Table 1.2. Summary of hydrogen bonds and their characteristics (D = donor, A = acceptor) Hydrogen bonding is also of great importan ce in biological systems. DNA, for example, is a molecular complex comprised of two strands of long chains of base pairs held together by hydrogen bonds. The replicatio n of DNA relies upon th e reversibility of hydrogen bonding as the process breaks then makes new hydrogen bonds facilitating data transcription and eventually cell replication.25 Without the occurre nce of hydrogen bonds base pairs would not interact, DNA could not replicate, and life could not exist. Strong Moderate Weak Hydrogen bond energy (kcal/mol) 15-40 4-15 Less than 4 D A distance () 2.2-2.5 2.5-3.2 Less than 3.2 D-H vs. H A X-H H A X-H > H A X-H >> H A Bond angles ( ) 170-180 >130 >90 Hydrogen bond interaction type covalent electrostatic electrostatic or dispersion

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4 Hydrogen bonding is a key element throughout this dissertation and it will be the main intermolecular interaction focuse d upon for crystal structure analysis. system overlap resulting in charge -transfer complexes will al so be highlighted. 1.4. The Design of Supramolecular Solids – Crystal Engineering Supramolecular chemistry was initially focused upon the study of supermolecules in solution. However, the field has since split into two direct ions: the study of supermolecules in solution and the study of supermolecules in the solid-state. The explorations into solid-state supramolecular chemistry led to the development of crystal engineering. The term crystal e ngineering was introduced by Pepinsky26, 27 in 1955 and was first practiced by Schmidt who utilized trans-cinnamic acids to design organic solidstate photochemical reactions.26, 28 The term “molecular engineering” was also introduced and used by Hippel to describe the building of materials and devices to order.29 Crystal engineering was later defined in 1989 by Desi raju as “the understanding of intermolecular interactions in the context of crystal packing and th e utilization of such understanding in the design of new solid s with desired physical and chemical properties”.30 Thus, Desiraju’s definition portrays the potential of crystal engineering to result in the development of novel materi als. Further exploration of organic supramolecular assemblies via crystal engineering by Etter,31-33 Desiraju, 30, 34-37 Wuest,3841 Aoyama,42, 43 Whitesides,44-48 Stoddart,49-51 and many others has since realized this potential, affording a plethora of materials that are sustained by various molecular recognition events, including supramolecular synthons.34, 37

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5 1.4.1. Supramolecular Synthons Supramolecular synthons have been defi ned as non-covalent bonding between at least two complement ary functional groups.34 The study of supramolecular synthons began with the carboxylic acid dimer form ation with acetic acid in solution52 and has since progressed into two di stinct types: the supram olecular homosynthon and the supramolecular heterosynthon.53 The supramolecular homosynthon is generated by a non-covalent interaction between two of the same moieties. A supramolecular heterosynthon also incorporat es a non-covalent interacti on however the interaction is between two different but complementary moieties. Supramolecular synthons are typicall y sustained via hydrogen bonds formed between two electronegative atoms where one atom is also covalently bound to a hydrogen atom. Additionally, other weaker interactions such as stacking54 can also be considered a supramolecular synt hon. Commonly employed supramolecular heterosynthons sustained via hydrogen bonding include carboxylic acid-amide,55-68 carboxylic acid-aromatic nitrogen,69-81 carboxylate-aromatic nitrogen,71, 82-84 alcoholaromatic nitrogen,85-92 and alcohol-amine.93-96 Typical distance ranges for these common supramolecular heterosynthons are ca. 2.5-2.8 , 2.4-2.8 , 2.5-3.0 , and 2.5-3.1 , respectively. Supramolecular homosynthons can also exist with any self complementary moiety such as a carboxylic acid or a prim ary amide. An example of an amide-amide supramolecular homosynthon and a carboxylic acid-amide supramolecular heterosynthon are shown in Figure 1.1. (a) and (b), respectively.

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6(a) (b) Figure 1.1. (a) Supramolecular homosynthon exemplified by an amide-amide dimer (b) Supramolecular heterosynthon exemplified by an acid-amide dimer A commonly employed supramolecular he terosynthon is the carboxylic acidaromatic nitrogen supramolecular heterosynt hon, most likely due to its strength and reliability.55, 64, 69-81, 97-107 Additionally, the aromatic nitrogen-alcohol supramolecular heterosynthon has also been researched to examine its dependability.85-92 A pictorial representation of the two supramolecular he terosynthons is provi ded in Figure 1.2. (a) (b) Figure 1.2. (a) Alcohol-aromatic nitrogen supramolecular heterosynthon (b) Carboxylic acid-aromatic nitrogen supramolecular heterosynthon The ability to manipulate supramolecular sy nthon formation to generate a desired supramolecular synthon has been explored by many. The work of Margret Etter is particularly noteworthy as, base d upon her experimental data, she developed a set of rules to determine the potential for supramolecular synthon formation given various donoracceptor systems.31, 33 Her studies concluded with th e development of three general

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7 rules: (1) all good proton donors and accepto rs are used (2) six membered ring intramolecular hydrogen bonds will form in pr eference to intermolecular hydrogen bonds and (3) the best proton donors and acceptors remaining after intramolecular hydrogen bonding will form intermolecular hydrogen bonds with each other.33 She also developed a plethora of more specific rules that applied only to certain functionalities. For further knowledge one is directed to her Accounts of Chemical Research article entitled “Encoding and Decoding Hydrogen-Bond Pattern s of Organic Compounds”. Etter was also influential in the development of gra ph set analysis of supramolecular synthons.32 Although the use of graph set notation to describe a supramolecular synthon can be beneficial, the complexity that arises from larger supramolecular synthons has limited the use of the terminology. 1.5. Cocrystals – A History The history of cocrystals began in 1844 with Friedrich Whler’s synthesis of quinhydrone from hydroquinone and quinone.108 The material, however, was not called a cocrystal. In fact, many early cocrystals were hidden under the guise of other names such as addition compounds,109 molecular complexes,110 organic molecular compounds,111 and solid-state complexes.112 The term “co-crystal” was not used until 1967 to describe the hydrogen bonded complex formed between 9-methyladenine and 1-methylthymine.113 The term was then later popularized by Margret Etter in the 1990’s. The debate over the term cocrystal began in 2003 with a contr oversial letter from Desiraju where he asks: “what is coto what?”.114 Desiraju continues to explain that he would prefer to call a multiple component syst em that is held together by non-covalent

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8 interactions a “molecular complex”. Dunitz re plies to Desiraju’s letter in agreement that the term is inaccurate and in elegant; however, he argues that the term molecular complex is too vague and could be in terpreted to include solvat es, inclusion compounds or amorphous solids. Dunitz also insists that th e hyphen remain as it is used to signify a “togetherness” of two components.115 Aakery later defined co crystals with a strict definition where three criteria must be satisf ied: the components must be neutral, the solid must be made from components that are solids under ambient conditions, and it must consist of homogenous crystalline material where th e components are present in stoichiometric ratios.116 However, Andrew Bond did not agree with th e restrictions placed by Aakery (specifically that all com ponents must be solids) as he calls the distinction “contrived and inappropriate”. He suggests that the term “multiplecomponent molecular crystals” be employed to describe a crystalline material containing components that are either liquid or solid under ambient conditions.117 Currently a ubiquitous definition for the term cocrystal does not exist. For the purpose of this dissertation, however, a cocrystal is define d as a stoichiometric multiple component crystal that is formed between two crystal line materials that are solids under ambient conditions. At least one of the component s is molecular and forms a supramolecular synthon with the remaining component.118, 119 Cocrystals are typically comprised of two or more molecules that contain multiple functional groups and are sustained by vari ous supramolecular synthons. In general supramolecular heterosynthons are used in the formation of co crystals; however, there are a few select examples where cocrystals are sustained via supramolecular mixed homosynthons, i.e. the carboxylic acid di mer formed by two chemically distinct

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9 carboxylic acids.120 Due to the frequent use of supramolecular synthons to sustain cocrystals, cocrystals have played an inte gral part in furthering the understanding of supramolecular synthons and their hierar chy. The seminal works of Aakeroy,116 Shattock,121 and Bis85 are particularly noteworthy as they employ cocrystallization to delineate supramolecular synthon formation in the presence of carboxylic acids, amides, aromatic nitrogens, alcohols, and cyanos. Aakery and co-workers tested Etter’s rules to determine if the strongest acid/base from their dataset would form a s upramolecular synthon with the next strongest acid/base.19, 116, 122-124 Specifically, Aakery targeted ternary cocrystal formation60, 116, 125, 126 by using three molecules that contained carbo xylic acid, amide, and aromatic nitrogen moieties to determine which of the many possi ble supramolecular synthons would persist, however, this resulted in ternary cocrysta ls that were sustained by carboxylic acidaromatic nitrogen and carboxylic acid-amide supramolecular synthons.58 An additional study for the generation of tern ary cocrystals involved tw o carboxylic acid containing molecules (one stronger acid, one weaker ac id) and one molecule with two aromatic nitrogen moieties of different basicities. The results confirmed one of Etter’s rules as the ternary cocrystals were sustained by the stronger acid forming a supramolecular synthon with the stronger base while the weaker ac id formed a supramol ecular synthon with the weaker base.116, 125 The ternary cocrystal is shown in Figure 1.3. with the stronger acid (3,5-dinitrobenzoic acid (left)) paired with the imidazole nitrogen (1-((3pyridyl)methyl)benzimidazole) and the weaker acid (3-(dimethylamino)benzoic acid (right)) paired with the aromatic nitrogen.

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10 Figure 1.3. Ternary cocrystal developed by establishing a synthon hierarchy Shattock121, 127 and Bis85, 128 have taken a different a pproach to delineating the hierarchy of supramolecular synthons with th e utilization of cocr ystallization. Their studies involved three functiona l groups and three combinati ons of molecules. Each experiment was comprised of two molecules, one with two moieties present on the same molecule and another molecule that only c ontained one moiety. All permutations of molecular combinations were attempted. The experiments were designed in such a way that if a supramolecular synthon hierarchy exis ted then two out of the three experimental arms would succeed in cocrystal formation wh ile the third would not form cocrystals. The experimental work was divided into two separate competitive studies. Bis’ work tested the supramolecular synthon formation be tween alcohols, aroma tic nitrogens, and cyanos128 while Shattock’s studies employed carboxy lic acids, aromatic nitrogens, and alcohols.127 From the first set of moieties it was de termined that the alcohol preferred to form a supramolecular synthon with the aroma tic nitrogen, not the cyano moiety. The second set of moieties was more complex as th e number of donor molecules increased to two with still only one acceptor. An additi onal unforeseen problem occurred due to the selection of molecules with more than one car boxylic acid or aromatic nitrogen moiety.

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11 Thus in some cocrystals both the carboxy lic acid-aromatic nitrogen and aromatic nitrogen-alcohol supramolecular heterosynthons were visualized. However, the study concluded that the carboxylic acid-aromatic nitrogen supramolecular heterosynthon was stronger than the alcohol-arom atic nitrogen due to the ab sence of cocrystal formation when a molecule containing both a carboxylic acid and aromatic nitrogen moiety was paired with an alcohol. Schematic repr esentations of the pot ential supramolecular heterosynthons from both studies are shown in Figure 1.4. The reliable supramolecular heterosynthons (a, c, d) are shown with a green check mark while supramolecular heterosynthons with low percentage of occu rrences (b, e) are indicated by a red X. Figure 1.4. Possible supramolecular synthons from supramolecular heterosynthon competitive studies. Green check marks indicate common supramolecular synthons. Red X’s indicate supramolecular synthons with a low percentage of occurrences The previously described crystal engin eering studies employ cocrystal formation to determine the reliability of supramol ecular synthon formation in a competitive situation. The success of these studies ha s provided valuable insight into the O O H N O H N O O H O H O H N O H NC (a) (b) (c)(d)(e) O O H N O H N O O H O H O H N O H NC (a) (b) (c)(d)(e)

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12 supramolecular synthon hierarchy th at can be applied to future cocrystallization attempts with molecules containing more than one moiety. That cocrystals are an expanding field that continues to gain interest from both academia and the pharmaceutical industry is made evident from a search of SciFinder Scholar for references in the chemical ab stracts that contain the term “cocrystal”.129 The search provided a list of 1,523 references. An alyzing those references by year elucidates their growing popularity. A pict orial representation is high lighted in Figure 1.5. The rapid increase can be attributed to their variety of applicatio ns such as non-linear optics for polar molecules,130-132 Polaroid film development,133 decrease tendency for hydration,134-138 improve thermal stability,139-141 chiral separation,142 improve compressibility and tabletting,143 increase % yield for solid-state synthesis,144 and alter solubility139, 145-154 which can lead to improved bioava ilability for active pharmaceutical ingredients. Figure 1.5. Analysis of SciFinder Scholar refere nces by year for the term “cocrystal” 0 50 100 150 200 250 2 008 2007 2 006 2 005 2 00 4 2 003 2 0 02 2 001 2 0 00 1 999 1998 1 997 Y ear

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13 1.5.1. Cocrystal Synthesis Cocrystals can be synthesized by various techniques includi ng dry grinding or neat grinding,155, 156 solvent-drop grinding (also cal led liquid-assisted grinding),119, 155, 157167 mixing, milling,168 reaction crystallization,169 slurring,158, 170-172 sonic slurring,161 and solution crystallization techniques designed to grow single crystals119 including slow evaporation from solution, vapor diffusion, a nd layering for liquid diffusion. The oldest cocrystallization technique is perhaps dry grinding as it was performed as early as the 1800’s.108 It was only since 2002 that solvent-drop grinding has been implemented for the synthesis of cocrystals.164 Grinding and milling are beneficial over traditional solution techniques as they are a “greener” approach requiring mu ch less solvent and cocrystal formation tends to occur at a faster rate with higher yields.155 Solvent-drop grinding with multiple solvents has also pr oven to be a reliable method to generate polymorphs of a particular cocrystal.173 Recently the ability to interconvert between cocrystals of different stoichiometries via so lvent-drop grinding has also been highlighted by Jones et.al.163 Additionally, the slurry methodol ogy, widely used as a screening technique in the pharmaceutical industry, can be advantageous when gram-level amounts of cocrystal are required. Attempts to illuminate cocrystal formati on conditions were initiated by studies of the two components interacting in solution. Rodrguez-Horne do pioneered the area with her studies of the carbamazepine nicotinamid e cocrystal in solution by measuring the amount of cocrystal formed w ith variable concentrations of either carbamazepine or nicotinamide present in solution.174 Her studies showed that the greater the concentration of nicotinamide in solution, the greater th e reduction in solubility of the cocrystal.175

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14 This is most likely due to the solid phase th at is present in equilibrium with the liquid phase shifting from cocrystal to nicotinamide.176 Additional studies to investigate the equilibrium between solid and liquid phases of two molecules in solution have been conducted by the determination of ternary phase diagrams.177 The ternary phase diagram plotted by Chiarella et al. for trans-cinnami c acid and nicotinamide was generated to assist in the understanding of why solven t-drop grinding can be such a successful cocrystallization technique in lieu of traditional solution crystallization methods.178 Chiarella179 concluded that in a solvent system wh ere the two components are of similar solubility then a 1:1 stoichiometric ratio so lvent-drop grind will produce the cocrystal due to the correct balance of cocrystal formers and solvent. However, if cocrystal formation is attempted in a solvent in which the two co mponents are of varying solubility then the region where the cocrystal formation occurs wi ll be skewed to one side of the ternary diagram. Thus if a slow evaporation e xperiment was attempted, which inherently progresses down the center of the phase diag ram as it looses solvent, the likelihood of cocrystal formation is decreased. 1.6. The Cambridge Structural Database and the Supramolecular Synthon Approach With the vast improvements in X-ray crys tallographic equipment within the past decade the amount of crystallographic data has grown exponentially as structural data can be collected and crystallographi c details resolved more quickly than ever before. The increase in crystal data is reflected in th e Cambridge Structural Database (CSD) which currently contains ca. 481,000 crystal structures.180 The CSD is a structural visualization

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15 and analysis software developed by the Camb ridge Crystallographic Data Centre. The contents of the CSD can be readily searched by multiple methods including chemical structures, names, authors, etc. The ability to search the CSD for a desired functionality181 can be useful in the design of cocrys tals, moreover, the ability to search for specified supramolecular homosynthons and heterosynthons make the CSD an invaluable tool for crystal engineering of supramolecular solids including cocrystals.182186 The first step in a cocrystallization expe riment is to conduct a search of the CSD for the moiety present on the target molecu le. The resulting entries are then cross referenced with the presence of a plethora of additional complementary moieties. The next step is to determine if the supram olecular homosynthon or heterosynthon is the dominant interaction between the moieties in question. If the supramolecular heterosynthon has a greater percentage of occu rrences then a cocrystal can most likely be made, however, if the supramolecular homos ynthon is dominant then the likelihood of cocrystal formation is reduced. This type of statistical analysis of the CSD has been coined the “supramolecular synthon approach”.85, 119, 121 The statistics that can be procured from the CSD is bene ficial for cocrystal synthesis and has proven to be fairly reliable for simple systems were there are only one or two functional groups such as carboxylic acid-aromatic nitrog en, alcohol-aromatic nitroge n, or carboxylic acid-amide. The major weakness of the CSD is that even with its ca. 481,000 entries there is still not enough data to address some competitive supramolecular synthon situations. This lack of data spawned the works of Shattock127 and Bis128 which has since provided partial guidance in the design of cocrystals in the presence of multiple functional groups.

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16 1.7. Solid-State Synthesis is Green Chemistry The emergence of green chemistry187 in the early 1990’s has lead to an increased interest in the development of many solid-state synthetic methodologies. Photodimerization,188 for example, is a widely accepted solid-state reaction technique first practiced in the early 1900’s, and inco rporates the principl es of topochemistry189-191 into solid-state organic synthesis. Schmidt’s192 exploration of topochemical reactions via photodimerizations193, 194 led him to further develop the field of topochemistry towards the development of the topochemical postula te, first proposed by Kohlschutter in 1919.195 The postulate states that a “r eaction in the solid state occurs with a minimum amount of atomic or molecular movement”.189 The postulate therefore implies that the reactivity of a complex is controlled by the distances a nd orientations established by the molecular packing within the crystal structure. Schmidt’s studies involving the [2+2] photodimerizations of and -cinnamic acids to their corr esponding truxillic acids led him to the conclusion that typically, if the reacting moieties are at a distance less than 4.2 apart in the solid-state, the photodimerization will occur.196 From these findings Schmidt was able to develop a variety of prin ciples which served to guide others in the field including the requirement for electron system overlap for photodimerization to occur. With these imposing restrictions, solid -state reactions tend to be more selective than those in solution, howeve r, if the reaction does occu r it is typically with higher yields and greater stereospecificity.197-199

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17 Figure 1.6. [2+2] Photodimerization of cinnamic acid to truxillic acid More recently, the field of solid-state synthesis has been explored by many scientists including Fumio Toda,197, 200, 201 Reiko Kuroda,202-204 and Gerd Kaupp.205-209 Interestingly, through the use of a multiple of reaction types, Kaupp has shown that solidstate reactions can and do often result in 100% yield.208 Kaupp employs multiple solidstate synthetic techniques su ch as grinding, heating, and photoirradiation and monitors the reactions with atomic force micr oscopy and scanning electron microscopy.210 With these powerful tools, he has found that mol ecular movement can occur across distances of greater than 4.2 theref ore questioning the guidelines imposed by Schmidt. In particular, anthracene can undergo photodi merization when the distance between anthracene molecules is 6.038 as was proven by atomic force microscopy. After analysis of a group of solid-sta te reactions that occur where the reactants ar e at a distance h v h v

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18 greater than 4.2 apart he c oncludes that “we found no funda mental differences between topochemically allowed and forbidden reactions”.211 1.7.1. Cocrystals and Solid-State Synthesis The influence of the principles of crys tal engineering upon co crystallization in solid-state synthesis has afforded an effec tive synthetic reaction design strategy. As was previously discussed, a cocrystal can be desi gned by utilizing the supramolecular synthon approach and the crystallographic informati on in the Cambridge Structural Database. The target molecule and cocrystal former ar e chosen such that complementary moieties are present, allowing for robust and reliabl e supramolecular heterosynthon formation. The cocrystal is then subjected to conditions under which the reaction can occur. [2+2] photodimerization212-217 and nucleophilic substitution reactions218 have thus far been successful in the utilization of cocrystals for so lid-state chemistry. It is believed that the presence of the cocrystal prio r to the reaction allows for the proper orientation of the molecules in the solid-state (less than 4.2 for the reac ting synthons) such that the reaction will occur faster and with a higher yi eld than if the cocrystal was not formed. Primary interactions commonly employed to sustain cocrystals are strong hydrogen bonds; however, cocrystals are also supported by other weaker interactions such as CH and stacking. Leonard MacGillivray has pioneered the ar ea of template directed solid-state synthesis via cocrystallization.212-215 A protypal cocrystal for MacGillivray is comprised of an aromatic dialcohol such as resorcin ol and an olefin containing two aromatic nitrogens. The cocrystal is sustained via alcohol-aromatic nitrogen interactions, which

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19 forces a geometrical alignment of the alkene segments such that the cocrystal facilitates the [2+2] photodimerization reaction. A pr ototypal example is shown in Figure 1.7. where the cocrystal is formed between resorc inol and trans-1,2-bis( 4-pyridyl)ethylene. The cocrystal allows for the appropriate ali gnment of the molecules such that when the solid is photoirradiated the [2+2] photodimerizat ions occurs resulti ng in rctt-tetrakis(4pyridyl)cyclobutane.87 The cocrystal is considered by MacGillivray to be a reaction template because without the formation of the cocrystal, the olefins would not be in the proper orientation in the solid for the reaction to occur. Ma cGillivrays recent work has implemented his cocrystal template photodime rization reactions for the development of novel ligands for the synthesis of metal-organic frameworks.219 Figure 1.7. MacGillivray’s [2+2] photodimeraztion utilizing a cocrystal template An additional example of a cocrystal incorporated in organic synthesis was conducted by Etter who performed a nucle ophilic substitution reaction employing a cocrystal as a reagent.218 The cocrystal, generated fr om solvent-drop grinding of 4h v h v

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20 chloro-3,5-dinitrobenzoic acid and 4-aminobe nzoic acid, was sustained by a carboxylic acid dimer and, in the solid st ate, the chlorine and the primary amine were in close proximity (less than 4.2) allowing for the SN2 nucleophilic substitution reaction to occur upon heating of th e cocrystal at 180C. Cocrystallization is also particularly am enable to condensation reactions in the solid-state. The condensation of a primar y amine and a carboxylic acid anhydride to generate an imide provides an exemplary ca se as the supramolecular synthon formation can be envisioned between the amine and anhydride moieties and the loss of water molecules can be accomplished by simple heating of solids. The focus of the second chapter of this dissertation addresses the use of cocrystals as reactive intermediates with an emphasis upon the cocrystals ability to ali gn the reactive moieties and bring them into close proximity to encourage the minimal am ount of molecular movement required to conduct the synthetic reacti on in the solid-state. 1.8. The Impact of Crystal Form A crystal has been suggested by Dunitz to be a “supermolecule par excellence ” 220 as it involves a complicated array of molecu lar recognition and peri odic arrangement to result in long range order. The molecu lar recognition events and desire for energy minimizations drive the a rrangement of the molecules in the crystal lattice.221 Additionally the particul ar arrangement determines the physi cal properties of the crystal, including polarizability,222 magnetic susceptibility, piezoelectricity,223 melting point, and solubility. The development of a crystal form is also of great importance in the pharmaceutical industry as crystalline form s tend to be more stable than amorphous

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21 forms.224 Some drugs, however, are still marketed as amorphous forms due to the improved solubility in comparis on to the crystalline competitor.225 The propensity for an alternate crys tal form of an active pharmaceutical ingredient (API) to posses different physical and pharmac okinetic properties from the original API is of great value to the pharm aceutical industry especially as many (ca. 60%) of the new APIs being developed are of low solubility.226 The increased occurrence of low solubility drugs can be attributed in part to the modeling methods used in the design of some new drugs. For example, the API zanamivir227 was synthesized after molecular modeling provided insight into the binding site s of the influenza virus. The drug was then designed to bind to the virus w ith the intent of virus inhibition.228 This drug design plan does not consider the physicochemi cal properties of the resulting API. 1.8.1. Crystal Form Types There are a plethora of crystal form types that can be isolated for an API. The synthesis and investigation of physical properties of various crystal forms is the subject of many review articles.229-243 The diversity of moieties a nd torsional flexibility of many APIs predisposes the formation of multiple crystal forms including, pharmaceutical salts, cocrystals, solvates, hydrates, cocrystals of salts, and polymorphs of all of the above. Some API’s, however, may not possess an i onizable group thus limiting its ability to form salts. In such a situation the API can then be targeted fo r cocrystal formation. Additional crystal forms such as solvates and hydrates that may not be intentionally created are not uncommon in the pharmaceuti cal industry. Polymorphs may also be formed for all crystal forms and are prev alent in ca. 50% of all drug substances.244

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22 All of the crystal forms highlighted above can alter the physicochemical properties of the API. The earliest crystal forms intentionally studied for their unique properties were pharmaceutical salts. Du e to the well establ ished history of pharmaceutical salts and their ability to alter physicochemical and pharmacokinetic properties, only one example will be provided herein. Pharmaceutical cocrystals,118 first developed in 2003, will be addressed in much greater detail as there are only a few published reports providing so lubility or pharmacokinetic data of pharmaceutical cocrystals. Pharmaceutical salts are materials form ed by an ionic API and a suitable, pharmaceutically acceptable counterion.245 They have been a part of crystal form selection for decades as they offer diversity of composition and can therefore exhibit a wide range of physicochemical properties.246 The most commonly used anion and cation in the generation of pharmaceutical salts is chloride and sodium, respectively. Pharmaceutical salts have been used to enha nce the solubility of poorly soluble APIs which represent approximately 40% of the drugs on the market247 and as many as 60% of APIs in development.248 Improving the solubility or dissolution rate of a Biopharmaceutics Classification System (BCS)249, 250 Class II API is possible via pharmaceutical salt formation.246 For example, in the late 1950’s Juncher and Raaschou251 developed three novel salt forms of pe nicillin V that exhibited superior dissolution profiles in comparison to th e original API. When conducting a pharmacokinetic study, it was observed that the salt form enabling the highest in vivo exposure of penicillin V was the same form that possessed the most rapid dissolution rate.

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23 The BCS scheme was developed as a me thod of classifying drugs based upon their solubility and permeability. A BCS type I drug is high solubility and high permeability, type II shows low solubility but high permeability, type III is high solubility and low permeabilit y, and type IV exhibits low solubility and low permeability. The definition of high solubility for the BCS system is determined by the ability of the largest dose size of the drug to dissolve in le ss than 250 mL of water over the pH range of 1-7.5. If the API does not fit these criteria then it is classified as low solubility. BCS defines high permeability as the ability for greater than 90% of the dose of the API to be absorbed. If the absorption is less than 90% then it is classified as low permeability. The initial intention of the BCS was to correlate the solubility and perm eability of a drug such that an estimation of absorption could be made Currently the federal drug administration implements the BCS as guidance for qualificatio n for a biowaiver, i.e. a waiver for the in vivo bioavailability and bioequivalence studies. To obtain a biowaiver from the federal drug administration there are many restrictions including that the drug must be BCS class I (high solubility, high permeability) and must be an immediate release drug that is administered as a solid dosage form.252 The importance of hydrates and solvates in pharmaceutical development has also been recognized.253, 254 Various examples have demons trated that the formation of hydrates and solvates can signifi cantly alter the physicochemical properties of APIs, such as chemical stability, sol ubility, and dissolution rate.255-258 A more recently applie d technique for crystal form development is pharmaceutical cocrystallization.118 Pharmaceutical cocrystals can be defined as multiple component crystals in which at least one co mponent is molecular and a solid at room

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24 temperature (the cocrystal former) and form s a supramolecular synthon with a molecular or ionic API.118 The cocrystal former must al so be a pharmaceutically acceptable compound.119, 121 Pharmaceutical cocrystals have demonstrated that they can profoundly modify the physicochemical properties of the parent API molecule136, 139-141, 145-147, 149-154, 259-268 and at least 90 APIs have been studied in the context of co crystallization. Often APIs that are targeted for pharmaceutical cocrystallization experience undesirable solubility and/or stability and possess multiple hydrogen bonding sites.269 The following sections summarize a set of existing pharmaceutic al cocrystals were their solubility and animal pharmacokinetic behavior is known. 1.8.2. Pharmaceutical Cocrystal s with Solubility Data Solubility can be defined as the concentr ation at which the solution phase is in equilibrium with the solid phase at a given temperature and pressure.270 The solubility of a pharmaceutical cocrystal is of great importa nce as it can be the limiting factor in the absorption of a drug.271 Solubilities of pharmaceutical co crystals have been measured in water, pH 1 HCl solutions, fasted and fed simulated gastric fluid, and fasted and fed simulated intestinal fluid. Variability amongst the conditions is attribut ed to the desire to mimic specific regions along the gastrointestinal tract to gain a be tter understanding of the drugs behavior after it is administered orally. Furt hermore a solubility study can indicate whether the cocrystal disassociates back to its orig inal components in solution by testing the solid post solubility study. The first dissolution profile for a pharmaceutical cocrystal was published by Almarsson et.al.154 The target API was itracon azole, an antifungal drug with poor

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25 aqueous solubility. The resulting pharm aceutical cocrystals include a fumaric acid, succinic acid, L-malic acid, L-tartaric acid, D-tart aric acid, and DL-tartaric acid cocrystal. The crystal structure of the itraconazole succ inic acid cocrystal is shown in Figure 1.8. The solubility of the succinic acid, L-malic acid, and L-tartaric acid cocrystals was measured in 0.1 N HCl and compared to an amorphous formulation of itraconazole coated on Sporanox beads and a crystalline form of itraconazole. The study showed that the L-malic acid cocrystal was as soluble as the on the market Sporonox bead form of itraconazole thus proving that a cocrystal can be just as solubl e as an amorphous form. Figure 1.8. Hydrogen bonding of itraconazole succinic acid cocrystal with succinic acid molecule in green During an attempt to generate pharmaceutical cocrystals of fluoxetine HCl a unique supramolecular synthon was discovered in 2004 by Childs et.al.153 The supramolecular synthon involved a secondary amine and a carboxylic acid hydrogen bonded together with a chloride anion positio ned in between. Childs’ JACS article published in 2004 highlighted three pharmaceu tical cocrystals with the commonly prescribed antidepressant that were all sust ained via the novel supr amolecular synthon. Fluoxetine HCl fumaric acid, fluoxetine HCl su ccinic acid, fluoxetine HCl benzoic acid

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26 cocrystals were synthesized from crystalliz ation of the HCl salt of fluoxetine with the respective cocrystal formers. The supr amolecular synthon is exemplified in the fluoxetine HCl succinic acid cocrystal shown in Figure 1.9. The disso lution profiles were conducted both on free flowing powdered co crystal and on compressed tablets of cocrystal. Both methods were conducted to elucidate the solubility of the cocrystals before forty minutes. The dissolution pr ofiles from the free flowing powder study showed that the benzoic acid cocrystal was the least soluble cocrystal. The fumaric acid cocrystal achieved a 30% improvement in sol ubility in comparison to fluoxetine HCl and the succinic acid cocrystal doubled the concentr ation of fluoxetine HCl. Interestingly, the succinic acid cocrystal concentration begins to decline after twenty minutes into a profile that is now commonly referred to as a spring and parachute profile.272 This behavior is attributed to the cocrystal initially enha ncing the solubility of the API but then disassociating into the origin al components in solution. Figure 1.9. Fluoxetine HCl succinic acid cocrystal supramolecular synthons were the Cl is shown in dark green

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27 The next solubility study published chr onologically incorporated both salts and cocrystals of saccharin with various APIs.152 When saccharin was complexed with quinine, hapoperidol, mirtazapine, pseudoephe drine, lamivudine, risperidone, sertraline, venlafaxine, zolepidem, and amlodipine the re sult was a pharmaceutical salt. Attempts to complex saccharin to piroxicam led to the only cocrystal reported in the study. The solubilites of the various saccharin salts pr eviously mentioned will not be covered in detail, however, it is noteworthy to mention that eight out of th e ten saccharin salts showed appreciably higher so lubility than the pure API. The piroxicam saccharin cocrystal, shown in Figure 1.10., obtained a so lubility level similar to that of pure piroxicam. Thus the conclusions of this study imply that salts can be more soluble than cocrystals. Figure 1.10. Intermolecular and intramolecular interactions found in the piroxicam saccharin cocrystal Norfloxacin, a potent antibacterial agen t, was targeted for salt and cocrystal formation due to its low aqueous solubility.151 When complexed with acidic molecules such as succinic acid, malonic acid, and male ic acid norfloxacin has formed salts. When

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28 complexed with isonicotinamide norfloxaci n remained neutral thus generating a cocrystal. The cocrystal was determined via single crystal X-ray diffraction to be a chloroform solvate. Figure 1.11. highlights the key supramolecular synthons including the persistent isonicotinamide dimer. Equilibrium solubility measurements were conducted for anhydrous norfloxacin, the cocrystal solvate, and three hyd rated salts. The solubility of the cocrystal improved by ca. 3-fo ld and the solubility of the salts improved ca. 20-45 fold. Figure 1.11. Supramolecular synthons present in the norfloxacin isonicotinamide cocrystal solvate highlighting the persistence of the am ide dimer, solvent molecules have been deleted for clarity Another interesting complex from a s upramolecular synthon perspective is the pharmaceutical cocrystal of a monophospha te salt, illustrated in Figure 1.12.139 The phosphoric acid cocrystal of a monophosphate salt is the first example of a salt cocrystallized with an inorganic acid. Early a ttempts to develop a suitable crystal form of the target API resulted in an unstable hydroc hloride salt. Furthermore, attempts to develop a stable crystalline form of the free base were unsuccessful. An extensive

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29 screening process provided th e phosphoric acid cocrystal of the phosphate salt that achieved a solubility greater than 250 mg/ml in water. Figure 1.12. Phosphoric acid cocrystal of a monophosphate salt Sildenafil, the active ingredient in Viagra, was also a target for cocrystallization.149 The currently marketed crystal form of Viagra is the citric acid salt of sildenafil that was synthesized to improve the poor aqueous solubili ty of sildenafil. However, the citrate salt proved to be only moderately soluble in water. Zegarac and coworkers have since developed an aspiri n cocrystal of sildenafil with improved solubility under acidic cond itions. Specifically, the intrin sic dissolution rate for the aspirin cocrystal was approximately twice that of the citrate salt. Due to the increased solubility of the aspirin cocrys tal under acidic conditions, the crystal form is particularly amenable as an oral dosage form. Desiraju has also targeted sildenafil for the development of novel crystal forms. Eleven di fferent solvates of th e saccharinate salt of sildenafil were identif ied and characterized via single crystal X-ray diffraction. The solubility of the solvated cr ystal forms was not determined.

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30 A study reported by Remenar et.al., high lighted the importance of excipients when measuring the solubility of a cocrystal.150 The celecoxib nicotinamide cocrystal, shown in Figure 1.13., was presented as an exam ple. Celecoxib is a COX-2 inhibitor and anti-inflammatory agent with an aqueous solubility of less than 1 gram/ml and is known to exist in four polymorphic forms. An exam ination of the literature of pure celecoxib revealed that the bioavailability could be altered based upon the formulation technique employed. The article attributed the differences in dissolution profiles, which varied with the formulation technique, to the variability in bioavailability. The focus of Remenar’s study was similar, except the dissolution study was of the celecoxib nicotinamide cocrystal. The solubility of the cocrystal was measured in aqueous solutions containing small percentages of sodium dodecyl sulfate on polyvinylpyrolle. It was found that the cocrystal was more soluble in solutions c ontaining higher levels of the excipients. Figure 1.13. Hydrogen bonding of the celecoxib nicotinamide cocrystal

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31 The solubility and stability of twenty-s even carbamazepine cocrystals has also been recently investigated.148 Carbamazepine has been extensively studied for cocrystal formation (carbamazepine aspirin cocrystal s hown in Figure 1.14.) and solution behavior in the presence of cocrystal formers. The most recent contribution of carbamazepine cocrystals incorporated both diacids and monoacids as cocrystal formers and in many cases led to polymorphic cocrystals. While no numerical solubility va lues were given, it was stated that the solubility of the cocrystal was dependent upon the cocrystal former concentrations. The stability of the cocrys tal was measured by testing the solid phase post slurry. The cocrystals were stirred in water and allowed to reach equilibrium. The remaining solid was tested post slurry and for thirteen cocrystals, was found to convert to carbamazepine dihydrate. Seven of the cocrys tals remained intact during the study. Figure 1.14. Carbamazepine aspirin cocrystal AMG 517, an API in development stages at Amgen for indications of chronic pain was recently the target for cocrysta llization. Ten cocrystals were developed

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32 employing cocrystal formers containing carboxylic acid moieties.146 The solubility of AMG 517 is very low in 0.01N HCl but slightly higher in fasted si mulated gastric fluid (FSGF) (5 g/mL) thus the dissolution profiles fo r AMG 517 and its cocrystals were measured in FSGF. All cocrystals except for the tartaric acid cocrystal were examined. Six of the nine cocrystals obtained their ma ximum solubility within 1-2 hours. Their concentrations then decreased throughout the remainder of the study producing a spring and parachute profile reminiscent of the fluoxe tine HCl succinic acid cocrystal previously mentioned. The solubility of the three remain ing cocrystals was less than that of AMG 517. Interestingly, powder X-ray diffraction st udies confirmed that the solids remaining after the dissolution study were AMG 517 hydrat e in all cases except for with the benzoic acid cocrystal. While the spring and parachut e type profile indicated that the benzoic acid cocrystal had converted to the dihydrate, powder X-ray diffraction showed that the remaining solid was in fact cocrystal. Th e DSC, however, suggested that the benzoic acid was not present in the crystal lattice, bu t was instead in solution. This argument was supported by HPLC analysis that indicated an increase in benzoic ac id concentration in solution.

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33 Figure 1.15. 2-point recognition supramolecular synthon of AMG 517 succinic acid cocrystal The next study describes the cocrystalli zation of two steroid-type molecules, exemestane and megestrol acetate, that coul d not be formulated as pharmaceutical salts due to their lack of strongly acidic or basic functionalities.147 Exemestane is used to treat breast cancer while megestrol acetate is us ed to reduce the suffering caused by some cancers and treats the loss of appetite in some AIDS patients. The unique cocrystal screening technique employed in this study invo lving dimethylsulfoxide slurries followed by lyophilization produced two novel cocrystals, exemestane maleic acid and megestrol saccharin. The solubility was obtained vi a intrinsic dissolution and loose powder dissolution measurements. Intrinsic dissolu tion studies showed that the exemestane maleic acid cocrystal solubility was of similar solubility to that of the pure drug while the megestrol saccharin cocrystal was twice that of the pure drug. The free flowing powder dissolution profiles indicate a similar solubility trend, w ith the megestrol cocrystal achieving a six-fold increase in solubility. Th e influence of particle size of the cocrystal was also measured but it did not have a strong impact upon the cocr ystal solubility.

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34 The most recent cocrystallization study that measures the solubility of the cocrystals was reported by Bak et.al.145 AMG 517 was again employed but complexed with alternative cocrystal formers containing ei ther amide or carboxylic acid moieties. In addition to AMG 517, six more transient recep tor potential vanilloid 1 antagonist APIs were targeted producing 15 cocrystals in to tal. AMG 517 produced 12 cocrystals while 3 (AMG 678809, AMG 831664, AMG 670129) of the additional 6 APIs each formed a cocrystal with sorbic acid. The solubility and dissolution profiles were measured for all 15 cocrystals in fasted simulated intestinal fluid. Many of the cocrystals resulted in a spring and parachute dissolution profile with the remaining solid conve rting to either the free base or hydrated free base. However, two of the AMG 517 cocrystals remained intact throughout the study. The most so luble cocrystal of AMG 517 was the L-malic acid cocrystal, highlighting an increase from 5 g/mL to 24 g/mL. A comparison of the two AMG 517 cocrystallization studies show s that both cocrystal formers containing carboxylic acids or amides can improve the solubility of the API. The sorbic acid cocrystals of AMG 678809, AMG 831664, a nd AMG 670129 also displayed marked improvements in solubility with the most notable increase of 0.9 g/mL to 14.8 g/mL for the AMG 670129 sorbic acid cocrystal. 1.8.3. Pharmaceutical Cocrystals with Animal Data Many of the APIs targeted for cocrystalliz ation are selected because of their low solubility and/or poor bioavail ability. Enhancing the solubility of a crystal form via cocrystallization can translate to an increase in drug presen t in solution and available at the absorption site in vivo Depending on the mechanism of absorption, a more

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35 concentrated solution of API can ultimately lead to a higher bioavailab ility (i.e. increased concentration of unchanged drug in the plasma). In each of the following case studies the solubility of a low solubility drug was increa sed via cocrystalliza tion. The effect of solubility improvement upon drug absorption and bi oavailability is summarized herein. The first publically availa ble study where an animal wa s administered a cocrystal was performed at Transform Pharmaceuticals Inc. Itraconazole, an antifungal drug, was the target API.267 The cocrystal with L-malic acid was dosed to dogs and found to reduce the time required to reach the maximum concentration (Tmax) by 10-80% over the pure drug. The maximum concentration (Cmax) and area under the curve (AUC) were also increased by 10-80%. The bioavailability (reported as 40%) for the cocrystal was equivalent to the currently administered amorphous form of itraconazole coated on Sporanox beads. Transform Pharmaceuticals Inc. also filed a patent in 2004 containing the results of an in vivo testing of the modafin il malonic acid cocrystal.265 Modafinil, used for indications of narcolepsy, is practically insoluble in wate r, however, the malonic acid cocrystal dissolved at a faster rate th an the pure API. The pharmacokinetic study utilizing a capsule formulation of the cocrys tal administered in a single dose study to dogs highlighted an increase in Cmax and bioavailability. The Tmax was practically unchanged despite the increas e in solubility at early time points. In 2006 Childs et al.,140 reported a set of five novel so lid phases of 2-[4-(4-chloro2-fluorophenoxy)phenyl]pyrimidine-4-carboxamid e, or CFPPC. CFPPC is a sodium channel blocker used for alleviating pain with an aqueous solubility of < 0.1 g/ml. Interestingly, the cocrystal comprised of CF PPC and glutaric acid showed an intrinsic

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36 dissolution rate ca. 18 times greater than pure CFPPC. The dog pharmacokinetic study resulted in an AUC increase from 374 to 1,234 ng h/ml for the 5 mg/kg dose and an increase from 889 to 2,230 ng h/ml for the 50 mg/kg dose. Thus after a single oral dose of the cocrystal the dogs exhibited an a pproximately 4-fold increase in plasma concentration over the pure API. Chronologically, the next cocrystal pharmac okinetic study details to appear in the literature pertained to the carbamazepine saccharin cocrystal.141 The study was a single dose administration of the cocrys tal and the marketed Tegretol tablet to beagle dogs. The results showed higher Cmax and AUC values for the cocrystal and a Tmax value that was one hour for the cocrystal and 1.75 hours for the Tegretol tablet. Furthermore the cocrystal reached slightly higher plasma le vels than the marketed drug, but remained within the standard error and therefor e was not statistically significant. The pharmaceutical cocrystal of a m onophosphate salt with phosphoric acid, previously mentioned for its improved solubi lity in comparison to the free base, is noteworthy as it briefly mentions the result s of a pharmacokinetic study. Unfortunately there are no details concerning th is portion of the study in the article. The article simply claims that the cocrystal “exhibited excellent in vivo performance”. 139 In 2008 Bak and co-workers highlighted the ability of a series of pharmaceutical cocrystals to improve the solubility of AMG 517.146,259 A particular focus was upon the AMG 517 sorbic acid cocrystal and it was studied with respect to its stability in vitro as well as its ability to modify the plasma concentration of AMG 517 in Sprague-Dawley rats. It was found that after oral administra tion of a 500 mg dose of the cocrystal, the

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37 Cmax and AUC0-inf was 8 and 9 times greater, re spectively, compared to oral administration of the same dose of pure API. The two most recent studies are from the patent literature. The first describes tenofovir which is a nucleotide reverse transc riptase inhibitor for the treatment of HIV.261 The commercially available form of tenofovi r is a fumarate salt however, the product contains various mixture of solid forms in unpred ictable ratios. In an attempt to solve the commercial product problem, tenofovir was cocrys tallized with fumaric acid resulting in a 2:1 molecular complex that could be isol ated cleanly. A pharmacokinetic study (a single dose Male Wister rat study) compari ng the cocrystal to th e existing salt form proved that the cocrystal was bioequiva lent to the on the market product. The most recent pharmacokinetic study of a pharmaceutical cocrystal describes the cocrystal formed between a Cglycoside derivative and proline.264 Previously the pure drug was found to crystallize as a clat hrate hydrate that interconverts from an anhydrous compound to a non-stoichiometric hydra te. The instability of the API led to the develop the additional crystal forms. The resulting 1:1 C-gl ycoside derivative Lproline cocrystal was administered as a susp ension to non-fasted mice. Levels of the cocrystal and original API were measured in the blood concluding th at the cocrystal was present at a sufficient level to treat diabetes. The patent further claims that the patient would experience the same or higher efficacy after administration of the cocrystal. As was made evident in the previously mentioned studies, the crystal form of a pharmaceutical can have a significant imp act upon the solubility and pharmacokinetic properties of an API. Table 1.3. provides a summary of the pharmacokinetic data presented in this chapter.

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38Table 1.3. Summary of the pharmacokinetic metrics for the presented pharmaceutical cocrystals API Cocrystal former Pharmacokinetic metrics Itraconazole L-Malic acid Bioavailab ility = 40%, Equivalent to amorphous drug Modafinil Malonic acid Increase Cmax and bioavailability CFPPC Glutaric acid Decrease Tmax, increase Cmax and AUC by 4-fold Carbamazepine Saccharin Increase AUC and Cmax, however, not statistically significant plasma level Monophosphate salt Phosphoric acid No data, stated “excellent in vivo performance” AMG 517 Sorbic acid Increased Cmax and AUC by 8 and 9 fold Tenofovir Fumaric acid Bioequivalent to commercially available drug C-Glycoside Derivative L-proline Cocrystal showed strong antihypoglycemic action 1.8.4. Polymorphism and the Pharmaceutical Industry A polymorph has been defined by McCrone as “a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state”.273 The number of compounds that exhibit polymorphism is uncertain as McCr one argues that the number of polymorphic compounds is proportional to the time and mo ney spent in research on that compound.274 In an attempt to quantify the number of known polymorphs a search of the CSD was conducted. The term “polymorph” retrieve d 15,633 entries out of 481,521 or 3% of the entire database. An important aspect of polymorphism is the inherent differences in physical properties between crystal forms.258, 275 Variations in properties such as solubility can have a dramatic impact upon the pharmacokinetic behavior of an API. Thus crystal form

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39 screening is of utmost importance in the pharmaceutical industry. However, traditional crystal form screening does not always reve al all possible polymorphs. The negative impact that crystal form screening ca n have upon the pharmaceutical industry is exemplified in the historic cases of ritonavir,276 ranitidine HCl,275 and paroxetine HCl.277 Ritonavir, marketed as Norvir was formulated as an oral liquid and a semi-solid capsule. Since both formulations were solutions of ritonavir there was little concern with crystal form. During early ma nufacturing of the capsules on ly the one crystal form of ritonavir was found. However, years later, a new form was discovered that was much less soluble than the original form. This ne w form was referred to as form II. Form II was soon found at all manufacturing facilities, dramatically reducing the supply of the original form. Form II was so much less solubl e that it could not be used to make the oral liquid or semi-solid capsule formulations vi a the current methods. Ultimately ritonavir had to be reformulated due to the omnipotent less soluble form II. Ranitidine HCl (Zantac), a histamine H2 antagonist originally developed by GlaxoSmithKline, was also found to be pol ymorphic. The polymorphic transformation of what is now called form I to form II occurred during the scale up manufacturing process. Form I was covered under an or iginal synthesis patent and form II was subsequently covered under an additional patent. Due to the success of the drug, many generic companies were waiting for form I to go off patent to introduce their own generic version on the market. Novopharm in particul ar attempted to reproduce form I from the claimed method in the patent, however, N ovopharm produced form II. Novopharm then tried to invalidate Glaxo’s patent for form II citing that they had reported a method for form I that actually produced form II; ther efore form II would be anticipated from the

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40 earlier patent. Novopharm eventually lost the case as Glaxo was able to prove that their method did lead to generation of form I in th e original researchers’ notebook. However, Novopharm was granted the ability to ma rket a pure product of form I. GlaxoSmithKline also entered into a legal battle over paroxetine HCl (Paxil ). The original form developed was a hemihydrate of paroxetine marketed since 1993. While waiting for Glaxo’s patent to expire, Apotex developed an anhydrate crystalline form of paroxetine HCl. Glaxo was aware of the anhydrate and its conversion to the hemihydrate under specific conditions that were claimed in their orig inal patent. Glaxo claimed that Apotex was operating under c onditions that would pa rtially convert the anhydrate to the hemihydrate that was covered u nder their patent. The legal battle ensued with the court ultimately ruling against Glaxo as they could not prove that Apotex would make the hemihydrate in sufficient quantities. 1.9. Summary Supramolecular chemistry has grown expone ntially since the de scription of the lock and key model in 1890. The subset of crystal engineering has also grown and attracted interest from many different facets including academia and industry. Contributing factors that have fueled the rapid development have been the advancements in X-ray technology as well as augmented intere st from large corporations and university collaborations. In particular the pharmaceutical industry is currently infatuated with the ability to fine tune a crystal form to possess desired physical and pharmacokinetic properties. The potentials and pitfalls of polymorphism are also a topic of current interest.

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41 Cocrystals in solid-state synthesis and cocrystals in pharmaceutical development both show great promise in their respective area s. Cocrystals as reaction intermediates or photodimerization templates have afforded novel materials typical ly coupled with increased reaction yields. Pharmaceutical cocr ystals have also proven their utility with their ability to change an AP I’s solubility and bioavailabil ity. The ability to manipulate the properties of a cocrys tal to customize a product is still a future goal but as the field of crystal engineering continues to grow and its applications extend, new materials will emerge with inherent properties that will most likely be the result of a designed experiment rather than serendipity. 1.10. References Cited (1) Lehn, J.-M., Supramolecular Chemistry Wiley, VCH: Bundesrepublik, Deutschland, 1995. (2) Steed, J. W.; Atwood, J. L., Supramolecular Chemistry John Wiley and Sons: West Sussex, United Kingdom, 2009; Vol. 2. (3) Lehn, J. M., Science 2002, 295 2400. (4) Lehn, J. M., Angewandte Chemie-Internatio nal Edition in English 1988, 27 89. (5) Wolf, K. L.; Wolff, R., Angewandte Chemie 1949, 61 191. (6) Behr, J.-P., The Lock-and-Key Principle, Volume 1, The State of the Art -100 Years On Wiley: West Sussex, England, 1995. (7) Pedersen, C. J.; Frensdor.Hk, Angewandte Chemie-International Edition 1972, 11 16. (8) Cram, D. J., Science 1983, 219 1177.

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42 (9) Graf, E.; Kintzinger, J. P.; Lehn, J. M.; Lemoigne, J., Journal of the American Chemical Society 1982, 104 1672. (10) Cram, D. J., Angewandte Chemie-International Edition in English 1988, 27 1009. (11) Cram, D. J.; Cram, J. M., Science 1974, 183 803. (12) Cram, D. J.; Cram, J. M., Accounts of Chemical Research 1978, 11 8. (13) Lehn, J. M., Annals of the New York Academy of Sciences 1986, 471 41. (14) Sirlin, C., Bulletin De La Societe Chimique De France Partie Ii-Chimie Moleculaire Organique Et Biologique 1984 5. (15) Fenniri, H.; Lehn, J. M.; MarquisRigault, A., Angewandte Chemie-International Edition 1996, 35 337. (16) Fenniri, H.; Lehn, J. M., Journal of the Chemic al Society-Chemical Communications 1993 1819. (17) Steed, J. W.; Turner, D. R., Core Concepts in Supramolecular Chemistry John Wiley and Sons: West Sussex, England, 2007. (18) Steiner, T., Angewandte Chemie-International Edition 2002, 41 48. (19) Aakery, C. B.; Seddon, K. R., Chemical Society Reviews 1993, 22 397. (20) Desiraju, G. R., Accounts of Chemical Research 2002, 35 565. (21) Pauling, L., The Nature of the Chemical Bond Cornell University Press: Ithica, NY, 1939. (22) Jeffrey, G. A.; Saenger, W., Hydrogen Bonding in Biological Structures SpringerVerlag: Berlin, Germany, 1991. (23) Pimentel, G. C.; McClellan, A. L., The Hydrogen Bond Freeman: San Francisco, 1960.

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43 (24) Desiraju, G. R.; Steiner, T., The Weak Hydrogen Bond: In Structural Chemistry Oxford University Press: New York, 1999. (25) Voet, D.; Voet, J. G., Biochemistry J. Wiley and Sons: New York, 2004. (26) Pepinsky, R., Physical Review 1955, 100 971. (27) Pepinsky, R.; Okaya, Y.; Siato, Y., Physical Review 1955 1857. (28) Schmidt, G. M. J., Pure and Applied Chemistry 1971, 27 647. (29) Hippel, A. R. V., Science 1962, 138 91. (30) Desiraju, G. R., Crystal Engineering: The Design of Organic Solids Elsevier: 1989. (31) Etter, M. C., Accounts of Chemical Research 1990, 23 120. (32) Etter, M. C.; Macd onald, J. C.; Bernstein, J., Acta Crystallographica Section BStructural Science 1990, 46 256. (33) Etter, M. C., Journal of Physical Chemistry 1991, 95 4601. (34) Desiraju, G. R., Angewandte Chemie-Internati onal Edition in English 1995, 34 2311. (35) Braga, D.; Grepioni, F.; Desiraju, G. R., Chemical Reviews 1998, 98 1375. (36) Desiraju, G. R., Chemical Communications 1997 1475. (37) Nangia, A.; Desiraju, G. R., Design of Organic Solids 1998, 198 57. (38) Simard, M.; Su, D.; Wuest, J. D., Journal of the American Chemical Society 1991, 113 4696. (39) Brunet, P.; Simard, M.; Wuest, J. D., Journal of the American Chemical Society 1997, 119 2737. (40) Wuest, J. D., Chemical Communications 2005 5830.

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44 (41) Ducharme, Y.; Wuest, J. D., Journal of Organic Chemistry 1988, 53 5787. (42) Aoyama, Y.; Endo, K.; Anzai, T.; Ya maguchi, Y.; Sawaki, T.; Kobayashi, K.; Kanehisa, N.; Hashimoto, H.; Kai, Y.; Masuda, H., Journal of the American Chemical Society 1996, 118 5562. (43) Endo, K.; Sawaki, T.; Koyanagi, M. ; Kobayashi, K.; Masuda, H.; Aoyama, Y., Journal of the American Chemical Society 1995, 117 8341. (44) Bain, C. D.; Troughton, E. B.; Tao, Y. T.; Evall, J.; Whitesides, G. M.; Nuzzo, R. G., Journal of the American Chemical Society 1989, 111 321. (45) Macdonald, J. C.; Whitesides, G. M., Chemical Reviews 1994, 94 2383. (46) Whitesides, G. M.; Grzybowski, B., Science 2002, 295 2418. (47) Whitesides, G. M.; Mathias, J. P.; Seto, C. T., Science 1991, 254 1312. (48) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M., Accounts of Chemical Research 1995, 28 37. (49) Amabilino, D. B.; Stoddart, J. F., Chemical Reviews 1995, 95 2725. (50) Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo, Y.; Beverly, K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R., Science 2000, 289 1172. (51) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F., Angewandte Chemie-International Edition 2002, 41 898. (52) Wolf, K. L.; Frahm, H.; H.Harms, Zeitschrift fr Physikalische Chemie (B) 1937, 36 237. (53) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodrguez-Hornedo, N.; Zaworotko, M. J., Chemical Communications 2003 186.

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60 (260) Cooke, C. L.; Davey, R. J., Crystal Growth & Design 2008, 8 3483. (261) E. Dova; J. M. Mazurek; Anker, J. Tenofovir disoproxil hemi-fumaric acid cocrystal. WO/2008/143500 2008. (262) Galcera, J.; Molins, E., Crystal Growth & Design 2009, 9 327. (263) Good, D. J.; Rodrguez-Hornedo, N., Crystal Growth & Design 2009, 9 2252. (264) Imamura, M. Cocrystal of CGlycoside Derivative and L-Proline. WO 2007/114475 A1, 2007. (265) M. Peterson; M. Bourghol Hickey; M. Oliveira; O. Almarsson; Remenar, J. Modafinil compositions. US 2005267209 A1, 2005. (266) Reddy, L. S.; Bethune, S. J.; Kampf, J. W.; Rodrguez-Hornedo, N., Crystal Growth & Design 2009, 9 378. (267) Remenar, J.; MacPhee, M.; Peterson, M.; Morissette, S. L.; Almarsson, . Novel Crystalline Forms of Conazoles and Me thods of Making and Using the Same. WO/2005/092884, 2005. (268) Schultheiss, N.; Newman, A., Crystal Growth & Design 2009, 9 2950. (269) Lipinski, C. A., Journal of Pharmacological and Toxicological Methods 2000, 44 235. (270) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G., Solid-State Chemistry of Drugs 2nd ed.; SSCI: West La fayette, Indiana, 1999. (271) Brouwers, J.; Brewster, M. E.; Augustijns, P., Journal of Pharmaceutical Sciences 2009, 98 2549. (272) Brewster, M. E.; Vandecr uys, R.; Verreck, G.; Peeters, J., Pharmazie 2008, 63 217.

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61 (273) Haleblian J; McCrone, W., Journal of Pharmaceutical Sciences 1969, 58 911. (274) McCrone, W. C., Polymorphism. In Physics and chemistry of the organic solid state Fox, D.; Labes, M. M.; Weissberger, A., Eds. Interscience Publishers: 1965; Vol. II, pp 725. (275) Bernstein, J., Polymorphism in Molecular Crystals Oxford University Press: New York, 2002. (276) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J., Pharmaceutical Research 2001, 18 859. (277) Hilfiker, R., Polymorphism in the Pharmaceutical Industry WILEY-VCH: Weinheim, Germany, 2006.

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62 Chapter 2 – Cocrystal Controlled So lid-State Synthesis of Imides 2.1. Preamble The chemical industry has played a majo r role in the production and accumulation of hazardous waste and toxins in the environment.1 Unfortunately, it was not until the 1960’s that the public became aware of the toxicity and harm to human health some chemicals, such as DDT (dic hlorodiphenyltric hloroethane),2-4 in the environment could cause. The increased public awareness began the conscious effort to reduce chemical waste and its presence in the environment. A giant leap forward was made in 1990 with the Pollution Prevention Act5 which stated that one should strive to prevent or reduce pollution whenever possible.6 This act facilitated the development of more environmentally friendly chemical practices th at lead to the creation of the chemical genre of green chemistry.7-12 Green chemistry has been define d as “the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture, and appl ication of chemical products”.13 Implementation of the twelve principles of green chemistry can provide greater reaction yields and less hazardous waste production, resulting in cheaper overall chemical synthetic methodologies.14 With the consideration of these benefits in mind, many chemists have strived to develop the field of solid-state sy nthesis, however, in some areas their focus has been relatively narrow in scope.15-17 For example, the particular application of

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63 cocrystal controlled solid-state synthesis (C3S3) has thus far been limited to photodimerizations or photopolymerizations18-27 and nucleophilic substitution.28 In the case of the former, one cocrystal former typi cally serves to align or “template” the reactant, which is the other co crystal former. In the case of the latter both cocrystal formers are reactants although there are exampl es in which the reactive moieties are in the same molecule and therefore generate polymeric structures.29 In this chapter, the details of an exploration into furthering the development of C3S3 are delineated for the design and synthesis of novel materials. C3S3, defined as the generation of a cocrystal in the solid-state which can then be utilized to conduct a chemical reaction, typica lly condensation, in order to generate novel materials, can be described as a two part process. The initial stage applies crystal engineering30, 31 design principles to a recently deve loped low waste, high yield cocrystal synthesis method which is followed by a tradit ional condensation reac tion that has been modified to be conducted in the solid-state. There are two strict sets of criteria for conducting a reaction by C3S3: 1) the materials must posses the appropriate moieties to sustain a reliable supramolecular synthon32, 33 and 2) the moieties required for the supramolecular heterosynthon must be chemical ly reactive such that when heated they lose a volatile component, typically wate r. Based upon the requirements imposed for C3S3, there are six reactions that fit this criteria, aldehyde + primary amine to generate a Schiff base,34 carboxylic acid + primary amine to make a secondary amide,35 carboxylic acid + carboxylic acid to form an anhydride,36 carboxylic acid + alc ohol to generate an ester,37 alcohol + alcohol to make an ether,35 and anhydride + primary amine to form an

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64 imide.38 This contribution will focus upon imid e formation employing an anhydride and primary amine via C3S3 as illustrated schematically in Figure 2.1. Figure 2.1. Reaction scheme for imide formation from primary amine and carboxylic acid anhydride via cocrystallization Imides represent a class of compound that is primarily synthesized in solution;39 however, there are prior examples that highli ght the ability to synthesize imides in the solid-state via microwave chemistry40-42 or upon a solid-phase support.43, 44 Both methods prepare imides via condensation of carboxylic acid anhydrides and primary amines (mechanism shown in Figure 2.2.) i.e. two functional groups that are complementary and could form a supramolecular synthon45; however, prior to 2007, there were only two entries (REFCODES: AMYGLA, BEFWEO) in the Cambridge Structural Database (CSD)46 that exhibit both the amine and anhydride moieties in the same entry, both of which were comprised of a single com ponent therefore neither were cocrystals. The lack of data in the CSD precludes a defini tive statement concerning the reliability of the supramolecular heterosynthon formation. C3S3 provides the opportunity to address the occurrence of this supramolecular heterosynthon and its potential to generate novel imides.

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65 Figure 2.2. Proposed reaction mechanism for carboxylic acid anhydride and primary amine producing an imide Cocrystals can be synthesized by various methodologies47-49 including the established solvent-drop grinding technique, i.e. two or more solid cocrystal formers are ground in the presence of a mi croliter amount of solvent.50-54 In the study presented herein, the cocrystals will be synthesized via solvent-drop grinding as it is the most environmentally friendly cocrystallization t echnique. The groups of acid anhydrides and primary amines depicted in Figures 2.3. and 2.4. respectively that were selected for this study include: AA1 = 1,4,5,8-naphthalenetetr acarboxylic acid dianhydride (NTCDA), AA2 = pyromellitic dianhydride, AA3 = maleic anhydride, AA4 = phthalic anhydride, AA5 = 3,3’,4,4’-biphenyltetracarboxylic dia nhydride, AA6 = 1,8-naphthalic anhydride, AA7 = 3,4,9,10-perylenetetracarboxylic dianhydr ide, PA1 = 2-methyl-4-nitroaniline, PA2 = 3-aminobenzoic acid, PA3 = melami ne, PA4 = 1,4-phenylenediamine, PA5 = 1,5diaminonaphthalene, PA6 = 1-adamantylamine, and PA7 = triphenylmethylamine. All combinations of the 7 anhydrides with 7 pr imary amines was investigated (49 total reactions) to determine the following: if they form cocrystals via solvent-drop grinding under ambient conditions; furthermore if the ground mixtures so obtained can be

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66 converted to imides simply by applying heat A summary of the results after grinding then heating are presented in Table 2.1. The majority of reactions studied were observed to form imides after heating but it was not always possible to isolate a cocrystal. However, three combinations of anhydride + amine were isolated as cocrystals that resulted in high yield, low waste formation of imides and will be discussed herein. An additional reaction where the imide condensatio n reaction intermediate was isolated in high yield will also be discussed. The analysis for reactions 1-4 includes reaction conditions and discussion of the differenti al scanning calorimetry (DSC) traces, UV-vis spectra, and color schemes for reactants, cocr ystals, and imides where appropriate. In addition the use of DSC to di scover cocrystal formation in situ will be addressed. Finally, the use of characteri zation techniques such as powde r X-ray diffraction (PXRD) and Fourier transform infrared (FT-IR) spect roscopy will be discussed for the detection of cocrystal and imide formation with a broad set of amines and anhydrides.

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67 Figure 2.3. Carboxylic acid anhydrides Figure 2.4. Primary amines

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68Table 2.1. Table of 49 reactions color coded to differentiate outcomes after solvent-drop grinding and heating 2.2. Results and Discussion 2.2.1. Reaction 1 2-methyl-4-nitroaniline and NTCDA 2.2.1.1. Synthetic Techniques and Characterization As revealed in Figure 2.8, 1,4,5,8-na phthalenetetracarboxylic dianhydride (NTCDA) and 2-methyl-4-nitroaniline form a 1:2 cocrystal, 1a which converts cleanly to diimide, 1b when heated at 180 C for 3 hour s in 75% yield. Conversion to 1b is expected as the distance between the ami no moiety and carbonyl carbon of the anhydride is ca. 3.42 , which is less than the 4.2 restriction of the topochemical postulate. 1b crystallized from DMF and DMSO, affo rding solvated single crystals of 1b Figure 2.11.

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69 represents the DMSO solvate of 1b and is presented in detail herein. The DMF solvate of 1b is not covered in detail as the solvate is isostructura l to the DMSO solvate. The cocrystal of NTCDA and 2-methyl-4-nitroaniline ( 1a ) is purple in color. The purple color of 1a contrasts the starting materials (pale yellow) and reaction product (orange) and is indicative of charge transfer complex.55 The solid-state UV-Vis spectrum of 1a exhibits a broad band at ca. 600nm a nd is shown in Figure 2.5. The UV-Vis spectrum of 2-methyl-4-nitroani line, NTCDA, and an ethanol grind are also shown for comparison purposes. Figure 2.5. UV-Vis spectrum of DMF solvent drop grind versus Methanol grind, NTCDA, and 2-methyl-4-nitroaniline 1a can be prepared from solution, solv ent-drop grinding with DMF or solventdrop grinding followed by heating and is su stained by charge tran sfer interactions between the aromatic rings of NTCDA and 2-me thyl-4-nitroaniline. Toda et al. has also shown the ability to generate charge tran sfer complexes from solid-state grinding.56 Interestingly, solvent-drop grinding with other solvents (chloroform, cyclohexane,

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70 DMSO, ethyl acetate, methanol, toluene, and water) affords mixtures of NTCDA and 2methyl-4-nitroaniline. However, heating of a mixture above the melting point of 2methyl-4-nitroaniline results in formation of 1a and additional heating at 150 C for three hours affords 1b These observations suggest that formation of 1a is a key step for facilitating or even controlling the condensation process. The progression of the reaction can be m onitored in the DSC (Figure 2.6.). The DSC trace for 1a (shown on the right in Figure 2.6.) e xhibits only one ph ase transition as the cocrystal melts and converts to the diimide 1b However, the DSC trace of a mixture (shown on the left in Figure 2.6.) shows two pha se transitions. On ce the mixture reaches the melting point of the 2methyl-4-nitroaniline (130 C) the first phase transition occurs. Here the amine melts and recrystallizes to form the cocrystal. The second phase transition corresponds to the melt of the cocrystal at ca. 155 C. After the melt of the cocrystal the dehydration occurs and the resulti ng solid is the diimide. The color changes due to the phase transitions from both 1a and the physical mixture (Figure 2.7) can be monitored in a Mel-temp device. 1a (purple) becomes orange after heating past 160 C and the yellow mixture turns purple as it converts to 1a. 1a then becomes orange as it converts to the diimide.

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71 Figure 2.6. DSCs highlighting the phase transitions that occur for mixtures (left) and cocrystal (right). All temperatures are in degrees Celsius. Figure 2.7 Color changes for reaction 1 2.2.1.2. Analysis of Crystal Structures The 2-methyl-4-nitroaniline NTCDA cocrystal, 2:1 ( 1a ) crystallizes in the space group P The basic supramolecular unit contains two 2-methyl-4-nitroaniline molecules and one NTCDA molecule. The self complementary hydrogen bonding capability of 2-methyl-4-nitroaniline between the primary amine donor and nitro acceptor moieties is the primary driving force sustaining 1a The amino moieties that hydrogen bond to neighboring nitro moieties allow for an NH O hydrogen bond distance of

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72 2.946(6) [N22-H22B O21: N O 2.946(6) HO 2.178 N-H O 145.47] resulting in infinite chains of 2-me thyl-4-nitroaniline molecules along the b -axis. The chains are related by an inve rsion center located in the center of an NTCDA molecule positioned between two 2-methyl-4-nitroanili ne chains. The centroid-plane distance between the 2-methyl-4-nitroani line and NTCDA is ca. 3.32 which is within the typical interaction range and furt her supports the charge transfer interaction. The carbonyl carbon atom of the NTCDA and the am ine nitrogen atom of the 2-methyl-4nitroaniline are separated by only 3.42 i.e. well within the 4.2 limit of the topochemical postulate.57, 58 The intermolecular interactions sustaining 1a are shown in Figure 2.8. The hydrogen bonding and charge transfer interactions exhibited by 1a collectively generate a lattice that can be envisioned as two ch ains of 2-methyl-4nitroaniline molecules with NTCDA molecules inserted in between the chains stacking in an AABAAB fashion as is shown in Figure 2.9. Furthermore, this 2:1 cocrystal supports the required stoichiometry and conforma tion for the topochemical reaction. Figure 2.8. Intermolecular interactions sustaining 1a. 1a obeys the topochemical postulate as the shortest distance between the nitrogen atoms of the amine moieties and the carbon atoms of the carbonyl moieties is 3.42

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73 Figure 2.9. Crystal packing of 1a viewed down the c -axis Heating the cocrystal and recrysta llizing the resulting imide from DMSO produces the solvated diimide of 1b shown in Figure 2.10. and 2.11. There are three independent diimides and one DMSO molecu le in the asymmetric unit. Diimide A (Figure 2.12. red) interacts via CH from the center of the molecule to the central region of neighboring diimide C (Figure 2.12. gree n) with a CH to ring centroid distance of 3.52 . Diimide B (Figure 2.12. bl ue) is held in position via a CH interaction of 3.21 sustained between the central CH re gion and the aromatic benzene ring of neighboring diimide A (Figure 2.12. red). Diimid es A and C continue in infinite chains parallel to the b -axis, packing in an alternating ABAB motif. Diimide B also forms infinite chains along the b -axis; however, the cavity betw een chains is filled by two equivalent DMSO molecules. Diimide B and DMSO also pack in an alternating ABAB motif. The dihedral angles of diimides A, B, and C are 82.41 85.12 and 79.18 respectively.

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74 Figure 2.10. Molecular structure of diimide 1b as generated via recrystallization of 1b from DMSO Figure 2.11. Crystal packing of 1b DMSO solvate (3:2) obtained via r ecrystallization from DMSO

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75 Figure 2.12. Color coded crystal packing of 1b DMSO : diimide A = red, diimide B = blue, diimide C = green, DMSO = yellow 2.2.2. Reaction 2 3-aminobenzoic acid and NTCDA 2.2.2.1. Synthetic Techniques and Characterization NTCDA and 3-aminobenzoic acid also form a purple cocrystal ( 2a ) via solventdrop grinding with DMF. Solvent-drop grinding with other solvents leads to mixtures of starting materials. Attempts at crystallization resulted in the formation of the less reactive 1,4-dioxane solvate of the cocrystal, 2a 1,4-dioxane, shown in Figure 2.16. The solid-state UV-Vis spectrum of 2a, shown in Figure 2.13., exhibits a broad band at 550 nm which is consistent with a charge-t ransfer complex. Furthermore, the distance between the reactive moieties (amine nitrog en and the carbonyl) was 3.14 . Therefore 2a also obeys the topochemical postulate as it converts to diimide 2b after heating for 24 hours at 200 C in 99% yield. Interestingly, the cocrystal also undergoes dehydration to the corresponding diimide after a few days under ambient conditions. Crystallization

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76 attempts of 2b were arduous due to the low solub ility of the diimide in many common organic solvents. However, 2b can be recrystallized from py ridine as the pyridine solvate of the 1:2 complex of 4 with pyridine. Figure 2.13. UV-Vis spectrum of DMF solvent-drop grind versus 3-aminobenzoic acid, methanol solvent-drop grind, and NDTCA The dehydration of 2a to 2b was also monitored in the DSC; however, it was not as straightforward as the prev iously described dehydration of 1a to 1b The DSC (shown in Figure 2.14., left) indicates that the cocrystal melt occurs at ca. 127 C; however, the first phase transition of the mixture (shown in Figure 2.14., right) does not occur until ca. 155 C. The melting points do not correlate due to the melting point of the cocrystal occurring before the melt of the lowest melti ng starting material (3-aminobenzoic acid). Thus, the DSC of the mixture is a unique case highlighting the ability of the material to melt, rearrange to the cocrystal which instan taneously melts and dehydrates to complete the condensation r eaction generating 2b The array of colors that are seen for this reaction (Figure 2.15.) are similar to that of reaction 1 where the same anhydride is

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77 employed and the cocrystal is a purple char ge transfer complex, however, the resulting imide ( 2b ) is gold whereas 1b is orange. Figure 2.14. DSCs highlighting the phase transitions that occur for cocrystal (left) and mixture (right). All temperatures are in degrees Celsius Figure 2.15. Colors of 3-aminobenzoic acid, NTCDA, dry grinding product, DMF grinding product, and final imide 2b 2.2.2.2. Analysis of Crystal Structures The 3-aminobenzoic acid NTCDA cocrystal 1,4-dioxane solvate ( 2a 1,4dioxane ) crystallizes in a 2:1:1 st oichiometry in the space group P with two molecules of 3-aminobenzoic acid, one molecule of NT CDA, and one molecule of 1,4-dioxane in

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78 the asymmetric unit. Similarly to 1a the primary amine molecule assists in the formation of infinite chains, however, in 2a 1,4-dioxane the primary amine molecules require the insertion of a 1,4-dioxane molecule to su stain the chain. The 3-aminobenzoic acid molecules do not favor the head to tail chai n most likely because of the meta-positioning of the amino moiety. The preferred orient ation is a centrosymmetric dimer centered above and below the NTCDA molecule. The 3-aminobenzoic acid centrosymmetric dimer is sustained via NH O=C [N11-H11A O11: N O 3.066(4) , H O 2.245 , N-H O 155.15] hydrogen bonds which link to a dditional dimers through 1,4-dioxane molecules [O12-H12 O31: O O 2.643(3) , H O 1.807 , N-H O 172.36] to generate chains that stack along the a -axis. As shown in Figure 2.16., NTCDA molecules stack in between the 3-aminobenzoic acid dime rs with an amine-carbonyl distance of ca. 3.14 . The distance between these reactive grou ps is much less than the requirement for the topochemical postulate therefore the conde nsation reaction should occur. In addition, the distance measured between a centroid in th e center of the 3-aminobenzoic acid dimer and the plane of a neighbori ng NCDTA molecule was found to be 3.17 . This distance is well within the typical interaction and further suppor ts the potential for charge transfer interactions. The 1,4-dioxane mol ecules can be removed with heat to obtain anhydrous 2a However, a single crystal structure of the anhydrous cocrystal could not be obtained as the sample did not re tain crystallinity after heating.

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79 Figure 2.16. Crystal packing of cocrystal 2a 1,4-dioxane Attempts at crystallization of the 3-aminobenzoic acid NTCDA diimide ( 2b ) resulted in a pyridine solvate of the 1:2 complex of 2b with pyridine. The solvate of 2b crystallizes in the space group P The basic supramolecular unit is comprised of one diimide, two pyridine molecules hydrogen bonded to the carboxylic acid moieties of the diimide, and one disordered pyridine mol ecule centered in the cavity between two diimide molecules. The crystal packing is sustained by various weak interactions including multiple CH O interactions such as pyridyl CH to carbonyl of the imide (ca. 3.25 ) and C=O of the carboxylic acid to th e central CH region of the imide (ca. 3.49 ). As shown in Figure 2.17. and 2.18., additional weak interactions ( system overlap of 6-memebered aromatic rings) sustain the diimide molecules as they progress along the c -axis. The dihedral angle between the naphthyl and benzen e rings of the diimide is 79.04

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80 Figure 2.17. Simplified crystal packing of the 1:2 complex of 2b with pyridine Figure 2.18. Crystal packing of the pyridine solvate of the 1:2 complex of 2b with pyridine

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81 2.2.3. Reaction 3 2-methyl-4-nitroanilne and pyromellitic anhydride 2.2.3.1. Synthetic Techniques and Characterization Interestingly, solvent-drop grinding with DMF of 2-methyl-4-nitroaniline and pyromellitic anhydride does not give a purple cocr ystal. The cocrystal ( 3a ) is orange most likely due to the reduc tion of the conjugated ring sy stem from naphthyl (NTCDA) to benzyl (pyromellitic anhydride). 3a can be synthesized from various techniques including solvent-drop grinding with DMF or methanol, solution crystallization, and grinding with heating. The UV-Vis absorbance maximum for 3a is ca. 400 wavenumbers which is expected for an orange complex, but is similar to the absorbance of the systems used for the reactants and therefore is not included. The si ngle crystal structure of 3a illuminates the bond distances from the amino group to the carbon of the carbonyl group on a neighboring anhydride. Based upon th e topochemical postulate, the distance between the reactive groups in 3a (ca. 3.78 ) is within range for the condensation reaction to occur. Furthermore, 3a can be converted cleanly to 3b in approximately 80 % yield after heating for ca. 2 days at 150 C. The different solid-st ate reaction rates of 1a 2a 1,4-dioxane solvate the unsolvated form of 2a and 3a is presumably an artifact of crystal packing. DSC traces for 3a and a mixture of the reactant s are shown in Figure 2.19. with 3a on the left and the mixture on the right. The DSC trace of the cocrystal shows two phase transitions at 138 C and 247 C. The literature melting point of 2-methyl-4nitroaniline (130 C) is similar to the first phase tr ansition suggesting that either the cocrystal may begin to disassociate at a sim ilar temperature or some excess amine may be present. Additional characterization techniques (FT-IR, PXRD calculated vs.

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82 experimental) confirm that the solid is at leas t 90% cocrystal. Thus it is likely that the melting point of the cocrystal is merely a fe w degrees higher than the melting point of 2methyl-4-nitroaniline. 3a continues to rearrange on the mo lecular level in the DSC as it converts to the diimide ( 3b ), indicated by the undulating baseline. The second phase transition at ca. 248 C is attributed to the melt of 3b The mixture shown on the right in Figure 2.19. shows the melt of the amine at ca. 131 C followed by a sharp recrystallization as the cocrystal ( 3a ) is formed. 3a then melts around 200 C and rearranges to generate 3b which melts at ca. 243 C. The color changes as the starting materials are heated to produce 3a then subsequently to 3b can be followed in the Meltemp device. Representative vi als are shown in Figure 2.20. Figure 2.19. DSCs highlighting the phase transitions that occur for cocrystal (left) and mixture (right). All temperatures are in degrees Celsius.

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83 Figure 2.20. Stepwise reaction of 2-methyl-4-nitroaniline and pyromellitic anhydride highlighting cocrystal formation (SDG = solvent-drop grind) 2.2.3.2. Analysis of Crystal Structures The 2-methyl-4-nitroaniline pyromellitic anhydride cocrystal ( 3a ) crystallizes in the space group P21/n The basic supramolecular unit is comprised of two 2-methyl-4nitroaniline molecules and one pyromellitic anhydride molecule. As was seen in 1a the 2-methyl-4-nitroaniline molecules in 3a form head-to-tail chains sustained by hydrogen bonds. The 2-methyl-4-nitroaniline mol ecules hydrogen bond via amine-nitro NH O interactions [N12-H12A O12: N O 2.943(5) , H O 2.159 , N-H O 148.06 ] that translate along the 2-fold axis. Pyromellitic anhydride molecules are inserted between the 2-methyl-4-nitroaniline chains interacting via NH O hydrogen bonds [N12H12B O22: N O 3.089(5) , H O 2.307 , N-H O 147.98 ] and N-O O-C interactions (ca. 2.90 ). A centroid to plane distance meas ured between the center of the 2-methyl-4-nitroaniline molecule and pyr omellitic anhydride plane was found to be 3.26 , which is within the range for interaction. The distance from the reactive

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84 amino group to the carbon of the anhydride ca rbonyl is ca. 3.78 which is within the distance requirements set by the topochemical postulate. Figure 2.21. Crystal structure of cocrystal 3a formed between 2-methyl-4-nitroaniline an d pyromellitic anhydride The diimide 3b, synthesized from the dehydration of cocrystal 3a, crystallizes in the space group P21/c The asymmetric unit contains half of the molecule with the inversion center located at its center. 3b translates along the b -axis at an angle such that the translation about the 21 screw axis results in a herr ingbone motif. The interplanar spacing between the central regi on of the diimide molecules is ca. 3.28 and is sustained mainly via CH O interactions, specifically from CH O=C (ca. 3.34 ) and CH O-N (ca.3.10 ). The dihedral angle between the ce ntral and exterior rings of the diimide is 75.82

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85 Figure 2.22. Molecular structure of diimide 3b Figure 2.23. Crystal packing of 3b 2.2.4. Reaction 4 1-adamantylamine and phthalic anhydride 2.2.4.1. Synthetic Techniques and Characterization When performing synthetic reactions the experimental outcome is not always what is expected. Reaction 4 was an exem plary case where a synthetic pathway led to the unexpected isolation of the condensation reaction intermedia te instead of the imide.

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86 The amic-acid condensation intermediate of 1-adamantylamine and phthalic anhydride ( 4a ) has been isolated from traditional solution methods for this particular reaction in 48% yield;59 however, in the solid-state under the conditions described herein, the intermediate can be isolated cleanly in ca. 90 % yield. 4a is synthesized via solventdrop grinding of 1-adamanytlamine and phtha lic anhydride together in a stoichiometric ratio followed by heating of the solid at 110 C for 1.5 hours. Suitable quality single crystals for of 4a single crystal X-ray analysis were obt ained from recrystallization of the heated material. The intermediate can then be heated further at 120 C for ca. 1 week to afford the imide 4b 4b was previously reported in the literature and appears in the CSD under refcode: QUSKUK. The DSC of 4a shows two phase transitions (Figure 2.24.). The initial phase transition corresponds to the literature melting point of 185 C.59 The breadth of the second phase transition is indicative of an im pure material but it could also be caused by degradation after the melt of 4a An additional factor that mu st be considered is that the imide condensation reaction is reversible. 4a can hydrolyze due to excess moisture in the air producing phthalic acid and 1-adamantylamine which melt at 210 C and 205 C, respectively. Therefore the second phase transition may be caus ed in part by the presence of either material. Heating 4a in an oven in the solid-state can result in the formation of 4b following the conditions previously mentioned. A DSC of the solid after heating confirms the synthesis of 4b as the DSC trace (Figure 2.25.) has one phase transition at ca. 142 C which corresponds to the literature melting point of 140 C.60

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87 Figure 2.24. DSC of 4a Figure 2.25. DSC of 4b

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88 2.2.4.2. Analysis of Crystal Structures The intermediate 4a formed from the reaction of 1-adamantylamine and phthalic anhydride crystallizes with one molecule in the asymmetric unit. 4a crystallizes in the space group P21/c and is primarily sustaine d by an atypical 2-point recognition dimer. The dimer is centrosymme tric and incorporates two carboxylic acid moieties and the carbonyl of th e adjacent secondary amide. The carboxylic acid-carbonyl OH O hydrogen bond distance is 2.682(3) [O12-H12 O11: O O 2.682(3) , H O 1.868 , N-H O 171.61 ] and the carbonyl-carbonyl intr amolecular bond distance is ca. 3.01 . Additional molecules of 4a are generated by a 21 rotation around the b -axis and a reflection about the c -axis followed by a translation. A de piction of the crystal packing is shown in Figure 2.26. To determine the probability of this particular synthon formation, a CSD search was conducted. The CSD revealed 803 entrie s that contained a carboxylic acid and a secondary amide.61 However when the search was rest ricted by two criteria: the moieties must both be on the same molecule and the am ide must also be ortho to the acid the number of entries reduced to 43. Of those 43 entries only 1 was sustained by the same synthon that is shown. If the amide is not restricted to a secondary amide then an additional 6 entries are revealed. Based upon th e relatively low number of entries in the CSD, the supramolecular heterosynthon highlig hted in Figure 2.26. can be considered rare in the presence of carboxylic ac id and amide moieties.

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89 Figure 2.26. Crystal packing of 4a

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90Table 2.2. Crystal structure parameters for cocrystals 1a-4a 1a 1b 2a 2b 3a 3b 4a Chemical formula (C7H8N2O2)2 C14H4O6 (C28H16N4O8)3 (C2H6SO)2 (C7H7NO2)2 C14H4O6 C4H8O2 (C28H14N2O8)05 C5H5N C5H5N (C7H8N2O2)2 C10H2O6 C24H14N4O8 C18H21NO3 Form weight 794.53 1765.60 824.58 726.66 980.41 486.39 299.36 Crystal System Triclini c Triclinic Triclinic Triclinic Monoclini c Monoclini c Monoclini c Space group P P P P P21/ n P 21/ c P21/ c a () 8.307(2) 11.309(3) 7.006(2) 7.1569(14) 7.373(3) 8.207(4) 13.045(7) b () 8.894(2) 12.204(4) 9.990(3) 8.1962(17) 13.969(6) 16.594(8) 9.761(5) c () 9.179(2) 16.403(5) 10.190(4) 15 .448(3) 11.025(3) 7.753(4) 12.785(7) (o) 110.230 (4) 89.651(6) 83.081(7) 98.287(4) 90 90 90 (o) 103.873 (5) 77.343(5) 81.603(7) 102.202(4) 93.695(8) 92.169(9) 110.402(8 ) (o) 97.109( 5) 64.623(6) 76.866(8) 96.564(4) 90 90 90 Vol (3) 601.6(3) 1985.8(10 ) 684.2(4) 866.6(3) 1133.2(7) 1055.1(8) 1525.7(14 ) Dcal (g cm3) 1.580 1.476 1.530 1.392 1.531 1.531 1.303 Z 1 1 1 1 2 2 4 Reflections collected 2412 8259 2810 3645 2623 2622 8766 Independen t reflections 1923 6472 2188 2852 1361 985 3420 Observed reflections 996 1558 1549 1549 986 724 1471 T (K) 100 100 100 100 100 100 293 R1 0.0788 0.0915 0.0677 0.0869 0.0593 0.0766 0.0535 w R2 0.2227 0.2108 0.1546 0.2019 0.1405 0.1667 0.1242 GOF 1.042 0.741 1.047 1.018 0.884 1.095 0.896

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91 2.2.5. C3S3 for the General Formation of Imides Whereas C3S3 can only be confirmed in the thre e reactions for which isolation of an anhydride-amine cocrysta l occurred, conversion of solvent-ground anhydride-amine mixtures to imides was a more general o ccurrence. 32 out of the total 49 reactions resulted in imide formation. 17 reactions di d not produce an imide. A summary of the results is presented in Table 2.1. Solven t-drop grinding followed by heating therefore appears to represent a feasible and general methodology for the preparation of imides. In the following segments the reaction purity a nd percent yield will be addressed via DSC and 1HNMR. Additionally, the ability to mon itor the reactions by FT-IR and PXRD will be discussed as well as the possibility of co crystal formation in situ in the DSC. 2.2.5.1. Imide Purity Initial monitoring for reaction comp letion included FT-IR and PXRD measurements. Additional characterization was conducted on the 32 successful imide formation reactions via DSC and 1HNMR. A typical DSC scan was 10 C/min from ca. 30 C-350 C. Analysis of the 32 samples i ndicated that 20/32 melted below 350 C; however, 6/32 showed no clear melt in the DSC which is most likely indicative of imide formation due to the lack of melt from eith er starting material. Unfortunately 13/32 samples gave either multiple or broad phase transitions, reducing the number of high purity reactions to 19. However, literature me lting points were compared to experimental DSC melts when possible resulting in 7/7 co rrelating melting points. A potential cause for some of the low purity r eactions could be the ratio at which the reactions were

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92 conducted. 5 of the reactions were performed in the presence of excess amine (PA4 or PA5) in an attempt to terminate the potentially polymeric reaction with free amines. 1HNMR characterization was attempted on the 32 samples; however, due to the limited solubility of some of the im ides, six (PA1+AA2, PA2+AA2, PA2+AA5, PA2+AA6, PA4+AA1, PA4+AA4) of the 1HNMR’s could not be obtained. In general the purity of the imides was relatively high ba sed on the low incidence of occurrence of excess signals in the 1HNMR. In reactions PA5+AA6, PA4+AA5, and PA4+AA2 the purity level appears lower but the additional peaks can be associated with the excess amine that was input into the reaction. The purity could perhaps be improved by following the heating with a washing step with an organic solvent such as methanol. Additionally, six samples (PA1+AA3, PA1+AA5, PA2+AA3, PA4+AA3, PA5+AA4, PA7+AA4) had a signal at ca.10 ppm which is indicative of the amic-acid reaction intermediate. Due to the reversibility of the reaction, the presence of some of the intermediate is not unlikely, especial ly after long term sample storage.62 The six samples that contained some intermediate could most likely be converted to the imide cleanly upon further heating. A summary of the DSC and 1HNMR data is presented in Table 2.3.

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93 Table 2.3. Summary of DSC and 1HNMR data (S.M. = starting materials, int. = intermediate, Lit. = literature value of melting point) Reactants DSC Mixture DSC Imide Melt Lit. Imide 1HNMR Input PA1+AA1 S.M. to Cocrystal to Imide >350 N/A imide 2:1 PA1+AA2 S.M. to Cocrystal to Imide 247 N/A insoluble 2:1 PA1+AA3 S.M. 137-broad N/A int. present 1:1 PA1+AA4 S.M. 202 20263 imide 1:1 PA1+AA5 S.M. to Imide 263 N/A int. present 2:1 PA2+AA1 S.M. to Cocrystal to Imide >350 N/A imide 2:1 PA2+AA2 S.M. to Imide 237-broad N/A insoluble 2:1 PA2+AA3 S.M. to Imide 230 23064 int. present 1:1 PA2+AA4 S.M. to Cocrystal to Imide 289 29065 imide 1:1 PA2+AA5 S.M. >350 N/A insoluble 2:1 PA2+AA6 S.M. 350 N/A insoluble 1:1 PA3+AA2 S.M. >350 N/A impurities 2:3 PA3+AA3 S.M. >350 N/A impurities 3:1 PA3+AA4 S.M. to Imide 276-broad N/A imide 1:3 PA4+AA1 S.M. to Cocrystal to Imide >350 N/A insoluble 1:1 PA4+AA2 S.M. >350 N/A excess amine 5:1 PA4+AA3 S.M. 268 N/A int. present 1:2 PA4+AA4 S.M. 246-broad 24766 insoluble 1:2 PA4+AA5 S.M. 350-broad N/A excess amine 5:1 PA4+AA6 S.M. to Cocrystal to Imide 285 N/A imide 1:1 PA5+AA1 S.M. 320-broad N/A excess amine 5:1 PA5+AA2 S.M. 233-broad N/A imide, low conc. 1:1 PA5+AA3 S.M. to Cocrystal to Imide 210-broad N/A minor impurities 1:2 PA5+AA4 S.M. to Imide 240 25067 int. present 1:2 PA5+AA5 S.M. 298-broad N/A excess amine 5:1 PA5+AA6 S.M. >350 N/A excess amine 5:1 PA6+AA3 S.M. to Imide 242-broad N/A minor impurities 1:1 PA6+AA4 S.M. 142 14060 imide 1:1 PA7+AA2 S.M. >350 N/A minor impurities 1:1 PA7+AA3 S.M. 206-broad N/A minor impurities 1:1 PA7+AA4 S.M. 154 17268 int. present 1:1 PA7+AA5 S.M. >350 N/A imide, low conc. 1:1

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94 2.2.5.2. Monitoring the Condensation Reaction via DSC The DSC has been an invaluable tool for the discovery and development of C3S3. The DSC can illuminate the phase transforma tion of a mixture of an amine and an anhydride to an imide by first capturing the melt of the lower melting component as it converts to the cocrystal then showing the cocrystal melt as it converts to the imide. Examples illustrating the process were pr esented in Figures 2.6, 2.14, and 2.19. With these details in mind, two questions are posed: can a cocrystal that could not be made by solvent-drop grinding be made in situ afte r melting the lower melting starting material in the DSC? Also, can the DSC run produce an imide that had otherwise failed from the synthetic method of appl ying heat in an oven? To address the initial question, stoichiome tric mixtures of starting materials were weighed out and ground together by hand without solvent. The physical mixtures of 46 reactions were analyzed via DSC at a scan rate of 10 C/min from ca. 30 C to 350 C. The results from this screen are shown in Table 2.3. Many of the DSC traces showed phase transitions corresponding to the melts of the individual starting materials and some were followed by a melt of the imide. Inte restingly, seven of the physical mixtures showed a phase transition that occurred after th e melt of the lower melting component and did not correspond to eith er starting material or to the imide. Based upon the prototypal DSC traces from reactions 1-3, this ph ase transition is most likely the melt of a cocrystal, thus revealing 4 additional conde nsation reactions cont rolled by a cocrystal intermediate. In situ cocrystal formation was possibl y observed for reactions of 3-aminobenzoic acid with phthalic anhydride (PA2-AA4), 1,4-phenylenediamine with NTCDA (PA4-

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95 AA1), 1,4-phenylenediamine with 1,8-na phthalic anhydride (PA4-AA6), and 1,5naphthalenediamine with maleic anhydrid e (PA5-AA3). Figur e 2.27. illustrates the mixture of 3-aminobenzoic acid and phthalic anhydride. The melting point of phthalic anhydride is 130 C, which correlates to the first phase transition of the DSC. The recrystallization immediately fo llowing that transition is be lieved to be the cocrystal formation which is quickly followed by the melt of the cocrystal. The last sharp phase transition occurs at 289 C and is asso ciated with the melt of the imide. Figure 2.27. DSC trace of mixture of 3-aminobenzoic acid and phthalic anhydride Figure 2.28. highlights the DSC trace of th e mixture of 1,4-phenylenediamine and NTCDA. Of the seven anhydrides employed in this study, NTCDA appears to be the strongest supporter of the supramolecular synthon as it is utilized in the formation of two out of the three cocrystals, thus considering the formation of additional cocrystals with NTCDA is quite likely. The melting point of th e amine is 145 C which can be attributed

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96 to the first endothermic melt. The initial exot hermic phase transitions that occurs at ca. 100 C is unique to this sample and may be an artifact of the amine. However, after the melt of 1,4-phenylenediamine a recrystallizatio n occurs wherein the cocrystal is most likely formed. The cocrystal is then heat ed until melting at ca. 257 C. The DSC does not show a melt for the imide as the me lting point is greater than 350 C. Figure 2.28. DSC trace of a mixture of 1,4-phenylenediamine and NTCDA The DSC trace of a mixture of 1,4-phe nylenediamine and 1,8-naphthalic anhydride is shown in Figure 2.29. The initial sharp phase tran sition can be attributed to the melt of 1,4-phenylenediamine which melts at 145 C. The recrystallization that occurs thereafter is associated with cocrystal formation. The melt at 178 C does not correspond to either starting material or the imide a nd is therefore most likely the melt of the cocrystal. Once the cocrystal melts the condensation reaction occurs generating the imide. The melting point of the synthesized imide was 284 C which is within a few degrees of the final phase transition from the mixture.

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97 Figure 2.29. DSC trace of a mixture of 1,4-phenylenediamine and 1,8-naphthalic anhydride Figure 2.30. depicts the DSC trace of a mi xture or 1,5-naphthalenediamine and maleic anhydride. Maleic anhydride was the lowest melting anhydride but also proved to be the most reactive as solvent-drop gri nding with DMF or DMSO lead to imide formation in many reactions. Due to solven t-drop grinding generating the imide instead of the cocrystal, the potential for isolation of a cocrystal was low. However, using a mixture of anhydride and amine may have genera ted a cocrystal in situ in the DSC. The first phase transition corresponds to the melt of maleic anhydride (51 C). Unlike the previous examples, only a subtle recrystallization is present after the melt. But a phase transition that does not correlate to either starting materials occurs at 140 C and is therefore attributed to the me lt of the cocrystal. The final phase change at 209 C is consistent with the melt of the imide.

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98 Figure 2.30. DSC trace of a mixture of 1,5-naphthalenediamine and maleic anhydride The possibility of synthesizing an imide that could not be generated in the oven during the temperature ramp r un in the DSC was also addres sed. Unfortunately, analysis of the 17 DSC traces of the mixtures (PA1+AA6, PA1+AA7, PA2+AA7, PA3+AA1, PA3+AA5, PA3+AA6, PA3+AA7, PA4+AA7, PA5+AA7, PA6+AA1, PA6+AA2, PA6+AA5, PA6+AA6, PA6+AA7, PA7+AA1, PA 7+AA6, PA7+AA7) concluded that no new imides were generated as there were no unidentifiable phase transitions. 2.2.5.3. Analysis of Cocrystals and Imides via PXRD PXRD diffractograms were collected at tw o points during the re action: once after solvent-drop grinding and again after heating. For the three reactions described in detail in sections 2.2.1-2.2.3 the PXRD diffractogram from the bulk ground cocrystal sample could be compared to the calculated PX RD diffractogram from the single crystal structure. An example of this is featured in Figure 2.31. The limitation of PXRD of the

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99 ground material is that without the calculated diffractogram, it is unclear what the new diffractogram corresponds to. The calcul ated diffractogram for the imide can be compared to the resulting imide to confirm bulk sample reaction completion, such as in Figure 2.32. However, to employ PXRD to co nfirm imide formation, a calculated pattern is also required. Therefore, coupled with single crystal analysis of the imide, PXRD can be a powerful tool for analysis of a C3S3 type reaction. Figure 2.31. PXRD diffractograms of eight solvent drop grinds, starting materials, and calculated cocrystal

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100 Figure 2.32. PXRD diffractograms of solvent drop grinds after heating for ca. 2 days at 150 C 2.2.5.4. Monitoring the Condensation Reaction via FT-IR Monitoring the C3S3 reaction by FT-IR was an excellent method for determining cocrystal formation after solvent-drop gri nding due to the predic table shift in strong carbonyl peaks to higher wavenumbers coupl ed with variable shifts in the NH2 region. An exemplary case is shown in Figure 2.33. After heating the ground solid in the oven the FT-IR spectrum was again collected and examined. Imide formation was easily monitored by further examination of two specified regions. Disappearance of the NH2 peaks and a shift to lower wavenumbers for the carbonyl peak (typically ca. 40 wavenumbers lower), shown in Figure 2.34., wa s indicative of imide formation.

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101 Figure 2.33. Infrared spectra (FT-IR) of NTCDA and 2-methyl-4-nitroaniline DMF solvent drop grind (red) compared to anhydride (purple) and amine (blue) Figure 2.34. FT-IR of imide (red) with starting materials

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102 For reactions where there was no cocrystal formation from the solvent-drop grinding the FT-IR spectra appeared as compilations of the respective amine and anhydride starting material. For reaction 4 wh ere the solvent-drop grinding produced the amic-acid reaction intermediate i.e. the anhydride ring opens affording a carboxylic acid and the amine covalently binds to the carbonyl producing a secondary amide, the carbonyl peak in the FT-IR spectrum is sh ifted to a lower wavenumber (Figure 2.35.) which could be confused with the imide form ation, however, additiona l heating shifts the carbonyl region even lower by ca. 30 wavenumbers as shown in Figure 2.36. Figure 2.35. FT-IR of intermediate (red) formed from phthalic anhydride (purple) and 1-adamantylamine (green)

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103 Figure 2.36. FT-IR of imide (red) generated from 1adamantylamine and phthalic anhydride 2.3. Conclusions Cocrystal controlled solid-state synthesi s is an invaluable synthetic methodology for the generation of new molecules with very little solvent waste a nd with high yield. Additionally, the incorporation of cocrystalli zation into organic synthesis is exemplary evidence for the vast utility of cocrystals. Of the 49 reactions atte mpted in this study 32 resulted in imide formation while 17 showed no reactivity. 3 of the 32 also proved to be controlled by a reactive cocrystal intermediate that, once heated, dehydrated to form the imide. The formation of the cocrystals was facilitated via the well established technique of solvent-drop grinding. Once the cocrystals were generated they were heated until the condensation reaction was completed. The temperatures and reaction times varied depending upon the starting materials, however, the sample was always heated above the melting point of the lowest melting component. Interestingly, a total of 4 additional

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104 cocrystals may have been isolated from hea ting a mixture of the reactants in the DSC, illustrating that the cocrystal can also be genera ted in situ as a reactive intermediate that can ultimately lead to imide formation. The development of novel materials via C3S3 with the isolation of a cocrystal as a reactive intermediate provides additional insight into th e method by which the reaction occurs. The greater understanding of the solid -state synthesis reaction of imides gained in this study serves as a model to be app lied to other solid-state or solution based reactions. The expansion of the field of solid -state organic synthesis will lead to the reduction of hazardous waste production, incr ease reaction yields, and make the overall synthetic process cheaper and more environmentally friendly. 2.4. Materials and Methods 2.4.1. Materials All materials were used as received without further purification from SigmaAldrich or Alfa Aesar. 2.4.2. Synthetic Methods A typical reaction involved solvent-drop grinding with chloroform, cyclohexane, DMSO, DMF, ethyl acetate, methanol, toluen e, and water for ca. 4 minutes by hand with an agate mortar and pestle. The solid was then transferred to a glass vial and heated in an oven at a temperature above the melting po int of the lowest melting component to facilitate imide formation. Reaction condi tions for each of the 32 successful imide formations are provided below:

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105 2-methyl-4-nitroaniline and NTCDA (PA1+AA1): 100 mg (0.66 mmol) of 2-methyl-4-nitroa niline and 88mg (0 .33mmol) of NTCDA were ground with ca. 20 L of DMF by hand in an agate mort ar and pestle for 4 minutes. The resulting purple cocrystal wa s then heated for 3 hours at 180 C to produce the imide. The imide was synthesized in ca. 75% yield. 2-methyl-4-nitroaniline and pyromellitic anhydride (PA1+AA2): 100 mg (0.66 mmol) of 2-methyl-4-nitr oaniline and 72 mg (0.33 mmol) of pyromellitic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting ora nge cocrystal was then heated for 50 hours at 150 C to produce the imide. The imide wa s synthesized in ca. 80% yield. 2-methyl-4-nitroaniline and maleic anhydride (PA1+AA3): 100 mg (0.66 mmol) of 2-methyl-4-nitroani line and 64 mg (0.65 mmol) of maleic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 40 hours at 60 C to produce the imide. The imide was synthesized in ca. 92% yield. 2-methyl-4-nitroaniline and phthalic anhydride (PA1+AA4): 100 mg (0.66 mmol) of 2-methyl-4-nitr oaniline and 98 mg (0.65 mmol) of phthalic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 16 hours at 150 C to produce the imide. The imide was synthesized in ca. 73% yield.

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106 2-methyl-4-nitroaniline and 3,3’,4,4’-biphe nyltetracarboxylic acid dianhydride (PA1+AA5): 100 mg (0.66 mmol) of 2-methyl-4-nitr oaniline and 97 mg (0.33 mmol) of 3,3’,4,4’-biphenyltetracarboxylic acid di anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 21 hours at 120 C to produce the imide. The imide wa s synthesized in ca. 87% yield. 3-aminobenzoic acid and NTCDA (PA2+AA1): 100 mg (0.73mmol) of 3-aminobenzoic ac id and 98 mg (0.36 mmol) of NTCDA were ground with ca. 20 L of DMF by hand in an agate mort ar and pestle for 4 minutes. The resulting purple cocrystal wa s then heated for 14 hours at 150 C to produce the imide. The imide was synthesized in ca. 99% yield. 3-aminobenzoic acid and pyromellitic anhydride (PA2+AA2): 100 mg (0.73mmol) of 3-aminobenzoi c acid and 79 mg (0.36 mmol) of pyromellitic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 16 hours at 180 C to produce the imide. The imide was synthesized in ca. 90% yield. 3-aminobenzoic acid and maleic anhydride (PA2+AA3): 100 mg (0.73mmol) of 3-aminobenzoic ac id and 72 mg (0.35 mmol) of maleic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 19 hours at 150 C to produce the imide. The imide was synthesized in ca. 92% yield.

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107 3-aminobenzoic acid and phthalic anhydride (PA2+AA4): 100 mg (0.73mmol) of 3-aminobenzoic ac id and 108 mg (0.73 mmol) of phthalic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 26 hours at 150 C to produce the imide. The imide was synthesized in ca. 88% yield. 3-aminobenzoic acid and 3,3’,4,4’-bi phenyltetracarboxylic dianhydride (PA2+AA5): 100 mg (0.73mmol) of 3-aminobenzoi c acid and 107 mg (0.36 mmol) of 3,3’,4,4’-biphenyltetracarboxylic dia nhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minut es. The resulting solid was then heated for 14 hours at 150 C to produce the imide. The imide was synthesized in ca. 85% yield. 3-aminobenzoic acid and 1,8-naphthalic anhydride (PA2+AA6): 100 mg (0.73mmol) of 3-aminobenzoic acid and 145 mg (0.73 mmol) of 1,8naphthalic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 23 hours at 150 C to produce the imide. The imide was synthesized in ca. 79% yield. melamine and pyromellitic anhydride (PA3+AA2): 200 mg (1.6 mmol) of melamine a nd 519 mg (2.4 mmol) of pyromellitic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 75 hours at 180 C and 26 hours at 150 C to produce the imide. The imide was synthesized in ca. 88% yield.

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108 melamine and maleic anhydride (PA3+AA3): 100 mg (0.79 mmol) of melamine and 26 mg (0.26 mmol) of maleic anhydride were ground with ca. 20 L of DMF by hand in an agate mort ar and pestle for 4 minutes. The resulting solid was then heated for 23 hours at 115 C to produce the imide. The imide was synthesized in ca. 79% yield. melamine and 1,8-naphthalic anhydride (PA3+AA4): 100 mg (0.79 mmol) of melamine and 471 mg (2.4 mmol) of 1,8-naphthalic anhydride were ground with ca. 40 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 23 hours at 115 C to produce the imide. The imide was synthesized in ca. 70% yield. 1,4-phenylenediamine and NTCDA (PA4+AA1): 100 mg (0.92 mmol) of 1,4-phenylenedia mine and 247 mg (0.92 mmol) of NTCDA were ground with ca. 20 L of DMF by hand in an agat e mortar and pestle for 4 minutes. The resulting solid was then heated for 5 hours at 115 C to produce the imide. The imide was synthesized in ca. 98% yield. 1,4-phenylenediamine and pyromellitic anhydride (PA4+AA2): 200 mg (1.8 mmol) of 1,4-phenylened iamine and 81 mg (0.36 mmol) of pyromellitic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 68 hours at 180 C to produce the imide. The imide was synthesized in ca. 78% yield. 1,4-phenylenediamine and maleic anhydride (PA4+AA3): 100 mg (0.92 mmol) of 1,4-phenylenediamine and 45 mg (0.46 mmol) of maleic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4

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109 minutes. The resulting solid wa s then heated for 23 hours at 115 C to produce the imide. The imide was synthesized in ca. 71% yield. 1,4-phenylenediamine and phtha lic anhydride (PA4+AA4): 100 mg (0.92 mmol) of 1,4-phenylenediamine and 98 mg (0.46 mmol) of phthalic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 5 hours at 115 C to produce the imide. The imide was synthesized in ca. 85% yield. 1,4-phenylenediamine and 3,3’,4,4’-biphe nyltetracarboxylic dianhydride (PA4+AA5): 100 mg (0.92 mmol) of 1,4-phenylenedia mine and 54 mg (0.18 mmol) of 3,3’,4,4’-biphenyltetracarboxylic dia nhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minut es. The resulting solid was then heated for 68 hours at 180 C to produce the imide. The imide was synthesized in ca. 82% yield. 1,4-phenylenediamine and 1,8-naphthalic anhydride (PA4+AA6): 100 mg (0.92 mmol) of 1,4-phenylenedia mine and 183 mg (0.93 mmol) of 1,8naphthalic anhydride were ground with ca. 20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 64 hours at 150 C to produce the imide. The imide was synthesized in ca. 78% yield. 1,5-diaminonaphthalene and NTCDA (PA5+AA1): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 34 mg (0.12 mmol) of NTCDA were ground with ca.10 L of DMF by hand in an agat e mortar and pestle for 4 minutes. The resulting solid wa s then heated for 68 hours at 180 C to produce the imide. The imide was synthesized in ca. 86% yield.

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110 1,5-diaminonaphthalene and pyromellitic anhydride (PA5+AA2): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 137 mg (0.63 mmol) of pyromellitic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 107 hours at 120 C to produce the imide. The imide wa s synthesized in ca. 84% yield. 1,5-diaminonaphthalene and maleic anhydride (PA5+AA3): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 31 mg (0.31 mmol) of maleic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 23 hours at 115 C to produce the imide. The imide wa s synthesized in ca. 79% yield. 1,5-diaminonaphthalene and phthalic anhydride (PA5+AA4): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 47 mg (0.31 mmol) of phthalic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 19 hours at 115 C to produce the imide. The imide wa s synthesized in ca. 82% yield. 1,5-diaminonaphthalene and 3,3’,4,4’-bi phenyltetracarboxylic dianhydride (PA5+AA5): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 37 mg (0.13 mmol) of 3,3’,4,4’-biphenyltetracarboxylic dianhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minut es. The resulting solid was then heated for 68 hours at 180 C to produce the imide. The imide was synthesized in ca. 77% yield.

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111 1,5-diaminonaphthalene and 1,8-naphthalic anhydride (PA5+AA6): 100 mg (0.63 mmol) of 1,5-diaminonaphthalene and 25 mg (0.12 mmol) of 1,8naphthalic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting so lid was then heated for 68 hours at 180 C to produce the imide. The imide wa s synthesized in ca. 73% yield. 1-adamantylamine and maleic anhydride (PA6+AA3): 100 mg (0.66 mmol) of 1-adamantylamine and 64 mg (0.66 mmol) of maleic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 20 hours at 120 C to produce the imide. The imide was synthesized in ca. 92% yield. 1-adamantylamine and phthalic anhydride (PA6+AA4): 100 mg (0.66 mmol) of 1-adamantylamine and 97 mg (0.66 mmol) of phthalic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 144 hours at 120 C to produce the imide. The imide was synthesized in ca. 96% yield. triphenylmethylamine and pyromellitic anhydride (PA7+AA2): 100 mg (0.39 mmol) of triphenylmethylamine and 84 mg (0.66 mmol) of pyromellitic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid was then heated for 48 hours at 140 C to produce the imide. The imide wa s synthesized in ca. 77% yield.

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112 triphenylmethylamine and maleic anhydride (PA7+AA3): 100 mg (0.39 mmol) of triphenylmethylamine and 38 mg (0.39 mmol) of maleic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 23 hours at 115 C to produce the imide. The imide was synthesized in ca. 86% yield. triphenylmethylamine and phthalic anhydride (PA7+AA4): 100 mg (0.39 mmol) of triphenylmethylamine and 57 mg (0.39 mmol) of phthalic anhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minutes. The resulting solid wa s then heated for 26 hours at 115 C to produce the imide. The imide was synthesized in ca. 90% yield. triphenylmethylamine and 3,3’,4,4’-bi phenyltetracarboxylic dianhydride (PA7+AA5): 100 mg (0.39 mmol) of triphenylmethylamine and 113 mg (0.39 mmol) of 3,3’,4,4’-biphenyltetracarboxylic dianhydride were ground with ca.20 L of DMF by hand in an agate mortar and pestle for 4 minut es. The resulting solid was then heated for 48 hours at 140 C and 29 hours at 180 C to produce the imide. The imide was synthesized in ca. 86% yield. Single crystal growth of 2-methyl-4 -nitroaniline NTCDA cocrystal (1a): Purple single crystals were obtained fr om dissolving approximately 20 mg of the cocrystal in 2 ml of 1,4-dioxane. The solution was partially covered with parafilm left to slowly evaporate under ambient c onditions. Single crystals of 1a were afforded within 14 days in ca. 20 % yield.

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113 Single crystal growth of 2-methyl -4-nitroaniline NTCDA diimide (1b): Orange single crystals were obtaine d by dissolving approximately 35 mg of 1b in 1 ml of DMSO. The solution was partially covered with parafilm left to slowly evaporate under ambient conditions. Single crystals of 1b DMSO were afforded within 7 days in ca. 60 % yield. Single crystal growth of 3-aminob enzoic acid NTC DA cocrystal (2a): Purple single crystals were obtained fr om dissolving approximately 20 mg of the cocrystal in 2 ml of 1,4-dioxane. The solution was partially covered with parafilm left to slowly evaporate under ambient c onditions. Single crystals of 2a were afforded within 3 days in ca. 43 % yield. Single crystal growth of 3-aminobenzoic acid NTCDA diimide (2b): Yellow single crystals were obtained from dissolving approximately 15 mg of 2b in 2 ml of pyridine. The solution was partially covered with parafilm left to slowly evaporate under ambient conditions. Single crystals of 2b pyridine were afforded within 20 days in ca. 55 % yield. Single crystal growth of 2-methyl-4-nit roaniline pyromellitic anhydride cocrystal (3a): Orange single crystals were obtained fr om dissolving approximately 20 mg of the cocrystal 3a in 2 ml of a 1:1 solvent mixture of chloroform and ethyl acetate. The solution was partially covered with parafilm left to slowly evaporate under ambient conditions. Single crystals of 3a were afforded within 22 days in ca. 15 % yield. Single crystal growth of 2-methyl-4-nitroaniline pyromellitic anhydride diimide (3b): Yellow single crystals were obtained fr om dissolving approximately 30 mg of 3b in 1 ml of DMF. The solution was partially cove red with parafilm left to slowly evaporate

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114 under ambient conditions. Single crystals of 3b were afforded within 14 days in ca. 36 % yield. Single crystal growth of 1-adamantylami ne phthalic anhydride intermediate (4a): Single crystals of the intermediate were obtained from dissolving approximately 50 mg (0.33 mmol) of 1-adamanytlamine and 49 mg (0.33 mmol) of phthalic anhydride in 4 ml of methanol. The solution was partially covere d with parafilm left to slowly evaporate under ambient conditions. Single crystals of 4a were afforded within 6 days in ca. 68 % yield. Single crystal growth of 1-adamantyla mine phthalic anhydride imide (4b): Single crystals of the imide product were obt ained by dissolving the heated material in ca. 2ml of distilled methanol and slow evaporation over several days. The unit cell parameters match the crystal structure of Refcode QUSKUK as deposited in the Cambridge Structural Database. 2.4.3. Characterization Methods Single-Crystal X-ray Diffraction : Single crystals were obtained for nine compounds. Attempts to crystallize 3 did not afford crystals suitable for single crystal Xray crystallographic analysis. Single crystal analysis for 1 2 and 5-10 was performed on a Bruker-AXS SMART APEX CCD diffractom eter with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low-temperature device. Data for 1 2 and 5-10 were collected at 100 K or 298 K. Lattice parameters were determined from least-squares analysis, and reflec tion data were integrated using SAINT.69

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115 Structures were solved by direct methods and refined by full matrix least squares based on F2 using the SHELXTL package.70 All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms bonded to carbon, nitrogen, and oxygen atoms were placed geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. Hydrogen atoms bonded to methyl groups were placed geom etrically and refined with an isotropic displacement parameter fixed at 1.5 times Uq of the carbon atoms. Powder X-Ray Diffraction (PXRD): 2-8 were characterized by a D-8 Bruker Xray Powder Diffractometer using a Cu K radiation ( = 1.54178 ), 50kV, 40mA. Data was collected over an angular range of 3 to 40 2 value in continuous scan mode using a step size of 0.05 2 value and a scan speed of 1.0 /min. Calculated PXRD: Calculated PXRD diffractograms were generated from the single crystal structures us ing Mercury 1.5 (Cambridge Cr ystallographic Data Centre, UK). Differential Scanning Calorimetry (DSC): Differential Scanning Calorimetry was performed on a TA Instruments 2920 DSC w ith a typical scan range of 35 C – 350 C, scan rate of 10 C/min, and nitrogen purge of ca. 70 psi. Fourier Transform Infrared Spectroscopy (FT IR): FT-IR analysis was performed on a Nicolet Avatar 320 FT-IR sp ectrometer equipped with a solid-state ATR accessory. UV-Vis Spectrophotometer (UV-vis): Purple co-crystals fr om reactions 1 and 2 were additionally characterized by UV-vi s from 350-800nm on a PerkinElmer Lambda 900 UV/Vis/NIR spectrometer

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116 Table 2.4. Hydrogen bond distances and parameters Compound Hydrogen Bond d(H...A)/ d(D...A)/ / 1a N-HO 2.18 2.946(6) 145.5 N-HO 2.55 3.194(7) 130.3 N-HO 2.39 3.255(8) 166.9 2a N-HO 2.24 3.066(4) 155.2 N-HO 2.46 3.217(4) 144.4 O-HO 1.81 2.643(3) 172.3 3a N-HO 2.16 2.943(5) 148.1 N-HO 2.31 3.089(5) 148.0 4a O-HO 1.87 2.682(3) 171.6 N-HO 2.34 3.318(3) 157.5

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117 2.5. References Cited (1) Sell, N. J., Industrial Pollution Control: Issues and Techniques Wiley and Sons: New York, 1992. (2) Ortega, P., Laboratory Investigation 1966, 15, 657. (3) Ortega, P., American Journal of Pathology 1969, 56, 229. (4) Turusov, V.; Rakitsky, V.; Tomatis, L., Environmental Health Perspectives 2002, 110, 125. (5) Agency, U. S. E. P. Pollution Prevention Act of 1990. http://www.epa.gov/p2/pubs/p2policy/act1990.htm (September 2009), (6) Freeman, H.; Harten, T.; Springer, J.; Randall, P.; Curran, M. A.; Stone, K., Journal of the Air & Waste M anagement Association 1992, 42, 618. (7) Warner, J. C.; Cannon, A. S.; Dye, K. M., Environmental Impact Assessment Review 2004, 24, 775. (8) Anastas, P. T.; Kirchhoff, M. M., Accounts of Chemical Research 2002, 35, 686. (9) Anastas, P. T. ; Williamson, T. C., Green chemistry: fronti ers in benign chemical syntheses and processes Oxford University Press, USA: 1998. (10) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R.; Anastas, P. T., Science 2002, 297, 807. (11) Tundo, P.; Anastas, P. T., Green Chemistry: Challenging Perspectives Oxford University Press, USA: 2000. (12) Clark, J. H., Green Chemistry 1999, 1, 1.

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118 (13) Anastas, P. T.; Warner, J. C., Green Chemistry Theory and Practice Oxford University Press: New York, 1998. (14) Lenardao, E. J.; Freitag, R. A.; Dabdoub, M. J.; Batista, A. C. F.; Silveira, C. D. In Green chemistry The 12 principles of gr een chemistry and it insertion in the teach and research activities 2003; Soc Brasileira Quimica: 2003; pp 123. (15) Ahluwalia, V. K.; Kidwai, M., New Trends in Green Chemistry Anamaya Publishers New Delhi, India, 2004. (16) Tanaka, K., Solvent-free organic synthesis Wiley-VCH: New York, 2003. (17) Toda, F., Organic solid state reactions Springer-Verlag Berlin Heidelberg: The Netherlands, 2005. (18) MacGillivray, L. R.; Reid, J. L.; Ripmeester, J. A., Journal of the American Chemical Society 2000, 122, 7817. (19) Fri i T.; MacGillivray, L. R., Zeitschrift Fur Kristallographie 2005, 220, 351. (20) MacGillivray, L. R.; Papaefstathiou, G. S.; Fri i T.; Hamilton, T. D.; Bucar, D. K.; Chu, Q.; Varshney, D. B.; Georgiev, I. G., Accounts of Chemical Research 2008, 41, 280. (21) MacGillivray, L. R.; Papaefstathiou, G. S.; Fri i T.; Varshney, D. B.; Hamilton, T. D., Templates in Chemistry I 2004, 248, 201. (22) Santra, R.; Biradha, K., Crystengcomm 2008, 10, 1524. (23) Chang, Y. L.; West, M. A.; Fowler, F. W.; Lauher, J. W., Journal of the American Chemical Society 1993, 115, 5991. (24) Kane, J. J.; Liao, R. F.; Lauher, J. W.; Fowler, F. W., Journal of the American Chemical Society 1995, 117, 12003.

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119 (25) Fowler, F. W.; Lauher, J. W., Journal of Physical Organic Chemistry 2000, 13, 850. (26) Lauher, J. W.; Fowler, F. W.; Goroff, N. S., Accounts of Chemical Research 2008, 41, 1215. (27) Wilhelm, C.; Boyd, S. A.; Chawda, S.; Fo wler, F. W.; Goroff, N. S.; Halada, G. P.; Grey, C. P.; Lauher, J. W.; Luo, L.; Marti n, C. D.; Parise, J. B.; Tarabrella, C.; Webb, J. A., Journal of the American Chemical Society 2008, 130, 4415. (28) Etter, M. C.; Frankenbach, G. M.; Bernstein, J., Tetrahedron Letters 1989, 30, 3617. (29) Sandor, R. B.; Foxman, B. M., Tetrahedron 2000, 56, 6805. (30) Pepinsky, R., Physical Review 1955, 100, 971. (31) Schmidt, G. M. J., Pure and Applied Chemistry 1971, 27 647. (32) Desiraju, G. R., Angewandte Chemie-Inte rnational Edition 2007, 46 8342. (33) Nangia, A.; Desiraju, G. R., Design of Organic Solids 1998, 198, 57. (34) Boyer, P. D., The Enzymes: Elimination and addition, aldol cleavage and condensation, other C-C cleavage, phosphorolysis; Hydrolysis (fats, glycosides) Academic Press: New York, 1972; Vol. 7. (35) Stoker, H. S., General, Organic, and Biological Chemistry Cengage Learning: Belmont, California, 2009. (36) Bloch, D. R., Organic chemistry demystified McGraw-Hill Professional: New York, 2006. (37) Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry: Reactions and Synthesis. Springer: New York, 2000. (38) Al-Malaika, S., Reactive Modifiers for Polymers Chapman and Hall: Cambridge, 1997.

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120 (39) Solomons, T. W. G.; Fryhle, C. B., Organic Chemistry 8th ed.; J. Wiley and Sons: New York, 2004. (40) Borah, H. N.; Boruah, R. C.; Sandhu, J. S., Journal of Chemical Research-S 1998 272. (41) Vidal, T.; Petit, A.; Loupy, A.; Gedye, R. N., Tetrahedron 2000, 56, 5473. (42) Martelanc, M.; Kranjc, K.; Polanc, S.; Kocevar, M., Green Chemistry 2005, 7, 737. (43) Short, K. M.; Ching, B. W.; Mjalli, A. M. M., Tetrahedron 1997, 53, 6653. (44) Short, K. M.; Ching, B. W.; Mjalli, A. M. M., Tetrahedron Letters 1996, 37, 7489. (45) Padwa, A. R.; Sasaki, Y.; Wolske, K. A.; Macosko, C. W., Journal of Polymer Science Part a-Polymer Chemistry 1995, 33, 2165. (46) Allen, F. H., Acta Crystallographica Section B-Structural Science 2002, 58, 380. (47) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A., Journal of Pharmaceutical Sciences 2008, 97 3942. (48) Zhang, G. G. Z.; Henry, R. F.; Borchardt, T. B.; Lou, X. C., Journal of Pharmaceutical Sciences 2007, 96, 990. (49) Maheshwari, C.; Jayasankar, A.; Kha n, N. A.; Amidon, G. E.; Rodriguez-Hornedo, N., Crystengcomm 2009, 11, 493. (50) Fri i T.; Jones, W., Crystal Growth & Design 2009, 9, 1621. (51) Karki, S.; Fri i T.; Jones, W., Crystengcomm 2009, 11, 470. (52) Shan, N.; Toda, F.; Jones, W., Chemical Communications 2002, 2372. (53) Bis, J. A.; Vishweshwar, P. ; Middleton, R. A.; Zaworotko, M. J., Crystal Growth & Design 2006, 6, 1048.

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121 (54) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J., Crystal Growth & Design 2009, 9, 1106. (55) Kuroda, R.; Higashiguchi, K.; Hasebe, S.; Imai, Y., Crystengcomm 2004, 6, 463. (56) Toda, F.; Miyamoto, H., Chemistry Letters 1995, 861. (57) Green, B. S.; Schmidt, G. M. J., Tetrahedron Letters 1970 4249. (58) Schmidt, G. M. J., Pure and Applied Chemistry 1971, 27 647. (59) Herr, M. 1-Adamantylamine derivatives. FR 1545316, 1968. (60) Orzeszko, A.; Lasek, W.; Switaj, T.; Stoksik, M.; Kaminska, B., Il Farmaco 2003, 58, 371. (61) CSD version 5.30, November 2007 re lease including May 2009 update. Search parameters: organics only, no ions, 3D coordinates determined, R<7.5%. 2009 (62) Dao, B.; Hodgkin, J.; Morton, T. C., High Performance Polymers 1999, 11, 205. (63) Guillaumel, J.; Lonce, S.; Pierr, A. ; Renard, P.; Pfeiffer, B.; Arimondo, P. B.; Monneret, C., European Journal of Medicinal Chemistry 2006, 41, 379. (64) Trujillo-Ferrara J.; Montoya Cano, L.; Espinoza-Fonseca, M., Bioorganic & Medicinal Chemistry Letters 2003, 13 1825. (65) Zavyalov, S. I.; Dorofeeva, O. V.; Rumy antseva, E. E.; Kulikova, L. B.; Ezhova, G. I.; Kravchenko, N. E.; Zavozin, A. G., Pharmaceutical Chemistry Journal 2002, 36, 440. (66) Fraga-Dubreuil, J.; Comak, G. ; Taylor, A. W.; Poliakoff, M., Green Chemistry 2007, 9, 1067. (67) Crippa, G. B.; Galimberti, P., Gazzetta Chimica Italiana 1929, 59, 510. (68) Meyer, E. v., Journal fuer Praktische Chemie 1911, 82, 521.

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122 (69) Bruker SMART, SAINT-Plus, SADABS, XP and SHELXTL Madison, Wisconsin, USA, 1997. (70) Sheldrick, G. M. SHELXTL, University of Gottingen: Germany, 1997.

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123 Chapter 3: Lamotrigine Crystal Forms: Synthesis, Characterization, and Evaluation 3.1 Preamble Crystal form development for an active pharmaceutical ingredient (API) typically results in a plethora of crystal forms including salts,1 cocrystals,2 solvates,3 hydrates,4 etc. which can be beneficial to the pharmaceutical industry. Pharmaceutical salts are materials form ed by an ionic API and a suitable, pharmaceutically acceptable counterion.1, 5 They have been a part of crystal form selection for decades as they offer diversity of composition and can therefore exhibit a wide range of physicochemical properties.1 Pharmaceutical cocrystals6 are a relatively new technology with the first pharmaceutical cocr ystal developed within the decade. The current focus of pharmaceutical cocrystallization is, much like a pharmaceutical salt, their inherent ability to change the properties of an API. A review of th e literature reveals that there have been eight 7-14 pharmaceutical cocrystal case studies with pharmacokinetic details reported to date, all of which support that pharmaceutical cocrystals are a viable option to enhance the clinical performance of a poorly soluble API. Pharmaceutical cocrystals are a particularly attractive crystal form option because they maintain the criteria for patentability. That is, they are novel, non-obvious, and of utility to the pharmaceutical industry.

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124 The importance of hydrates and solvates in pharmaceutical development has also been recognized.4, 15 Various examples have demonstrat ed that the formation of hydrates and solvates can significantly alter the physicochemical pr operties of APIs, such as chemical stability, solubility and dissolution rate.16-19 With this in mind, we report a study of lamotrigine (6-(2,3-dichlorophenyl)-1,2,4triazine-3,5-diamine), a triazine drug amenable to crystal engineer ing design strategies that exhibits poor solubility and dissolution rate in its pure crystalline form. Lamotrigine is marketed as Lamictal by GlaxoSmithKline for oral administration as a compressed or chewable tablet. It is primarily used as an anti-convulsant drug for the treatment of epilepsy as well as in the treatment of psyc hiatric disorders such as bipolar disorder.20, 21 In particular, lamotrigine is used for the treatment of generalized seizures associated with Lennox-Gastaud syndrome22 and it can be used in conjunction with other anti-epileptic drugs such as carbamazepine, phenytoin, phenobarbital, primidone or valproate.23 An additional and perhaps less common use fo r lamotrigine is for the treatment of neuropathic pain, cluster headaches, and migraines.24 Lamotrigine, a white to pale cream-colored powder with a pKa of 5.7, is very slightly soluble in water (0.17 mg/mL at 25 C) and only slightly soluble in 0.1 M HCl (4.1 mg/mL at 25 C).25 Various attempts have been made to solve the use limitations of lamotrigine due to its poor solubility. Briefly, these approaches have involved the exploration of a pletho ra of crystal forms,26-30 including salt forms, and re duction of the particle size.31 Recently eight novel crystal forms of lamotrigine were reported by Galcera et al.,32 with only two salt forms (saccharinate and DL-hemitartrate dimethyl sulfoxide solvate) reaching a greater maximum aqueous solubility than pure lamo trigine. A benzoate dimethylformamide

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125 solvate,33 hydrogen phthalate dimethylformamide solvate,34 methanol solvate,35 isoethoinate,36 dimethylformamide solvate,37 methanesulfonate,38 and a monohydrate39 have also been reported; however only limite d solubility data is available concerning these crystal forms. Some of the aforem entioned crystal forms, particularly those involving certain salt forms, ar e undesirable for certain routes of administration, such as parenteral, due to their acidity. Other formul ations contain ingredients that are not safe for human consumption such as dimethylformam ide. Clearly, there is a strong scientific and clinical need to develop novel forms of lamotrigine that have significantly improved physicochemical properties, including aqueous solubility, which can be formulated for use in various delivery routes, su ch as oral administration. To generate novel crystal forms of lamo trigine an analysis based upon crystal engineering40-42 molecular recognition,43 and supramolecular synthons,44 was conducted to determine complementarities between a number of pharmaceutically acceptable and approved materials containing carboxylic ac id, alcohol, and primary amide moieties and lamotrigine. It showed that lamotrig ine can form complexes with two dominant supramolecular synthon motifs, with or w ithout the aminopyridine dimer. Among all pharmaceutically acceptable and/or approved compounds with hydrogen-bonding functionality, a variety of guest molecules that were likely to form either of these two motifs with lamotrigine were selected for this study and are shown in Figure 3.1. All selected guest molecules except butylated hydroxyanisole successfully formed complexes with lamotrigine, resulting in ten novel lamotrigine crystal forms. Details of the supramolecular synthon approach and the development of ten crystal forms of lamotrigine from established cocrystallization techniques45-48 are presented herein.

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126 Additionally, solubility and pharmacokinetic studies were conducted upon a subset of these crystal forms and are described herein. 3.2 Results and Discussion 3.2.1 Salt vs Cocrystal Lamotrigine has the ability to form both salts and cocrystals due to its relatively basic nature (pKa = 5.7). By selecting cocrysta l formers with a range of varying acidities, the formation of lamotrigine pharmaceutical salts or cocrystals would be expected. The pKa difference between lamotrigine and the adduct, pKa (i.e. pKa = pKa base pKa acid), is widely accepted as the key to pred icting whether a salt or a cocrystal will form.5, 49, 50 It is generally considered that if pKa > 3 the resulting compound will be a salt (exemplified in this study by saccharin); wher eas the result is typi cally a cocrystal if pKa < 0. For pKa between 0 < pKa < 3 the outcome can be either a salt or cocrystal or a complex with partial proton transfer.51 The pKa and pKa values52-55 involved in this study are summarized in Table 3.1. It is noted that the pKa values of three cocrystal formers (i.e. adipic acid, L-malic acid and nicotinic acid) fall in the variable region. Interestingly, all of these co crystal formers produce lamotrigine salts, as evidenced by the proton location and bond lengt h analysis from the single crystal X-ray diffraction data. Analysis of the carbonyl re gion of the solid-state FTIR spectrum also supports the formation of lamotrigine salts.

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127Table 3.1. pKa values and the resulting pKa values for the lamotrigine salts Figure 3.1 Molecular structures of cocrystal and salt formers 3.2.2 CSD Analysis In order to prepare novel crystal forms of lamotrigine, a crystal engineering40-42 study incorporating supramol ecular design and the mol ecular functionality of lamotrigine, i.e. the supramolecular s ynthon approach, was conducted. The crystal structure of pure lamotrigine exhibits tw o dominant supramolecular synthon motifs, the aminopyridine dimer (motif 1) and the amine-ar omatic nitrogen synthon (motif 2). Motif 1 and motif 2 are depicted in Figure 3.2. AcidpKa pKa Adipicacid4.43 3.44 4.92 1.60 1.27 2.26 0.78 4.10 L-Malic acid Nicotinic acid Saccharin AcidpKa pKa Adipicacid4.43 3.44 4.92 1.60 1.27 2.26 0.78 4.10 L-Malic acid Nicotinic acid Saccharin

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128 Figure 3.2 Motif 1 involves breaking the aminopyridine dimer and motif 2 retains the aminopyridine dimer but breaks the exterior bifurcated interaction The introduction of an additional compleme ntary component to the crystal lattice of lamotrigine could lead to an interrupti on of motifs 1 or 2 by either: breaking the aminopyridine dimer (breaking motif 1) or brea king the exterior bifurcated interactions between the aromatic nitrogen moieties of one lamotrigine to the primary amine moieties of two additional lamotrigine molecules (breaking motif 2). An analysis of the Cambridge Structural Database (CSD)56, 57 indicates that breaking either motif is feasible given a complementary secondary component. Disruption of motif 1 occurs in 26 out of 81 aminopyridine entries (32%) and disruption of motif 2 occurs in 39 out of those 81 entries, or 48% of the time. In order to understand the hydrogen bonding of the primary amine moiety of the diaminopyridine moiet y, the 39 entries that break motif 2 were analyzed. Among those entries 95% (37/39) sh ow the exterior am ine moiety hydrogen

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129 bonding to the second molecule while only 2 entries (5%) show the exterior amine moiety hydrogen bonding to a molecule of the same kind, i.e. another diaminopyridine (Refcodes: AMCQUN, GICWOF). Based on these CSD statistics,57 breaking the supramolecular synthons of motif 1 and motif 2 is feasible, however, there remains a tendency towards persistence of the aminopyridine dimer. Identification of complementary cocrystal formers for lamotrigine by statistical examination of the percentage of occurrence of supramolecular homosynthons versus supramolecular heterosynthons was al so addressed via a CSD analysis.57 Interactions between an aminopyridine moiety and car boxylic acid, primary amide, and alcohol moieties were examined in order to determin e if the supramolecular heterosynthon or the supramolecular homosynthon would be more prominent (Table 3.2., aminopyridine was chosen instead of diaminopyridine to provide a larger dataset fo r the statistical analysis).

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130Table 3.2 Comparison of supramolecular hom osynthon versus supramolecular heterosynthon with aminopyridines and complementary moieties To conduct the supramolecular homosynthon and heterosynthon analysis, a broad distance range was initially selected and then reduced by visual inspection to determine the appropriate ranges for defining hydrogen bon d contact limits. The values given in Table 3.2. are a refined dataset which incl udes only aminopyridine and one additional Complem entary Moiety No. of entries w/ both group s % Homosynthon occurrence: Aminopyridine Refined dataset (distance range) %Homosynth on occurrence: Cocrystal former Refined dataset (distance range) %Heterosyntho n occurrence refined dataset Heterosynthon Distance Range () Refined dataset Carboxyli c acid 91 40/91 (44%) (N N 2.92-3.17) 0 42/91-acid (46%) 28/91carboxylate (31%) N(py) O 2.50-2.80 N(am ) O 2.71-3.10 (aci d and carboxylate) Primary amide 15 2/15 (13%) (N N 3.04-3.077) 1/ 15 (6%) (N O 2.98) 1/ 15 (6%) N(py) N 2.97 N(am ) O 3.06 Alcohol 307 66/307 (21%) (N N 2.92-3.17) 78/ 307 (25%) (O O 2.612. 92) 100/307 (33%) N(py) O 2.67-2.90 N(am ) O 2.78-3.19

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131 moiety sustained by a specified supramol ecular heteroor homosynthon interaction within a defined distance range. Our an alysis concluded that, in general, the supramolecular heterosynthons were more dominant than the homosynthons. The alcohol moiety was the most statistically favored to interact with the aminopyridine moiety as there was 33% (100/307) ve rsus 21% (66/307) occurrence for the supramolecular heterosynthon and homosynthon, respectively. However, the addition of a carboxylic acid to a molecule sustaine d via an aminopyridine supramolecular homosynthon has previously been explored and successfully resulted in the formation of cocrystals and salts.58, 59 Thus it is not surprising that there was also a preference for the aminopyridine-acid supramolecular hetero synthon, with a higher percentage of occurrence attributed to the carboxylic acid group (43/ 91, 46%) than the carboxylate group (28/91, 31%). Interestingly, the carboxylic acid homosynt hon does not occur in the presence of the aminopyrid ine functional group. There ar e 15 structures that contain aminopyridine and primary amide moieties 2 of which form the aminopyridine supramolecular homosynthon, 1 forms the amide dimer, and 1 forms the aminopyridineamide supramolecular heterosynthon. Unfort unately, this paucity of data precludes determination of the reliability of the aminopyridine-amide supramolecular heterosynthon. However, the CSD analysis i ndicates that aminopyridines are likely to form supramolecular heterosynthons with mo lecules containing alcohols and carboxylic acids. A general observation when searching for entries with an aminopyridine was the numerous examples of aminopyridines with barb ituric acid derivatives. Specifically, the CSD contains a set of 35 aminopyridine-barbit uric acid derivative co crystals synthesized by Whitesides et al.60-62 This dataset indicates that the aminopyridine-amide

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132 supramolecular heterosynthon is a reliable synthon. However, due to the nature of the study, cocrystal formers that are utilized must at least be on the generally regarded as safe (GRAS) list, precluding the se lection of cocrystal formers containing amide moieties. Thus a range of carboxylic acids, alcohols, and amides were chosen for crystal form development however, only six resulted in novel crystal forms. Figure 3.1. illustrates the formers that resulted in novel crystal forms. 3.2.3 Motif 1 versus Motif 2 The crystal forms presented herein break ei ther motif 1 or motif 2 present in pure lamotrigine by incorporating a complementary cocrystal former. Motif 1 is broken in 4 out of 9 structures while the remaining crys tal forms contain motif 1 but break motif 2. Specifically, crystal forms 2 4 7 9 and 10 break motif 2 while forms 1 5 6 and 8 break motif 1. The individual motifs and how they impact the physicochemical properties of the crystal form are di scussed in the following segments. 3.2.4 Crystal Structure Descriptions Cocrystals of lamotrigine methylparaben form I ( 1 ) crystallize in the space group P 21/ n 1 crystallizes concomitantly in the presence of pure methylparaben and lamotrigine tetrahydrofuran solvate. The as ymmetric unit contains one lamotrigine and one methylparaben molecule. The lamotrig ine aminopyridine dimer is not observed in 1 (Figure 3.3.). Instead the stru cture is a corrugated tape comp rised of individual chains of alternating lamotrigine methylparaben mo lecules sustained primarily by two hydrogen bonds (Figure 3.4.). Specifically, the aroma tic nitrogen N2 of the triazine ring is

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133 hydrogen bonded to the hydroxyl moiety of the methylparaben [O1-H10O N2: O N 2.651(4) , H N 1.831 , O-H N 164.8 ] and the amine in the 5-position of lamotrigine is hydrogen bonded to the car bonyl group of the ester moiety of methylparaben [N5-H3N O2: N O 2.823(4) , H O 1.971 , N-H O 162.7 ]. The chains of extend parallel to the 2-fold axis. Neighboring chains ar e related by a center of inversion and are held together by va rious weak interactions including C-H N and Cl Cl interactions to form a corrugated tape. The phenyl rings of the lamotrigine molecule are twisted to a di hedral angle of 88.03 . Figure 3.3 Supramolecular synthons exhibited by 1

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134 Figure 3.4 1 breaks motif 1 as shown in the hydrogen bonding pattern Lamotrigine methylparaben form II ( 2 ) can be obtained via grinding, slurry, or melt. Crystals of 2 exist in space group P with one lamotrigine and one methylparaben in the asymmetric unit (Figure 3). The chlorina ted phenyl ring backbone of lamotrigine is disordered over two distinct positions with 40% and 60% occupanc ies, respectively. The attached chlorine atoms are refined over three positions with occupancies of 40%, 40% and 20%, respectively. A comparison of the crystal structures of 1 and 2 reveals that they exhibit different molecular packing arrangements. Unlike 1 2 exhibits lamotrigine centrosymmetric aminopyridine dimers [N3-H3B N4: N N 3.121(4) , H N 2.246 , N-H N 172.3 ]. The lamotrigine dimers connect to neighboring dimers via methylparaben molecules, thereby forming s upramolecular ribbons that extend parallel to the a -axis [N5-H5A O1: N O 3.036(4) , H O 2.205 N-H O 157.3 ; O1-

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135 H1C N2: O N 2.711(4) , H N 1.876 , O-H N 173.3 ]. The methylparaben molecule also serves as a bridge to join these supramolecular ribbons via N-H O interactions [N5-H5B O2: N O 2.931(4) , H O 2.129 , N-H O 151.2 ]. Figure 3.5 Breaking motif 2 shown in the hydrogen bonding of 2

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136 Figure 3.6 Crystal packing of 2 The cocrystal of lamotrigine and nicotinamide ( 3 ) was prepared from a melt of a 1:1 ratio of lamotrigine and nicotinamide as evidenced by PXRD characterization. Efforts to prepare quality single crystals of 3 for single crystal XRD analysis are unsuccessful to date. 4 ( lamotrigine nicotina mide monohydrate ) crystallizes in the space group P with the asymmetric unit cons isting of one molecule of la motrigine, one molecule of nicotinamide and one water molecule. Motif 2 is broken by the double insertion of water molecules while the lamotrigine am inopyridine dimer persists [N3-H2N N4: N N 3.039(2) , H N 2.243 , N-H N 154.2 ]. The water molecules facilitate the formation of a supramolecular ribbon mo tif. The ribbon is formed along the b -axis as the lamotrigine dimers are linked by water molecules via N-H O and O-H N interactions

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137 [N5-H3N O1-H5O N2: N O 2.930(2) , H O 2.089 , N-H O 165.3 , O N 2.822(2) , H N 1.967 , O N 171.7 ]. In addition, nicotinamide molecules form centrosymmetric amide dimers that pack pe rpendicularly in between the lamotrigine water ribbons forcing a separation between th e supramolecular ribbons approximately the length of two nicotinamide molecules (Figure 3.7.) [N7-H8N O2: N O 2.915(3) , H O 2.056 , N-H O 176.7 ]. The water molecules within the supramolecular ribbons also hydrogen bond to the nicotinamide dimers via additional O-H N interactions that are high lighted in Figure 3.8. [O1-H6 N6: O N 3.039(3) , H N 2.162 , O-H N 166.5 ]. The voids generated by the nicotinamide dimers separating the supramolecular ribbons are filled by a dditional supramolecula r ribbon-nicotinamide dimer units. These supramolecular units are stabilized by interactions between the chlorinated lamotrigine ring and th e nicotinamide aromatic ring. Figure 3.7. Supramolecular synthons present in 4

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138 Figure 3.8. Crystal packing of 4 interrupting motif 2 The salt of lamotrigine and saccharin ( 5 ) crystallizes in space group P 21/ c The asymmetric unit contains one lamotrigine ca tion and one saccharin anion. The structure of 5 does not contain the aminopyridine dimer; however, formation of the dimer is possible with protonation of the most basic nitr ogen (N2) as it is no t incorporated in the lamotrigine dimer. The basic supramolecular unit in 5 is a tetramer formed between two lamotrigine and two saccharin ions where the N2 is protonated. Lamotrigine and saccharin are associated via two 2-po int recognition aminopyridine-sulfonamide supramolecular heterosynthons [N2+-H1N N6: N N 2.819(2) , H N 1.940 , N+H N 177.5 ; N3-H2N O1: N O 2.830(2) , H O 1.954 , N-H O 173.5 ]. The C3-N2-N1 angle of the triazine ring in the crystal structure of 5 is 123.4 which correlates to the previously reported values for protonated lamotrigine63 and the expected

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139 trend for protonated aminopyridines, i.e. higher angles than those of a neutral aminopyridine.63, 64 The tetramer is formed from two adjacent supramolecular heterosynthon dimers, shown in Figure 3.9., that are further connected by primary aminecarbonyl interactions [N3-H3N O1: N O 2.818(2) , H O 2.054 , N-H O 144.7 ]. Each tetramer is hydrogen bonded to four additional tetramers via either sulfonylamine or sulfonyl-chlorin e interactions [N5-H4N O2: N O 2.889(2) , H O 2.194 , N-H O 135.5 ; Cl1 O3 3.068(3) ]. A view of the overall crystal packing can be seen in Figure 3.10. Figure 3.9. Tetrameric motif present in 5

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140 Figure 3.10. Crystal packing of 5 6 ( lamotrigine adipate salt ) crystallizes in space group of P 21/ c with two lamotrigine cations and one adipate anion in the asymmetric unit (Figure 3.11.). The molecular packing of 6 is based upon 2-point supramol ecular heterosynthons between the aminopyridinium and carboxylate moieties, involving an N-H O hydrogen bond [N3H3N O1: N O 2.942(2) , H O 2.110 , N-H O 157.5 ] and a N+-H O– chargeassisted hydrogen bond [N2+-H1N O2-: N O 2.627(2) , H O 1.790 , N-H O 158.1 ]. Proton transfer is evidenced by the C-O bond distances of the carboxylate group (1.248(2) and 1.272(2) ) and the geometry of the lamotrigine triazine ring. The C3N2-N1 angle of the triazine ring in the crystal structure of 6 is 122.4(2) . Each discrete unit, comprised of two lamotrigine cations and one adipate anion, is hydrogen bonded to

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141 eight nearby lamotrigine-adipat e units through the lamotrigine NH2 moieties and neighboring carboxylate [N3-H2N O1: N O 2.861(2) , H O 2.057 , N-H O 151.5 ; N5-H4N O2: N O 2.760(2) , H O 1.931 , N-H O 156.5 ]. Each adipate anion is hydrogen bonded to four additional discrete units via C-O H-N interactions. The overall packing can be viewed in Figure 3.12. as staggered supramolecular units of lamotrigine-adipate runni ng parallel to either (010) or (001) with Cl pi interactions. Figure 3.11. Supramolecular synthons of 6 do not form motif 1

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142 Figure 3.12. Crystal packing of 6 The lamotrigine and L-malic acid salt ( 7 ) crystallizes in P 21/c The asymmetric unit is comprised of two lamotrigine catio ns and one L-malate anion (Figure 3.13.). Lamotrigine dimers are formed via a noncentrosymmetric dimer sustained by N-H N hydrogen bonds [N5-H5N N14: N N 2.956(6) , H N 2.078 , N-H N 174.6 ; [N15-H15 N4: N N 3.082(6) , H N 2.215 , N-H N 168.6 ]. The L-malate anion hydrogen bonds to the lamotrigine dimer such that a supramolecular chain is formed. Proton transfer occurs between both car boxylate groups (C20-O 1: 1.275(5); C20-O2: 1.235(6); C23-O4: 1.257(6); C23-O5: 1.275(6)) of Lmalate and aromatic nitrogen atoms of lamotrigine [N12+-H12N O1-: N O 2.632(5) , H O 1.766 , N-H O 167.8 ; C19-N12-N11 angle 123.16 ]. The lengths of the C-O bonds are typical of a carboxylate moiety and the C19-N12-N11 angle of 123.2 is consistent with that of a protonated

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143 aromatic nitrogen. The supramolecular chains generated from two lamotrigine cations alternating with one l-malate anion, hydroge n bond to an additional l-malate anion forming a sheet perpendicular to the bc -plane. The sheets interact via NH O hydrogen bonds [N3-H3NA O1: N O 2.790(5) , H O 2.086 , N-H O 136.3 ; N13H13A O5: N O 2.928(5) , H O 2.135 , N-H O 149.6 ] to chains that run through the ac -plane, thereby generating a 3D stru cture. Figure 3.14. highlights the supramolecular sheet with only one row of pe rpendicular chains present for clarity. Figure 3.13. Supramolecular synthons of 7 generating motif 1, breaking motif 2

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144 Figure 3.14. Crystal packing of 7 highlighting a chain running perpendicular to the sheet The dimethanol solvate of the salt form ed by lamotrigine and nicotinic acid ( 8 ) crystallizes in space group P 21/ c with proton transfer obs erved from the carboxylic acid group to N2 on the triazine ring [N2+-H1N O2-: N O 2.729(3) , H O 1.880 , N-H O 161.7 ; C3-N2-N1 angle 122.8 ]. The ba sic supramolecular unit is comprised of one lamotrigine cation, one nicotinate anion, and two methanol molecules. The structure of 8 reveals that the nicotinate anion breaks the lamotrigine dimer. Similarly to 5 two pairs of lamotrigine nicotinate adducts interact to form tetrameric motifs sustained by charge assisted N+-H Oand N-H O hydrogen bonds (Figure 3.15.) [N3-H2N O3: N O 2.764(3) , H O 1.9223 , N-H O 159.4 , N3-H3N O3: N O 2.872(3) H O 2.061 N-H O 152.8 ]. In addition, four meth anol molecules attach to the exterior of each tetramer by hydrogen bonding to lamotrigine cations and nicotinate

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145 anions. Two methanol molecules inte ract with carboxylate groups via O-H O hydrogen bonds [O1S-H6S O2: O O 2.777(2) , H O 1.974 , O-H O 159.7 ], while the other two methanol molecules are inserted be tween N5 and the aromatic nitrogen of the nicotinate [N5-H4N O4S: N O 2.755(3) , H O 1.881 , N-H O 171.8 , O4SH7S N6: O N 2.699(3) , H N 1.863 , O N 172.7 ]. The methanol molecules that interact with the carboxylate moiety act as hydrogen bond donors to the carboxylate while also accepting a hydrogen bond from a lamotrigine of an adjacent tetramer disposed perpendicularly [N5-H5N O1S: N O 2.816(3) , H O 2.012 , N-H O 151.3 ]. The crystal packing of the tetr americ units is shown in Figure 3.16. Figure 3.15. Breaking motif 1 shown in the hydrogen bonded assembly of 8

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146 Figure 3.16. Crystal packing of tetrameric units of 8 A small set of lamotrigine solvates, in cluding a monomethanol solvate, have previously been reported in the literature. Details of the monomethanol solvate crystal packing that supports the overa ll structure were also provi ded. Herein the crystal structures of the monomethanol solvate and a novel dimethanol solvate are explored. The lamotrigine dimethanol solvate ( 9 ) was obtained from an atte mpted cocrystallization of lamotrigine and butylated hydr oxyanisole from methanol. 9 crystallizes in C 2/ c with the asymmetric unit comprised of one lamo trigine and two methanol molecules. 9 retains the lamotrigine dimer motif and the supramolecular unit consists of one lamotrigine dimer and two separately hydrogen bonded metha nol molecules. The lamotrigine supramolecular homosynthon dimer in 9 is centrosymmetric [N3-H1N N4: N N 3.084(3) , H N 2.213 , N-H N 170.6 ]. In addition, N3 and N5 amines form

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147 hydrogen bonds with methanol molecules (Figure 3.17.) [N3-H2N O2: N O 2.824(2) , H O 2.210 , N-H O 126.6 ; N5-H3N O2: N O 2.862(2) , H O 2.109 , NH O 143.1 ]. Hydrogen bonds are also observe d between methanol molecules and aromatic nitrogen atoms N1 and N2 [O1-H6O N1: N O 2.987(2) , H N 2.159 , N-H O 168.6 ; O2-H5O N2: N O 2.654(2) , H N 1.824 , N-H O 169.9 ]. The lamotrigine dimers and methanol molecules hydrogen bond to form a ribbon that extends along the c -axis. A ribbon is highlighted in yellow in Figure 3.18. Two inversion center related ribbons interact via CH-N and Clinteractions thus forming a ribbon bilayer. The bilayers stack along the b -axis in an abab motif, as shown in Figure 3.18. Figure 3.17. Crystal form 9 breaking motif 2

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148 Figure 3.18. Bilayers formed in crystal packing of 9 Comparison of literature monomethanol solvate (Refcode KADPAG) The methanol solvate preexisti ng in the litera ture from 198935 contains one lamotrigine and one methanol molecule in th e basic supramolecular unit and crystallizes in the P 21/ n space group. The lamotrigine dimetha nolate presented herein (Figure 3.17 and 3.18) sustains a 1:2 ra tio (lamotrigine:methanol) and crystallizes in the C 2 /c space group. Interestingly, the monomethanol a nd dimethanol solvate both crystallize by breaking motif 2. The centrosymmetric lamotrigine aminopyridine dimer is exhibited by both solvates; the distinction can clearly be seen when looking at the ribbons of lamotrigine aminopyridine dimers. In the dime thanol solvate, the ribbon is flat extending along the b -axis (Figure 3.18., yellow ribbon), however, in the monomethanol solvate the ribbon is corrugated with a dihedral a ngle of 65.14 (Figure 3.19., yellow ribbon).

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149 Variations can also be found in the hydroge n bonding scheme of the amine moieties in the 3 and 5-positions. Notably the amine in the 3-position is hydrogen bonded to a methanol in the dimethanol solvate, whereas in the monomethanol solvate the methanol exhibits a short contact to a neighboring chlorine atom. Figure 3.19. Crystal packing of KADPAG in CSD highlighting a corrugated chain of lamotrigine methanol units Crystals of 10 ( lamotrigine ethanolate monohydrate ) form in space group P 21/ c with an asymmetric unit that is comprised of one lamotrigine, one ethanol and one water molecule. 10 exhibits the lamotrigine dimer as shown in Figure 3.20. In the crystal structure of 10 the basic supramolecular unit is the lamotrigine aminopyridine dimer sustained by two symmetrically related hydrogen bonds [N3-H2N N4: N N 3.006(2) , H N 2.191 , N-H N 153.7 ]. The lamotrigine dimers are further hydrogen bonded via water molecules [N3-H1N O1: N O 2.928(2) , H O 2.295 , N-H O

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150 128.8 ; N5-H3N O1: N O 2.848(2) , H O 1.973 , N-H O 173.2 ] and ethanol molecules [N5-H4N O2: N O 3.042(2) , H O 2.346 , N-H O 136.2 ] to form a supramolecular ribbon that translates along the 2-fold axis. The ribbons, shown in Figure 3.21., illustrate the water hydrogen bonding in the central region of the ribbon while the ethanol molecules hydrogen bond to the exte rior. Individual supramolecular ribbons interact via Clinteractions to form a corrugated layer. The layers are connected through hydrogen bonds that occur between water and ethanol molecules [O1-H9O O2: O O 2.829(2) , H O 1.942 , O-H O 178.8 ], thereby generati ng a brickwall motif. The supramolecular synthons invo lved in the structure of 10 are reminiscent of pure lamotrigine; however, the insertion of the wa ter and ethanol molecules force neighboring lamotrigine dimers further apart than in the pure crystalline material. Figure 3.20. Crystal form 10 interrupting motif 2

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151 Figure 3.21. Ethanol water lamotrigine ribbons

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152Table 3.3 Crystallographic data and structure refinement parameters for compounds 1-2, 4-10 1 2 4 5 6 7 8 9 10 Chemical formula C9H7Cl2N5 C8H8O3 C9H7Cl2N5C8H8O3 C9H7Cl2N5 C6H6N2O H2O C9H8Cl2N5 C7H5NO3S C9H8Cl2N5 (C6H9O4)05 (C9H8Cl2N5)2 C4H5O5 C9H8Cl2N5 C6H4NO2 (CH4O)2 C9H7Cl2N5 (CH3OH)2 C9H7Cl2N5 C2H5OH H2O Formula weight 408.24 408.24 396.24 439.28 329.17 646.28 443.29 320.18 320.18 Crystal System Monoclinic Triclinic Triclinic Monoclinic Monoclin ic Monoclinic Monoclinic Monoclinic Monoclinic Space group P21/ n P P P21/ c P21/ c P21 P21/ c C 2/ c P21/ c a () 5.2729(9) 8.8957(18) 7.3047(6) 18.447(5) 13.068(3) 10.728(2) 7.648(3) 19.326(4) 7.1308(14) b () 14.330(3) 11.409(2) 8.4939(7) 6.954(2) 7.4 98(2) 10.2003(19) 15.863(6) 17.584(3) 8.3566(16) c () 23.822(4) 12.040(2) 14.6964(12 ) 14.762(4) 14.069(3) 12.721(2) 16.803(7) 8.2698(15) 24.018(5) (o) 90 107.05(3) 105.081(5) 90 90.00 90 90 90 90 (o) 92.795(3) 102.10(3) 90.580(5) 107.978(4) 96.755(4) 107.634(13) 90.072 (6) 97.820(3) 94.565(3) (o) 90 112.50(3) 95.244(5) 90 90.00 90 90 90 90 Vol (3) 1797.9(6) 1005.0(4) 876.21(12) 1801.2(9) 1369.0(6) 1326.6(4) 2038.5(15) 2784.2(9) 1426.7(5) Dcal (g cm3) 1.508 1.349 1.502 1.620 1.597 1.618 1.444 1.528 1.491 Z 4 2 2 4 4 2 4 8 4 Reflections collected 8611 4879 7400 9108 6576 9647 10331 5746 8317 Independen t reflections 3159 3370 2842 3273 2407 3848 3642 2421 3273 Observed reflections 2056 2420 2406 3033 2230 3499 2698 2127 2886 T (K) 100 100 296 100 100 100 100 100 100 R1 0.0626 0.0642 0.0352 0.0338 0.0317 0.0461 0.0419 0.0341 0.0367 w R2 0.1002 0.1380 0.0920 0.0893 0.0894 0.1271 0.0938 0.0889 0.0917 GOF 1.095 1.070 1.024 1.043 1.040 1.097 1.021 1.054 1.022

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153 Figure 3.22. Dissolution profiles in water for lamotrigine and crystal forms 2-5 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5 050100150200 Time (min)Concentration (mg/mL) Lamotrigine:Saccharin (5) Lamotrigine Lamotriginenicotinamide (3) Lamotriginemethylparaben form II (2) Lamotriginenicotinamide hydrate (4) Figure 3.23. Dissolution profiles at pH = 1 for lamotrigine and crystal forms 2-5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 050100150200Time (min)Concentration (mg/mL Lamotrigine Lamotrigine:nicoinamide (3) Lamotrigine:saccharin (5) Lamotrigine:methylparaben form II (2) Lamotrigine:nicoinamide hydrate (4) 3.3. Solubility and Dissolution Study As shown in Figures 3.22. and 3.23., solubility and dissolution studies were conducted for 2, 3, 4, 5 and pure lamotrigine. The solubility of 5 has been reported

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154 elsewhere32 and is re-examined in this study. The maximum concentration of pure lamotrigine in water and pH 1 HCl solution differ by approximately 10% with the higher solubility of lamotrigine exhi bited under more acidic conditions The dissolution study in water revealed that 5 reached a maximum concentra tion of ca. 0.45 mg/ml. This observation is in agreement with the re ported literature aqueous solubility.65 However, given that the solubility of lamotrigin e increases under more acidic conditions, the improved solubility of 5 in water might be rationalized by the inadvertent decrease in pH due to the dissolution of saccharin. The maxi mum concentrations of the other crystal forms in water were ca. 0.21 mg/ml, 0.30 mg/ml, 0.23 mg/ml, and 0.28 mg/ml for 2 3 4 and pure lamotrigine, respectiv ely. It was also found that 4 exhibited the lowest concentration in water after 4 hours, which is not surprising as hydrates are typically considered to be less soluble than the corresponding anhydrate.4, 66 An examination of the dissolution profile s generated at pH 1 indicates that 2 sustains the highest concentration throughout the four-hour study achieving a maximum concentration of ca. 3.8 mg/ml. 4 however, also reaches a maximum concentration of ca. 3.8 mg/ml after only 5 minutes, but it then proc eeds to decline over th e remainder of the study. This particular type of profile is a product of the “s pring and parachute effect” and has been exhibited by a number of phar maceutical cocrystals reported recently.13, 67, 68 This profile is significant because it shows that a greater concentration of API can be achieved at a much faster rate depending upon the crystal form. A similar trend is also exhibited by 4 under aqueous conditions; however, the maximum concentration of 4 was less than that of pure lamotrigine. A slurry of 3 stirred for 5 minutes in acidic media, achieved a concentration ca. 36% greater than pure lamotrigine. Interestingly, 5 which

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155 exhibits the highest concentration in aqueous solution, achieves the lowest concentration in acidic media (1.3 mg/ml). Overall, the disso lution profiles revealed that, in pure water, 5 is the most soluble crystal form but under acidic conditions (pH = 1), 2 is the more soluble crystal form. A recently published article suggests that the solubility of the co crystal is directly proportional to the solub ility of its components,69 more specifically, the solubility ratio plotted against the solubility of the cocrysta l former divided by the solubility of the API should result in a linear relationship. A similar analysis of crystal forms 2-5 reported herein, however, does not generate a linear plot. In fact, within this set of case studies, no clear correlation exists with respect to the so lubility of the salt/cocrystal former and the solubility of the resulting crystal form. Th e aqueous solubility of nicotinamide is ca. 1 g/ml, the highest of all cocrystal former s studied (methylparaben = 1 g/400ml and saccharin = 1 g/290ml), and it is also a hydrotrope that is frequently used for solubility improvement,70 however, the crystal form s containing nicotinamide ( 3 and 4 ) are not the most soluble in aqueous solutions. Instead 5 is the most soluble crystal form most likely due to the acidic saccharin molecule alte ring the pH of the solution to favor the dissolution of lamotrigine. The low correlati ons may be due to the small dataset or the inclusion of both protonated and unprot onated species in the dataset. Correlations between solubility and crys tal packing were al so investigated. 5 which breaks motif 1, achieved a greater c oncentration in water than under acidic conditions (pH = 1). 2 and 4 which break motif 2, show markedly improved concentrations in the acidic so lution (pH = 1) but exhibited mu ch lower concentrations in water. Based on this dataset it can be conc luded that, for this particular case study,

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156 lamotrigine cocrystals that break motif 2 are more soluble than pure lamotrigine under acidic conditions (pH = 1) while lamotrigine salts that break motif 1 are more soluble than pure lamotrigine in aqueous solutions. Ho wever, the enhanced aqueous solubility of 5 may be attributed to the inhe rent acidity of saccharin. 3.4. Animal Pharmacokinetic (PK) Study A single dose rat pharmacokinetic study was conducted by Vasyl Sava and Shijie Song at the James A. Haley VA hospital in Tampa. The serum concentration of lamotrigine that resulted from single-dose oral gavage of 3 4 5 and pure lamotrigine was measured in Sprague-Dawley rats over a 24-hour time period (Figure 3.24). 2 was not studied due to its instability after three m onths of aging at 40 C in variable humidity. An examination of the serum concentrations after dosing with 3 4 and 5 shows that the PK profile can be s ubstantially altered via cocrystal or salt formation. Two hours after dosing the average serum concentration of 5 was 3.5 g/ml which is ca. 1.5 times the level shown for pure lamotrigine (2.3 g/ml). 3 and 4 showed a decrease in the serum concentration by ca. 40% and 68%, respectively, compared to the pure lamotrigine. The area under the curve (AUC0-24hr) for 3 4 5 and pure lamotrigine was calculated to be 37, 26, 66, and 60 g/ml, respectively. A comparison of the average serum concentrations reveals that 5 is clearly the desired crystal form for further pharmaceutical development as 5 exhibits the highest initial serum c oncentration and achieves the greatest AUC0-24hr.

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157 Figure 3.24. Rat serum concentrations of lamotrigine, 3, 4 and 5 An analysis of the serum concentrations for 3, 4, and 5 in the rat in terms of crystal packing concluded that 5, which broke motif 1, experienced an initial boost in serum concentration of lamotrigine. Meanwhile, serum levels for cocrystals 3 and 4, which retained the aminopyridine dimer and br oke motif 2, were an average of ca. 54% less than that of pure lamotrigine, thus sugge sting that crystal forms that break motif 1 could exhibit higher serum concen trations than forms that br eak motif 2. Interestingly, the greatest improvements in the PK study and the dissolution study occur when the aminopyridine dimer is broken. This case st udy also illustrates that pharmaceutical cocrystals and salts can have a significant impact upon drug development as they can greatly alter the PK profile of the parent drugs. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5024681012141618202224 Time (hour)Serum concentration (ug/ml) Lamotrigine Lamotrigine:saccharin (5) Lamotriginenicoinamide (3) Lamotriginenicoinamide hydrate (4)

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158 3.5 Conclusions In summary, the work presented herein exemplifies how salt or cocrystal formers can generate novel crystalline forms of preexisting APIs with different physicochemical properties. Lamotrigine was targeted for crystal form development with the goal of improving its solubility and clin ical performance. Ten crystal forms of lamotrigine were developed via the supramolecula r synthon approach. The new cr ystal forms differed from pure lamotrigine in that either supramolecu lar synthon motif 1 (the aminopyridine dimer) or motif 2 (the amine-aromatic nitrogen hydrogen bond) were broken. Motif 2 was broken in 5 out of 10 structures (50%) while only 4 out of 10 structures (40%) broke motif 1. Interestingly, the majority of the cr ystal forms that did not contain motif 1, with the exception of 1, were all lamotrigine salts. Several crystal forms were tested to dete rmine solubility, dissolution rate and rat PK profiles. Out of ten crystal forms, four ( 2 3 4 and 5 ) were selected for dissolution studies and three ( 3 4 and 5 ) were selected for PK studies The solubility/dissolution study was conducted under aqueous conditions and under acidified (pH = 1) aqueous conditions. The dissolution profiles for 2 and 4 achieved concentration levels similar to lamotrigine in aqueous media while 3 maintained a concentration equivalent to the maximum solubility of lamotrigine. The average concentrations achieved from 2 3 4 and 5 during dissolution measurements from the acidic media surpassed the levels of pure lamotrigine by ca. 48%, 19%, 18%, and 58% resp ectively. In the ra t PK study, the serum concentrations for 3 and 4 were less than pure lamotrigine by 37% and 26%, respectively. 5 however, exhibited an initia l increase in the serum con centration of ca. 66%. After

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159 approximately 3 hours the serum concentration of 5 reduced to a level similar to that of pure lamotrigine. The influence of a particular cocrysta l former upon solubility and rat PK was examined. The analysis compared the solubility of the cocrystal former and the solubility and serum concentration of the subsequent cr ystal form. For this dataset, the most soluble cocrystal former did not lead to th e most soluble crystal form. In addition, a comparison of the rat PK data to the solubility of the crystal form revealed that the crystal forms that achieved the greatest aqueous solubility also reached the highest concentrations in the rat PK da ta. The solubility of the crystal form in the acidic solution did not correspond to the PK data. The influence of supramolecular synthon motif upon solubility and PK was also examined. Of the crystal forms where th e solubility and rat PK was measured ( 3 4 5 ) the only crystal form that broke the aminopyridine dimer ( 5 ) also achieve d the highest concentration in aqueous soluti on and rat serum, suggesting th at breaking the lamotrigine aminopyridine dimer can lead to crystal form s with desirable physicochemical properties. Therefore when considering both aqueous disso lution and animal PK data of the crystal forms presented herein collectively, 5 exhibited the targeted physicochemical properties with substantial improvements, and would be an appropriate candidate for further development.

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160 3.6 Materials and Methods 3.6.1 Materials Lamotrigine was supplied by Jai Radhe Sale s, India with a purity of 99.79% and was used without further purification. All other chemicals were supplied by SigmaAldrich and used withou t further purification. 3.6.2 Synthesis of Compounds 1-10 Lamotrigine was reacted with six compounds shown in Figure 3.1, namely methylparaben, nicotinamide, saccharin, adip ic acid, L-malic acid, and nicotinic acid, resulting in the formation of ten crystalline co crystals, salts, or solvates of lamotrigine. Synthesis of lamotrigine methylparaben cocrystal form I (1:1), 1 0.0117 g (0.046 mmol) lamotrigine and 0.0750 g (0.490 mmol) methylparaben were dissolved in ca. 2 ml tetrahydrofuran (THF) and left to evaporate at room temperature. Colorless crystals were afforded within seven days. 1 crystallized concomitantly with methylparaben and lamotrigine THF solvate. Single crystals of 1 were isolated from this mixture. Synthesis of lamotrigine methylparaben cocrystal form II (1:1), 2 This cocrystal was made via multiple methods: (i) solvent-drop grinding – 0.0722 g (0.282 mmol) lamotrigine was ground with 0.0458 g (0.301 mmol) methylparaben with 40 l of THF for 30 minutes in a mechanical ball-mill with ca. 100% conversion; (ii) slurry – 0.0486 g (0.190 mmol) lamotrigine and 0.0294 g (0.193 mmol) methylparaben were slurried with ca. 3 ml water at room temperature for 24 hours. 2 was isolated via filtration in 70% yield; (iii) melt – 0.0751 g (0.293 mmol) lamotrigine and 0.0485 g

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161 (0.319 mmol) methylparaben were placed in an oven at 115 C for 2 hours. 2 was obtained via slow cooling to room temperatur e in 97% yield. Singl e crystals of X-ray diffraction quality were obtained from slow cooling of the melt. Synthesis of lamotrigine nicotinamide cocrystal (1:1), 3 This cocrystal was prepared via multiple methods: (i) so lvent-drop grinding – 0.2081 g (0.813 mmol) lamotrigine and 0.2056 g (1.68 mmol) nicotinamide were ground with 40 l of methanol for 30 minutes in a mechanical ball-mill with ca. 100% conversion; (ii) melt – 0.7105 g (2.77 mmol) lamotrigine and 0.3496 g (2.86 mmol ) nicotinamide were heated at 125 C for 2.5 hours resulting in 98% yield; (iii) lamotrigine nicotinamide cocrystal hydrate, 4 can be dehydrated to isolate 3 after heating at 160 C for 6 hours. Synthesis of lamotrigine nicotinami de cocrystal monohydrate (1:1:1), 4 This cocrystal was made from two methods: (i ) slurry – 0.0641 g (0.250 mmol) lamotrigine and 0.0614 g (0.503 mmol) nicotinamide (1:2 mola r ratio) were slurri ed with ca. 1 ml ethyl acetate for 24 hours. The resulting soli d was isolated and filtered for further use with 92% yield; (ii) solution – 0.1021 g (0.399 mmol) lamotrigine and 0.0515 g (0.422 mmol) nicotinamide dissolved in 600 l of n-butanol and left to slowly evaporate at room temperature. Colorless crystals of 4 were formed within two weeks in 95% yield. The crystals were dehydrated in an oven at 160 C for 6 hours to form anhydrous cocrystal 3 Synthesis of lamotrigine saccharinate salt (1:1), 5 This salt was made via multiple methods: (i) slurry – 50.20 g (196 mmol) lamotrigine and 35.50 g (194 mmol) saccharin were slurried in 500 mL water ov ernight under ambient conditions. The solid was isolated via filtration in 83% yield. (ii) solution – 0.0102 g (0.040 mmol) lamotrigine and 0.0103 g (0.056 mmol) saccharin were dissolved in ca. 2 ml methanol

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162 and slowly evaporated at room temp erature. Colorless crystals of 5 were afforded within seven days in 94% yield. Synthesis of lamotrigine adipate salt (2:1), 6. 0.0158 g (0.062 mmol) lamotrigine and 0.0108 g (0.074 mmol) of adipic acid were dissolved in ca. 2 ml methanol and left to slowly evaporate at room temperature. Colorless crystals of 6 appeared within seven days in 91% yield. Synthesis of lamotrigine malate salt (1:1), 7 0.0199 g (0.078 mmol) lamotrigine and 0.0120 g (0.089 mmol) L-malic acid were dissolved in ca. 2 ml methanol and left to slowly evaporate at room temperature. Colorless crystals of 7 appeared within seven days in 92% yield. Synthesis of lamotrigine nicotina te dimethanol solvate (1:1:2), 8 A solution of ca. 2 ml methanol, 0.0148 g (0.058 mmol) lamotrigine and 0.0075 g (0.061 mmol) nicotinic acid was left at room temperature to slowly evaporate. Colorless crystals of 8 formed after two days in 78% yield. Synthesis of lamotrigine dimethanol solvate (1:2), 9 0.0213 g (0.083 mmol) lamotrigine and 0.0148 g (0.082 mmol) butylated hydroxyanisole were dissolved in ca. 2 ml methanol and left to slowly evaporate at room temperature. Colorless crystals of 9 were afforded within five days in 93% yield. Synthesis of lamotrigine et hanol monohydrate (1:1:1), 10 0.0819 g (0.320 mmol) lamotrigine and 0.0415 g (0.340 mmol) nico tinamide were dissolved in ca. 3 ml of a 1:1 ethanol:water solution mixture while heating followed by rapid cooling. The sample was left at room temper ature and allowed to slowly ev aporate. Colorless crystals of 10 were afforded within two weeks in 74% yield.

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163 3.6.3 Crystal Form Characterization Single-Crystal X-ray Diffraction: Sing le crystals were obtained for nine compounds. Attempts to crystallize 3 did not afford crystals suitable for single crystal Xray crystallographic analysis. Single crystal analysis for 1 2 and 5-10 was performed on a Bruker-AXS SMART APEX CCD diffractom eter with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low-temperature device while 4 was collected using Cu K radiation ( = 1.54178 ). Data for 1 2 and 5-10 were collected at 100 K. Data for 4 was collected at 296 K. Lattice parameters were determined from least-squares analysis, a nd reflection data were integrated using SAINT.71 Structures were solved by direct methods and refined by full matrix least squares based on F2 using the SHELXTL package.72 All non-hydrogen atoms were refined with anisotropic displacement para meters. All hydrogen atoms bonded to carbon, nitrogen, and oxygen atoms were placed geomet rically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. Hydrogen atoms bonded to methyl groups were placed geometrically and refined with an isotropic displacement parameter fixed at 1.5 times Uq of the carbon atoms. Powder X-Ray Diffraction (PXRD): 2-8 were characterized by a D-8 Bruker Xray Powder Diffractometer using a Cu K radiation ( = 1.54178 ), 40kV, 40mA. Data was collected over an angular range of 3 to 40 2 value in continuous scan mode using a step size of 0.05 2 value and a scan speed of 1.0 /min. Crystal form 1 could not be made in sufficient quantities to collect an experimental PXRD.

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164 Calculated PXRD: Calculated PXRD diffractograms were generated from the single crystal structures us ing Mercury 1.5 (Cambridge Cr ystallographic Data Centre, UK) for the following complexes: 1-2 4-10 Differential Scanning Calorimetry (DSC): Differential Scanning Calorimetry was performed on a Perkin Elmer Diamond DSC with a typical scan range of 25 C – 280 C, scan rate of 10 C/min, and nitrogen purge of ca. 30 psi. Fourier Transform Infrared Spectroscopy (FT-IR): FT-IR analysis was performed on a Perkin Elmer Spectrum 100 FT-IR spectrometer equipped with a solidstate ATR accessory. Ultraviolet-Visible Spe ctroscopy (UV/Vis): UV/Vis analysis was performed on a Perkin Elmer Lambda 25 UV/Vis spectrophotometer. High Performance Liquid Chromatography (HPLC): Analysis was performed on an HPLC system (Perkin Elmer Instru ments LLC) comprising the following units: a series 200 Gradient Pump; a 785A UV/VIS Det ector; a series 200 Autosampler; an NCI 900 Network Chromatography Interface and a 6 00 Series Link. The system was operated by a Total Chrome Workstation. The sample hol der temperature was kept at 4 C with a flow rate of 1 mL/min. The column wa s a Microsorb-MV 300-5 C-18 (250 x 4.6 mm x 1/4”). The mobile phase consisted of a mixture of phosphate buffer (pH 3.0) with methanol (1/1, v/v). The phosphate bu ffer was prepared from 50 mmol/L Na2HPO3 water solution with pH-contro lled HCl titration. Thermal Gravimetric Analysis (TGA): TGA analysis was performed on a Perkin Elmer STA 6000 with a typical scan range of 30 C – 300 C scan rate of 10

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165 C/min, and nitrogen purge of ca. 20 psi. The resulting thermograms were processed using Pyris version 9. 3.6.4 Solubility and Dissolution Study Dissolution studies were performed on 2 3 4 and 5 allowing for representative crystal forms from different crystal form categor ies (i.e. salt, cocrysta l and solvate) to be compared against the original API. Both deionized water (25 C) and pH 1 aqueous solution (0.1 M HCl, 37 C) were used. Th e crystal forms were sieved to achieve a particle size between 53 and 75 m. The dissolution study was conducted using an excess of free flowing solid in ca. 100 ml solv ent that was stirred with a magnetic stir bar at a rate of ca. 200-300 rpm. A liquots were filtered with 0.45 m filters after 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150, 180, and 240 minutes. The resulting solution was processed and the concentration of lamo trigine was measured using a UV-Vis spectrophotometer. The experiment was repeat ed twice to allow for statistical analysis. 3.6.5 Animal Pharmacokinetic (PK) Study Twenty-four hour animal PK studies we re conducted using a single-dose oral administration of lamotrigine as well as 3 4 and 5 5 male Sprague-Dawley rats (225250 g) with pre-implanted indw elling jugular vein catheters were used for each crystal form. The animals were allowed water ad libitum and fasted overnight before drug administration. The crystal forms were administered via oral gavage with a dosage of 10 mg/kg lamotrigine or its equivalent, in th e suspension vehicle of a 5% PEG and 95% methyl cellulose aqueous solution. After dos ing, 0.2 ml of blood was withdrawn at 0, 30,

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166 60, 120, 180, 240, 480, 720, and 1440 minutes. The bl ood samples were processed and analyzed by HPLC according to the literature.73 Table 3.4. Hydrogen bond distances and parameters Compound Hydrogen Bond d(H...A)/ d(D...A)/ / 1 NH O 1.97 2.823(4) 162.7 OH N 1.83 2.651(4) 164.7 OH N 2.72 3.545(4) 167.1 2 NH O 2.20 3.036(4) 157.4 NH O 2.13 2.931(4) 151.3 NH O 2.49 3.116(4) 129.1 NH N 2.25 3.121(4) 172.3 OH N 1.88 2.711(4) 173.3 4 NH O 2.06 2.915(3) 176.7 NH N 2.43 3.192(3) 148.3 NH O 2.09 2.930(2) 165.3 NH N 2.35 3.164(3) 157.5 NH O 2.28 2.944(2) 133.7 NH N 2.24 3.039(2) 154.1 OH N 1.97 2.822(2) 171.7 OH N 2.16 3.039(3) 166.4 5 NH O 2.05 2.818(2) 144.7 NH O 1.95 2.830(2) 173.5 NH N 1.94 2.819(2) 177.5 NH O 2.19 2.889(2) 135.5

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167 6 NH O 1.93 2.760(2) 156.5 NH O 2.06 2.861(2) 151.5 NH O 2.11 2.942(2) 157.4 NH O 1.79 2.6270(19) 158.0 7 NH N 2.08 2.956(6) 174.6 NH O 2.22 2.792(5) 122.2 NH O 2.09 2.790(5) 136.3 NH O 1.91 2.786(6) 174.5 NH O 1.86 2.707(5) 161.9 NH N 2.21 3.082(6) 168.6 NH O 2.11 2.968(5) 164.1 NH O 2.14 2.928(5) 149.5 NH O 1.88 2.754(5) 175.0 NH O 1.77 2.632(5) 167.8 OH O 2.09 2.744(5) 134.6 8 NH O 1.88 2.729(3) 161.7 NH O 1.88 2.755(3) 171.9 NH O 2.01 2.816(3) 151.3 NH O 2.06 2.872(3) 152.8 NH O 1.92 2.764(3) 159.4 OH O 1.97 2.777(2) 159.6 OH N 1.86 2.699(3) 172.7 9 NH O 2.21 2.824(2) 126.7 NH N 2.19 3.059(2) 170.0 NH O 2.11 2.8621(18) 143.1 NH O 2.24 2.930(2) 135.7

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168OH N 1.82 2.654(2) 169.9 OH N 2.16 2.9874(19) 168.6 10 NH O 2.35 3.0422(18) 136.2 NH O 1.97 2.8481(18) 173.2 NH O 2.29 2.9276(18) 128.8 NH N 2.19 3.0055(19) 153.7 OH N 2.10 2.9014(18) 158.5 OH O 1.94 2.8288(17) 178.8 OH N 1.95 2.7919(18) 168.2 NH O 2.52 3.1870(18) 133.2 3.7. References Cited (1) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C., Journal of Pharmaceutical Sciences 1977, 66 1. (2) Zaworotko, M.; Arora, K., Pharmaceu tical co-crystals: A new opportunity in pharmaceutical science for a long-known but little studied class of compounds. In Polymorphism in Pharmaceutical Solids 2nd ed.; Brittain, H. G., Ed. Informa Healthcare: 2009. (3) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W., Advanced Drug Delivery Reviews 2001, 48 3. (4) Khankari, R. K.; Grant, D. J. W., Thermochimica Acta 1995, 248 61. (5) Stahl, P. H.; Wermuth, C. G., Handbook of Pharmaceutical Salts: Properties, Selection, and Use WILEY-VCH: Zurich, 2002. (6) Almarsson, .; Zaworotko, M. J., Chemical Communications 2004 1889.

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174 (70) Alaa Abdul Rasool; Hu ssain, A. A.; Dittert, L. W., Journal of Pharmaceutical Sciences 1991, 80 387. (71) Bruker SMART, SAINT-Plus, SADABS, XP and SHELXTL Madison, Wisconsin, USA, 1997. (72) Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997. (73) Castel-Branco, M. M.; Almeida, A. M.; Falcao, A. C.; Macedo, T. A.; Caramona, M. M.; Lopez, F. G., Journal of Chromatography B 2001, 755 119.

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175 Chapter 4 Meloxicam crystal forms: Synthe sis, Characterization, and Evaluation 4.1. Preamble The ability to alter the physicochemical properties of an active pharmaceutical ingredient (API) by changing the crysta l form has had a major impact upon the pharmaceutical industry 1-3 and has lead to the developmen t of a crystal form screening process that is now a ro utine technology implemented to discover crystal forms including, but not limited to, salts,4 hydrates,5 solvates,6 and cocrystals7 with desired properties.8, 9 In this chapter a crystal engineering10-12 based crystal form screening process will be exploited to generate novel cr ystal forms of meloxica m with a particular focus upon generating pharmaceutical cocrystals13 with desired physicochemical properties. Meloxicam or (4-hydroxy-2-methyl -N(5-methyl-1,3-thiazol-2yl)-2H-1,2benzothiazin-3-carboxamide,1,1-dioxide) is a non-steroidal anti-i nflammatory (NSAID) and antipyretic drug used for indications of rheumatoid and osteoarthritis,14 postoperative pain15, 16 and fever.17 Originally developed by Boehringer Ingleheim, meloxicam is marketed in Europe under the brand names Mel ox or Recoxa. Meloxicam is available as a tablet (7.5 or 15 mg dose) and as an oral suspension (7.5mg/5ml dose).18 The pure active pharmaceutical ingredient (API) is a yell ow solid that is practically insoluble in water, but a greater solubility can be achie ved under more basic conditions. Meloxicam

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176 is also very slightly solubl e in various organic solvents.19 The variability in solubility related to change in pH is due to the different crystal forms of meloxicam. Under acidic conditions meloxicam is present in solution in its cationic form and in basic solutions meloxicam is present in its anionic form. Under more neutral pH conditions meloxicam will either be in its zwitterionic or enolic form, depending on the polarity of the solvent.20, 21 The different crystal fo rms are shown in Figure 4.1. Figure 4.1 Anionic, Cationic, and Zwitterionic forms of Meloxicam Meloxicam is effective at relieving various types of pain and patients experience fewer side effects with meloxicam than with other NSAIDS,22, 23 however, the drug can take more than two hours to reach a therapeutic concentration in humans.24 This may be caused by the inherently low solubility of meloxicam under acidic conditions such as S N O N S N O O O H H S N O N S N O O O H H S N O N S N O O O H H S N O N S N O O O H Meloxicam AnionMeloxicam Cation S N S N O O O O H N H H Meloxicam Zwitterion S N O N S N O O O H H S N O N S N O O O H H S N O N S N O O O H H S N O N S N O O O H Meloxicam AnionMeloxicam Cation S N S N O O O O H N H H Meloxicam Zwitterion

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177 inside the stomach. Meloxicam dissolves and is absorbed once in the more basic conditions of the small intestines, achieving a bioavailability of 89% with substantial protein binding.25 For meloxicam, the poor solubility of the API has been determined to be the rate limiting step in the absorp tion, distribution, metabolism, and excretion (ADME) process.26 Enhancement of meloxicam’s low aqueous solubility has been the subject of many publications re sulting in various solvates,27 ethanolamine salts,28 cyclodextrin inclusion complexs,26 or metal complexes with potassium and calcium.29 Other crystal forms include amm onium salts and sulfate salts.20 Preparation of different polymorphic crystal forms of meloxicam21 and improvements to the dissolution profile30, 31 are also discussed in recent patent literatu re. Due to the low solubility of meloxicam impairing the absorption, the goal is to improve the solubility of meloxicam via pharmaceutical cocrystallization to potentia lly reduce the time needed for absorption. With a faster absorption rate the patient will reach therapeu tic levels in the bloodstream and achieve efficacy in less than two hours. 4.2. Results and Discussion 4.2.1. Reliability of Cocrystal or Salt Formation A literature search for crystal forms of meloxicam provided numerous examples including pharmaceutical salts such as those generated via complexation with mono-, di-, and triethanolamine.28, 32 Due to the plethora of preexisting salt forms in the scientific literature that do not show ear lier efficacy, the purpose of this study was to generate pharmaceutical cocrystals of meloxicam as studi es have shown that they can increase the plasma concentration at early time points.33-40 The pKa values for meloxicam are 1.09

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178 and 4.18.32 The 1.09 is associated with the eno lic OH group while the 4.18 is linked to the nitrogen on the sulfathiazole ring. Th e enolic OH is much less accessible from a crystal engineering perspectiv e as it is involved in intramolecular hydrogen bonding to the neighboring ketone or NH moieties. Therefore a set of molecules containing carboxylic acid moieties were chosen as cocrys tal formers for their ability to potentially interact with the su lfathiazole ring. It is generally accepted as a rule that the difference in the pKa of the base minus the pKa of the acid must be less than zero if the desired outcome is a neutral complex (i.e. cocrystal).41, 42 To generate a salt one would select two molecules with a difference in pKa of three or more units.43, 44 For the region in between ( pKa 0-3) the ability to predetermine whether the resulting comple x will be neutral or charged is difficult.45 Due to the relatively acidic nature of the sulfathiazole moiety, there remains a fairly large library of molecules that possess a carboxylic aci d moiety that are also generally regarded as safe (GRAS) that can be employed to form pharmaceutical cocrystals of meloxicam. The carboxylic acids that were chosen for th is study include: 1-hydroxy-2-naphthoic acid (HNA), glutaric acid, L-malic aci d, aspirin, and salicylic acid. The acids are represented by line drawings in Figure 4.2. The pKa’s of the carboxylic acids that were chosen and the difference in pKa between meloxicam and the former are shown in Table 4.1.46-50 Based upon the rules described above all of the crystal forms reside in the ambiguous region thus a detailed analysis of the resulti ng crystal form will be required to determine salt or cocrystal formation.

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179 Table 4.1. pKa values and pKa values for meloxicam and a set of carboxylic acids Figure 4.2. Line drawings of the carboxylic acids used to form pharmaceutical cocrystals with meloxicam 1.16 AcidpKa pKa Meloxicam 4.18 3.02 4.13 3.46 0 0.05 0.72 HNA Glutaric acid L-Malic acid Asprin Salicylic acid 3.50 2.90 0.68 1.28 1.16 AcidpKa pKa Meloxicam 4.18 3.02 4.13 3.46 0 0.05 0.72 HNA Glutaric acid L-Malic acid Asprin Salicylic acid 3.50 2.90 0.68 1.28 AcidpKa pKa Meloxicam 4.18 3.02 4.13 3.46 0 0.05 0.72 HNA Glutaric acid L-Malic acid Asprin Salicylic acid 3.50 2.90 0.68 1.28 OH O HO O OH O HO OH O O HO OH O O O OH O OH OH 1-Hydroxy-2-Napthoic acidGlutaric acid L-Malic acid AspirinSalicylic acid OH O HO O OH O HO OH O O HO OH O O O OH O OH OH 1-Hydroxy-2-Napthoic acidGlutaric acid L-Malic acid AspirinSalicylic acid

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180 4.2.2. Cambridge Structural Database (CSD) Analysis A key step in developing pharmaceutical cocr ystals is to analyze the target active pharmaceutical ingredient (API) from a crystal engineering10 perspective, i.e. to analyze the molecule from a supramolecular synthon approach. This methodology partitions the target molecule into its simplest functionalities and statistically examines the percentage of occurrence of supramolecular homoand heterosynthons. The targeted supramolecular synthons are typically sust ained via hydrogen bonds as they are strong and directional in nature. The supramolecular synthon approach can be applied for the synthesis of novel pharmaceutical cocrystals of meloxicam. Th e strategy involves an understanding of the supramolecular chemistry of meloxicam including the feasibility of supramolecular synthon formation therefore requiring an anal ysis of the supramol ecular synthons present in pure meloxicam. Form I of meloxicam, f ound in the Cambridge Structural Database (CSD)51 (Refcode: SEDZOQ) indicates that mel oxicam forms chains that are sustained by sulfonyl-amide dimers and sulfathiazole-alc ohol supramolecular synthons, shown in Figure 4.3. The chains are held together by various weak in teractions, stacking along the a -axis in a slipped fashion.

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181 Figure 4.3. Meloxicam chains sustained by sulfonyl-amide dimers and sulfathiazole-alcohol supramolecular synthons Thus for cocrystallization, one or all of these supram olecular synthon motifs must be interrupted. A target moiety for me loxicam is the aromatic nitrogen of the sulfathiazole and the NH of the neighboring amide. When in the proper conformation, these moieties have the abil ity to provide an ideal twopoint recognition site for an additional molecule that contains a donor a nd an adjacent acceptor such as a carboxylic acid or amide moiety. A CSD analysis52 was conducted that examined the percentage of supramolecular synthon formation of the amino-azole func tionality (5-membered ring containing a nitrogen and primary amine) with carboxylic ac id, primary amide, and alcohol moieties. Specifically the analysis examined the lik elihood of supramolecu lar homosynthon versus supramolecular heterosynthon formation. A sear ch of the CSD for entries containing the amino-azole moiety revealed 505 hits. Interestingly 214/505 or 42% exhibited the 2-pt recognition amino-azole supramolecular homosynthon dimer. Examining the CSD for

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182 entries containing both amino-azole and carboxylic acid moieties afforded 7 entries. The amino-azole supramolecular homosynthon was seen in only 1 out of the 7 entries (14%). The carboxylic acid dimer or catemer supramolecular homosynthon was not present in any of the 7 entries. The supramolecular he terosynthon, however, was exhibited in 4/7 or 57% of the time. Thus the amino-azole – ca rboxylic acid supramolecular heterosynthon is more likely to occur than the supramolecular homosynthon. Due to the potential for meloxicam to generate salts or neutral comp lexes the potential for the amino-azole to generate a supramolecular heterosynthon w ith a carboxylate was also examined. A search for crystal structures that contain both moieties resulted in 24 hits. The aminoazole supramolecular homosynthon appeared in only 1 entry (4%) where a carboxylate was also present. The carboxylate – am ino-azole 2-pt recognition supramolecular heterosynthon dimer was much more prominent, appearing in 13/24 or 54% of the entries. Thus the supramolecular hetero synthon is more likely to occur than the supramolecular homosynthon for an amino-azole in the presence of a carboxylate. The occurrence of supramolecular homosynthon vers us heterosynthon was also questioned in the presence of a primary amide moiety. Ho wever, only 1 entry was revealed in the CSD that contained both functionalities and ne ither supramolecular synthon was present precluding a conclusion of the reliability of supramolecular synthon formation. A search of the CSD for entries contai ning an amino-azole and alc ohol was also conducted. The two moieties were present in 38 entrie s with the amino-azole supramolecular homosynthon being the dominant interac tion. The alcohol su pramolecular synthon occurs in 5 out of 38 entries or 13% of the time. The supramolecular heterosynthon occurs in 6/38 entries (16%) while the am ino-azole supramolecular homosynthon occurs

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183 in 13/38 entries (43%). Clear ly with the supramolecular homosynthon occurrence greater than the supramolecular heterosynthon, the pot ential for cocrystal formation is low by employing a cocrystal former that contains an alcohol functional group. A summary of the results from the amino-azole moiety supramolecular homosynthon and heterosynthon formation is presented in Table 4.2. A closer look at the data gathered from the CSD reveals that many of the searches for the amino-azole moiety coupled with an additional functional group consisted of a relatively small number of entries. Furtherm ore, the conclusions from the data could be considered not statistically significant due to the lack of informati on. Therefore further CSD analysis was conducted employing a simp le azole (5-membered ring containing a nitrogen). The reliability of supram olecular heterosynthon versus homosynthon formation between an azole and a carboxylic acid, primary amide, and alcohol were examined in the CSD. Due to the inability of the azole to form a supramolecular synthon with itself; only the homosynthon formation of the carboxylic acid, primary amide, and alcohol moieties in the presence of an azole was examined. A search of the CSD for entries that contained an azole and a carboxylic acid moiety resu lted in 269 hits. A closer look at the 269 entries reveal ed that the carboxylic acid dime r or catemer occurred in 41 entries, or 15% of the time. However, wh en the 269 entries were investigated for the presence of the azole-carboxylic acid s upramolecular heterosynthon 120 entries were identified, suggesting that th e heterosynthon will occur 45% of the time. Thus when an azole and carboxylic acid are present in the same crystal structure the supramolecular heterosynthon is statistically more likely to occur. When complexing a carboxylic acid to a basic moiety were the pKa is large, the acid will prot onate the basic moiety, resulting

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184 in a carboxylate. Due to the possibility of protonation with meloxicam, carboxylate-azole interactions were also searched in the CS D. 56 entries contained both moieties. 20 (36%) contained the carboxylate-azole supr amolecular heterosynthon in the crystal structure, suggesting that it is a viable targ et supramolecular heterosynthon. A search of the CSD for the azole and primary amide moiety in the same crystal structure revealed 115 entries. 66 (58%) of those entries were found to contain the amide dimer or catemer while only 37 (32%) were sustained via the amide-azole supramolecular heterosynthon. These statistics elucidate the strength of the amide supramolecular homosynthon in the presence of the azole functional group and furt her indicate that a co crystal of meloxicam with a molecule containing a primary amide mo iety is unlikely to occur. The complexing of alcohols and azoles was also studied in the CSD. There were 977 entries that contained both moieties. 21% (202) po ssess the alcohol homos ynthon but 40% (386) were sustained by the supramolecular heterosynt hon formation. Statistically this suggests that the supramolecular heterosynthon is almost twice as likely to form as the homosynthon. Collectively comparing th e occurrence of the supramolecular homosynthon to the heterosynthon, the hetero synthon formation dominates in all cases except when in the presence of a primary amide. Carboxylic acid and alcohol functionalities proved to be quite reliable for generating supramolecular heterosynthons and can be complexed with an azole moiety ca. 40% of the time. The results of these searches are depicted in Table 4.3.

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185 Table 4.2. Percent occurrence for supramolecular hom osynthons and heterosynthons with aminoazoles in the presence of carboxylic acids, carboxylates, primary amides, and alcohols Table 4.3. Percent occurrence for supramolecular hom osynthons and heterosynthons with azoles in the presence of carboxylic acids, carboxylates, primary amides, and alcohols Based on the success rate of supramolecu lar heterosynthon formation with azoles and carboxylic acids, a meloxicam cocrystal sc reen with cocrystal formers containing carboxylic acid moieties was conducted. Me loxicam was reacted with 1-hydroxy-2naphthoic acid, glutaric acid, L-malic acid, aspirin, and salicylic acid. The cocrystallization attempts resulted in seve n crystal forms, namely meloxicam 1-hydroxy2-naphthoic acid cocrystal, me loxicam glutaric acid cocrys tal, meloxicam L-malic acid cocrystal of a salt, meloxicam aspirin cocrysta l, meloxicam salicylic acid cocrystal form Complemen tary Moiety No. of entries w/ both groups % Homosynthon occurrence: amino-azole % Homosynthon occurrence: Cocrystal former % Heterosynthon occurrence Heterosynthon Distance Range () Carboxylic acid 7 1/7 (14%) 0 4/7 (57%) 2.60-2.80 Carboxylate 24 1/24 (4%) N/A 13/24 (54%) 2.60-2.80 Primary amide 1 0 0 0 N/A Alcohol 38 13/38 (43%) 5/38 (13%) 6/38 (16%) 2.60-3.00 Complementary Moiety No. of entries w/ both groups % Homosynthon occurrence: Cocrystal former % Heterosynthon occurrence Heterosynthon Distance Range () Carboxylic acid 269 41/269 (15%) 120/269 (45%) 2.50-2.90 Carboxylate 56 N/A 20/56 (36%) 2.60-2.90 Primary amide 115 66/115 (58%) 37/115 (32%) 2.60-3.30 Alcohol 977 202/977(21%) 386/977 (40%) 2.60-3.00

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186 I, II, and III. All crystal forms were analyzed in te rms of supramolecular synthons as well as physical and pharmacokinetic pr operties and are pr esented herein. 4.2.3. Crystal Structure Descriptions The meloxicam 1-hydroxy-2-naphthoic acid cocrystal 1 crystallizes in the space group P The asymmetric unit contains one meloxicam and one 1-hydroxy-2naphthoic acid molecule. The basic supramol ecular unit is comprised of two meloxicam molecules and two 1-hydroxy-2-naphthoic acid molecules with the inversion center located in the center of th e meloxicam dimer (shown in Figure 4.4.). The meloxicam dimer is a common motif found in many meloxi cam cocrystals and is sustained by two planar meloxicam molecules inte racting via electrostatic inte ractions between the alcohol, ketone and sulfathiazole moieties. In 1 meloxicam sustains in tramolecular alcoholketone interactions and binds to the neighboring meloxicam via an S OH interaction at a distance of 3.148(6) to form the meloxica m dimer. The exterior of the meloxicam dimer hydrogen bonds to two 1-hydroxy-2-napht hoic acid molecules via two 2-point recognition carboxylic acid-thiazo le/NH interactions [O2-H2 N1: O N 2.596(6) , H N 1.763 , O-H N 170.90 , N2-H2 O2: N O 2.935(6) , H O 2.086 , NH O 161.66 ] This two point recognition supram olecular synthon motif is quite robust as it is found in all cocrystal forms repor ted herein. The hydroxyl group of the 1hydroxy-2-naphthoic acid ortho to the car boxylic acid moiety is involved in intramolecular hydrogen bonding which is expected based upon Etter’s rules.53 The overall packing, illustrated in Figure 4.5 is sustained by supramolecular units of

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187 meloxicam and 1-hydroxy-2-naphthoic acid mo lecules that stack upon each other along the a -axis in a slipped fashion with an interplanar spacing of 3.735 . Figure 4.4 Supramolecular unit of 1 Figure 4.5 Crystal packing of four supramolecular units of 1 Crystal form 2 is the meloxicam glutaric acid cocrystal The asymmetric unit of 2 is comprised of one meloxicam and one glut aric acid molecule and crystallizes in the space group P The meloxicam centrosymmetric dimer is also present in 2 and is sustained by an S OH interaction between two planar meloxicam molecules with a

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188 distance of 3.224(2) . Meloxi cam also participates in OH O (ca. 2.62 ) intramolecular hydrogen bonding. Interestingly, glutaric acid util izes one of its carboxylic acid moieties to form a cent rosymmetric carboxylic acid dimer [O4-H4 O3: O O 2.646(2) , H O 1.808 , O-H O 175.96 ] with a neighboring glutaric acid. The second free carboxylic acid moiety hydr ogen bonds to the meloxicam molecule resulting in the unexpected 1:1 stoi chiometery. The carboxylic acid-azole supramolecular heterosynthon dimer is su stained by hydrogen bond interactions that afford the common 2-point recognition motif. The OH N and NH O interaction are shown in Figure 4.6. [O2-H2 N1: O N 2.675(2) , H N 1.837 , O-H N 174.24; N2-H2 O1: N O 2.849(2) , H O 1.990 , 165.07]. The culmination of supramolecular homosynthon and heterosynt hon dimers ultimately results in the formation of a zig-zag ch ain that cuts through the ac -plane. The chains stack along the a axis and are separated by a meloxicam plan e to plane distance of 3.502 . Figure 4.7. highlights the crystal packing of multiple chai ns with the meloxicam dimers and glutaric acid dimers disposed in a columnar arrangem ent. The angle sustained between the C1C2-C3 of the glutaric acid molecule in 2 is atypical. The C1-C2-C3-C4 torsion angle in both polymorphs of pure glutaric acid is ca.170, however, in 2 ; the same angle is 52.89. A search of the CSD for additional glutaric acid cocrystals afforded multiple hits however; examining the glutaric acid molecules for the similar smaller torsion angle resulted in only two hits: caffeine glutar ic acid cocrystal (R EFCODE: EXUQUJ) and theophylline glutaric acid cocrystal (REFC ODE: XEJXIU). The conformations of the glutaric acid molecules pr esent torsion angles of 79.34 and 65.18, respectively.

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189 Figure 4.6. Meloxicam glutaric acid cocrystal ( 2 ) supramolecular synthons highlighting the meloxicam and glutaric acid dimers Figure 4.7. Crystal packing of multiple chains of 2

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190 The asymmetric unit of the meloxicam L-malic acid cocrystal of a salt ( 3) contains one meloxicam cation, one neutra l meloxicam, and one L-malate anion. 3 is therefore considered a cocrystal of a salt and crystallizes in the space group P 1. Based upon the pKa it was not predicted that the L-ma lic acid would protonate meloxicam, however, crystal forms do not always follow the pKa general guidelines. In 3 the meloxicam dimer persists but is unique as it is comprised of one cation and one neutral meloxicam and is sustained by two S OH interactions (3.20(2) , 3.28(2) ). Figure 4.8. illustrates the interactions between th e anion, cation, and neutral molecule. 3 is primarily sustained by the L-malate anion act ing as a bridge to connect the meloxicam dimers ultimately forming a chain. The L-mala te bridge protonates the sulfathiazole ring via the O-+HN interactions [O1-+H1-N1: O-+N 2.70(3) , H O 1.849 , O-+HN 168.90 ; O2-+H2-N2: O-+N 2.89(3) , H O 2.045 , O-+H-N 168.31 ] and hydrogen bonds to the sulfathiazole of the neutral meloxicam via OH N and NH O interactions [O4-H4 N4: O N 2.73(3) , H N 1.919 , O-H N 172.42 ; O5 H5N5: O N 2.90(3) , H O 2.078 , O-H N 160.08 ]. Thus the L-malate and meloxicams generate a 2D structure compri sed of chains that stack parallel along the a axis with an interplanar spacing of 3.176 , shown in Figure 4.9. The supramolecular chains exhibited by 3 are reminiscent of those seen in 2 which is unsurprising due to the employment of a diacid as a cocrystal former in both cocrystallization experiments. The supramolecular synthon analysis of 3 proves that the sulfathiazole ring and the NH of the amide is an excellent synthon recognition point for both carboxylic acids and carboxylates.

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191 Figure 4.8. Supramolecular synthons in 3 showing a neutral and cationic meloxicam and an anionic L-malate Figure 4.9. Stacked layers of the meloxicam L-malic acid cocrystal of a salt ( 3 ), L-malate anions are shown in green. The meloxicam aspirin cocrystal (4) crystallizes in the space group P 21/c. The asymmetric unit contains one meloxicam mol ecule and one aspirin molecule, shown in Figure 4.10. The meloxicam dimer is again present in 4 ; however, the planar meloxicam molecules are held into the dimer conforma tion at a distance of 3.632(2) apart by weak

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192 interactions. This distance is the furthest distance of all th e cocrystals in this study that contain the dimer. The primary interacti ons sustaining the cocrystal are the hydrogen bonds present between the carboxylic acid moie ty of the aspirin molecule and the sulfathiazole/NH moiety of the meloxicam. The resulting supramolecular heterosynthon is the 2-point recognition hydrogen b onded dimer which affords the basic meloxicam:aspirin supramolecular unit shown in Figure 4.10. The OH N hydrogen bond distance is 2.665(3) [O2-H2 N1: O N 2.665(3) , H N 1.850 , O-H N 173.36 ] and the NH O distance is 2.856(3) [N2-H2 O1: N O 2.856(3) , H O 2.015 , N-H O 165.60 ]. Additional meloxicam:aspirin supramolecular units are generated by translation along the 21 screw axis running parallel to the a -axis (Figure 4.11.). As the meloxicam:aspirin units extend along the a -axis they simulate a corrugated sheet that propagates with a dihedral angle of 73.69 . The corrugated sheets then stack upon each other separated by a distance of ca. 3.87 producing a herringbone motif. Figure 4.10. Meloxicam aspirin cocrystal ( 4 ) basic supramolecular unit

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193 Figure 4.11. Units of the meloxicam aspirin cocrystal ( 4 ) translating along a 21 screw axis The supramolecular unit of the meloxicam salicylic acid cocrystal form III (5) is comprised of one molecular meloxicam a nd one molecular salicy lic acid, shown in Figure 4.12. and crystallizes in the space group P 21/c. The cocrystal is primarily sustained by the salicylic acid hydrogen bonding to the meloxicam via the carboxylic acid to sulfathiazole/NH supramolecu lar heterosynthon. The carboxylic acidsulfathiazole OH N hydrogen bond distance is 2.627(5) [O2-H2 N1: O N 2.627(5) , H N 1.836 , O-H N 161.74 ] and the NH-carboxylic acid NH O distance is 2.975(5) [N2-H2 O1: N O 2.975(5) , H O 2.139 , N-H O 164.02 ]. This hydrogen bonding motif generate s a discrete unit contai ning one meloxicam and one salicylic acid molecule. Th e salicylic acid OH moiety is involved in intramolecular hydrogen bonding with its carboxylic acid. Th e meloxicam dimer does not exist in 5 as the meloxicam molecules in the neighbori ng supramolecular units are perpendicular rather than parallel. The supramolecular units in 5 translate along the 21 screw axis at a dihedral angle of 88.80 and are sustained by various weak interactions (Figure 4.13.). 5

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194 is the only cocrystal reported herein that does not exhibit the meloxicam dimer. The absence of the dimer may contribute to its unique solubility and pharmacokinetic properties. Single crystals of suitable quali ty for single crystal X -ray diffraction of the meloxicam salicylic acid form I ( 7 ) or form II ( 6 ) could not be obtained. Figure 4.12. Meloxicam salicylic acid cocrystal form III ( 5 ) 2-point recognition supramolecular synthon Figure 4.13. Meloxicam salicylic acid units translating along a 21 screw axis

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195 Table 4.4. Crystal structure parameters for cocrystals 1-5 4.2.4. Melting Point Analysis It has been shown that the melting point of the cocrystal can typically be found in between the melt of the cocrystal form er and the target active pharmaceutical ingredient.54, 55 Recent literature has also attempted to predict melting points56 and correlate melting points of materials to chemi cal structure of small simple molecules with some success.57 However, predicting melting poin ts of larger molecules such as pharmaceuticals proves to be a nontrivial task. 1 2 3 4 5 Chemical formula C14H13N3O4S2 C11H8O3 C14H13N3O4S2C5H8O4 C14H14N3O4S2 C14H13N3O4S2 C4H5O5 C14H13N3O4S2 C9H8O4 C14H13N3O4S2 C7H6O3 Form weight 539.60 483.51 836.88 531.55 489.50 Crystal System Triclinic Triclinic Triclinic Monoclinic Monoclinic Space group P P P1 P21/ c P21/ c a () 6.978(2) 7.202(3) 7.278(9) 6.8015(7) 11.1028(9) b () 12.135(2) 8.462(3) 8.550(2) 19.1397(2) 11.8549(9) c () 15.189(2) 18.428(7) 15.150(2) 18.752(2) 16.4728(2) (o) 113.07(3) 80.761(7) 84.11(2) 90 90 (o) 92.68(3) 85.486(7) 81. 62(4) 94.907(8) 97.255(6) (o) 95.85(2) 70.877(6) 70.489(15) 90 90 Vol (3) 1172(3) 1046.9(7) 877.6(19) 2432.1(4) 2150.8(3) Dcal (g cm-3) 1.529 1.534 1.583 1.452 1.509 Z 2 2 1 4 4 Reflections collected 2414 6350 3902 17777 15380 Independent reflections 2414 4554 3151 4302 3662 Observed reflections 1875 3752 1719 3163 2281 T (K) 100 100 298 293 293 R1 0.0471 0.0375 0.1124 0.0411 0.0556 w R2 0.1075 0.0973 0.2846 0.1015 0.1526 GOF 0.991 1.009 1.253 0.987 1.072

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196 The melting points of the meloxicam crystal forms 1-7 were measured via differential scanning calorime try (DSC) and compared to the melting points of both meloxicam and the respective cocrystal form er. The melting points of the cocrystal formers were obtained from materials safety datasheets.58-62 A summary of the results are presented in Table 4.5. The melting points for all the cocrystals were found to follow the trends found in the literature. The cocrystals melted a bove the melt of the cocrystal former and below the melting point of meloxicam. The polymorphic salicylic acid cocrystals resulted in similar melting points with little variation between crystal forms. A graphical representation of the data is s hown in Figure 4.12. where the melting point of the cocrystal is plotted vs. the melting point of the cocrystal former. The R2 value was calculated to be 0.7335 thus showing an overall good correlation between the melting points of the two materials. Table 4.5. Melting points for meloxicam, cocrystal formers, and there corresponding cocrystals Crystal form Melting point of former C Melting point of cocrystal C Meloxicam 254 254 1-Hydroxy-2-naphthoic acid 183 225 Glutaric acid 95 149 L-Malic acid 101 200 Aspirin 136 164 Salicylic acid form III 159 210 Salicylic acid form I 159 205 Salicylic acid form II 159 206

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197 Figure 4.14. Plot for analysis of melting point of cocrystal versus melting point of cocrystal former 4.2.5. Solubility and Dissolution Study Solubility and dissolution measurem ents of five cocrystal forms ( 1-5 ) and pure meloxicam were conducted at 37 C in pH 8 phosphate buffer. A pH 8 buffer was chosen because it is believed that meloxicam is abso rbed in the more basic conditions of the intestine where the most basic regions can reach a pH of 8.26, 63 A phosphate buffer was employed so that the pH of the solution c ould not vary with th e addition of acidic cocrystal formers. 6 was not tested because the cocrystal could not be made in gram level quantities. 7 was also not tested because it di d not pass 1 month of the accelerated stability test (40 C, uncontrolled humidity). The di ssolution profiles are shown in Figure 4.15. The maximum solubility achieved for pur e meloxicam after four hours was ca. 0.8 mg/mL which is similar to the reported literatu re solubility of (ca. 1 mg/mL in a pH 8 solution).27 The cocrystal that achieved the highest and lowest solubility after four hours Melting point of cocrystal former vs. cocrystal R2 = 0.7335125 145 165 185 205 225 245 265 050100150200250300 Melting point of cocrystal formerMelting point of cocrysta Meloxicam:Salicylic acid form I (6) Meloxicam:Salicylic acid form III (5) Meloxicam:L-Malic acid (3) Meloxicam:1-Hydroxy-2-naphthoic acid (1) Meloxicam:Aspirin (4) Meloxicam:Glutaric acid (2) Meloxicam Meloxicam:Salicylic acid form II (7)

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198 was 1 and 2 respectively. Since the project goal was to reduce the time it takes for the meloxicam to reach therapeutic levels, th e cocrystals that obtained the highest concentrations at the earliest time points were the most desirable. 3 reached a concentration of 1.06 mg/ml at the 5 minute tim e point, the highest of all the cocrystals tested. 5 was second with a concentration of 0.96 7 mg/ml after 5 minutes. Cocrystals 1 2 and 4 obtained similar low concentrations (ca. 0.4 mg/ml) and pure meloxicam reached a 0.100 mg/ml concentration after 5 minutes. The dissolution profile for 3 was an exemplary “spring and parachute” model that unfortunately experienced a receding concentr ation that decreased by half after 1 hour. The inflated early concentration was most likel y due to the high solubility of the cocrystal former, L-malic acid, which was the most sol uble cocrystal former in the pH 8 buffer solution (961 mg/ml). The spring and parachute type dissolution profile is becoming more of a common occurrence amongst cocrystals.55, 64-66 First shown by Childs in the dissolution of fluoxetine HCl succinic acid cocrystal,64 the spring and parac hute model portrays the ability of the cocrystal former to improve the solubility of the API at early time points. This can be advantageous for decreasing th e time required for the API to reach maximum concentration. Over time, at a rate that is cocrystal dependant, the cocrystal falls apart and the concentration in solution reduces back do wn to a level similar to that of the pure API. It has been postulated by Rodrguez-Hornedo that the ch ange in solubility of the API is related to the solubility of the cocrys tal former. Specifically, the solubility of the cocrystal former is directly proportional to the solubility of the related cocrystal.67 Her theory is predicated upon the analysis of a selected set of carbamazepine, theophylline,

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199 and caffeine cocrystals. To determine if he r findings were more of a general occurrence or an anomaly, the solubility of the cocrysta l formers employed herein were compared to the solubility of the resulting cocrystals. The solubility of glutaric acid, aspirin, 1-hydroxy-2-naphthoic acid, and salicylic acid were measured at 741, 14, 11, and 10 mg/ml, respectively. Based upon the observations with L-malic aci d one would expect that 2 (meloxicam glutaric acid cocrystal) would achieve the second highest initial solubility, but it did not. 5 with a cocrystal former solubility of 10 mg/ml was second, with a dissolution profile that was also a spring and parachute. Therefore the solubility of the cocr ystal former did not correlate to the solubility of the cocrys tals presented here. These findings are contradictory to recently published results.67 The maximum concentration achieved by 5 was 1.29 mg/ml after 20 minutes of slurring, which was greater than a 3-fold improvement over meloxicam. This improvement in solubility could provide th e improved absorption required for patients to reach an earlier efficacy. Intere stingly, the dissolution profile for 5 and 4 merge after approximately 1 hour and both cocrystals ma intain a similar concentration for the remainder of the study. This may be due to the hydrolysis of aspirin to salicylic acid in aqueous solutions. The dissolution profile for 1 was unique as the therm odynamic solubility was not obtained after 4 hours of slurring. The maximum concentration measured for 1 in this study was 1.35 mg/ml. 1 was also intriguing because the solid material remaining after the dissolution study was intact cocrysta l based on powder X-ray diffraction. The remaining solids post dissolution study for 2-5 and pure meloxicam were found to be

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200 meloxicam form I also based upon powder X-ray diffraction. The stability of 1 in solution is most likely a refl ection of its high melting point which is indicative of high lattice energy68 (225 C, the highest of all reported cocrystals). Figure 4.15. Dissolution profiles for meloxicam and five crystal forms in pH 8 buffer, 37 C 4.2.6. Animal Pharmacokinetic (PK) Study The single dose rat pharmacokinetic study wa s conducted by Vasyl Sava and Shijie Song at the James A. Haley VA hospital in Tampa. Samples 1-6 and pure meloxicam were tested. The plasma concentrations as a function of time are shown in Figure 4.16. 7 was not studied because the cocrystal lattice collapsed after 1 month of exposure to 40 C in uncontrolled humidity. The maximum plasma co ncentration achieved at the end of the 4 hour study was 60.9 g/ml by form 4 The concentrations for 3 and 6 were similar to the maximum obtained for meloxicam; however, a ll three crystal forms showed similarly low plasma levels averaging ca. 38 g/ml. The plasma concentration for 2 however, led to a Dissolution Profiles Meloxicam Crystal forms pH 8, 37C0 0.2 0.4 0.6 0.8 1 1.2 1.4 050100150200250Time (min)Concentration (mg/mL Pure Meloxicam Meloxicam:Aspirin (4) Meloxicam:Salicylic acid form III (5) Meloxicam:1-Hydroxy-2naphthoic acid (1) Meloxicam:Glutaric acid (2) Meloxicam:L-Malic acid (3)

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201 very intriguing profile. Duri ng the first hour of the study 2 had a profile similar to the meloxicam profile. But, during the last 3 hour s the concentration in creased at a faster rate than pure meloxicam resulting in a 4 hour plasma concentration that was 15 g/ml greater than pure meloxicam. An examination of the areas under the curve (AUC) for the cocrystals presented in this study shows that 4 has the highest AUC, followed by 1 The AUC’s for 3 and 6 are similar and greater than pure meloxicam, however, they exhibit the lowest for all cocr ystals in this study. 5 exhibits a similar profile to 1 but 5 experiences a much higher plasma concentra tion after 15 minutes. Since the goal of the study was to generate cocrystals with an earlie r onset of efficacy, the desired crystal form must show a plasma concentration at the earl iest time point that is equivalent to the maximum obtained by pure meloxicam. This criterion eliminates 1 and 4 even though they show the greatest AUCs because they take over an hour to reach their maximum concentrations. 5 is therefore the cocrystal to take further into additional studies. Interestingly, 5 obtains the highest plasma conc entration after 15 minutes and is also the most soluble cocrystal after a 10 mi nute slurry in pH 8 solution at 37C. The solubility of cocrystals 1-4 after 10 minutes and their pl asma concentrations after 15 minutes were examined further to determine if a general correlation existed between the solubility and plasma concentration. Figure 4.17. highlights the linear trend ( R2 = 0.8651) that can be drawn illustrating that the more soluble the cocrystal at 10 minutes the greater the improvement in plasma concentration at early time points. These results show that to quicken the onset of a drug that is well absorbed but has low solubility; a more soluble cocrystal will increase the earl y plasma concentrations such that the drug could reach therapeutic concentrat ions at a faster rate.

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202 Figure 4.16. Rat plasma concentrations after single dose administration of meloxicam and six cocrystals Figure 4.17. Cocrystal and meloxicam solubility versus rat plasma concentration Rat Plasma Concentrations of Meloxicam Crystal Forms0 10 20 30 40 50 60 70 050100150200250 Time (min)Concentration (microg/ml ) Meloxicam:L-Malic acid (3) Meloxicam:Aspirin (4) Meloxicam:1-Hydroxy-2naphthoic acid (1) Meloxicam:Salicylic acid form I (6) Meloxicam:Salicylic acid form III (5) Meloxicam:Glutaric acid (2) Pure Meloxicam Cocrystal solubility (10min) vs. plasma concentration (15min)R2 = 0.8561 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 0.000.200.400.600.801.001201.40 Solubility (mg/mL)Plasma concentration (microg/mL) Meloxicam:Salicylic acid form III (5) Meloxicam:L-Malic acid (3) Meloxicam:1-Hydroxy-2-naphthoic acid (1) Meloxicam:Aspirin (4) Meloxicam:Glutaric acid (2) Meloxicam

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203 4.3. Conclusions The ability to modify the physical propert ies of an API but still maintain its therapeutic attributes by alte ring the crystal form is an im portant area of research and discovery. In this contribution seven novel cr ystal forms of meloxi cam are presented and analyzed based upon their supramolecular synthons, melting points, solubility, and PK profiles. A prominent aspect of cocrystals 1-4 is the presence of the meloxicam dimer. The meloxicam molecules in 5 however, are juxtaposed such that the dimer cannot form. A salient feature in 1-5 is the 2-point recogniti on carboxylic acid-azole/NH supramolecular heterosynthon. An analysis of the melting points of 1-7 and the respective cocrystal formers illustrated that the melting points of the cocrystals were typically in between the melting points of meloxicam and the cocrystal former. The highest melting cocrystal, 1 was also the only cocrystal to remain intact throughout the solubility/dissolution study. The solubility and dissolution profiles for 1-5 showed that after 4 hours 1 was the most soluble and 2 was the least soluble cocrystal. The solubility of the cocrystal was not related to the solubili ty of the cocrystal former. Due to the purpose of the study, i.e. decrease the time taken for meloxicam to r each therapeutic concentrations, the greater solubility of the cocrystal at the early tim e points was of greater importance than the solubility at 4 hours thus narrowing the desirable cocrystal list down to 3 and 5 To select one both solubility/di ssolution and PK data was considered. The AUCs from the rat PK data were the lowest for 2 3 and 6 1 and 4 showed a plasma concentration that gradually incr eased over the 4 hour period resulting in therapeutic concentratio ns after approximately 30 minutes to 1 hour. 5 however, reached

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204 the therapeutic concentration after 15 minutes thus 5 would be the desired crystal form for future product development as it expe rienced the solubility and pharmacokinetic profile that is most likely to reduce the time needed to obtain the therapeutic concentration and patient efficacy. Unfort unately, there are known complications when aspirin, which hydrolyzes to salicylic aci d, is administered concomitantly with meloxicam. The acid causes an incr ease in the AUC by 10% and the maximum concentration increases by 24%. There is no explanation in the literature for this conundrum but results presented in this study indicate that the e ffect is most likely due to cocrystal formation. The cocrystals of meloxicam presented herein provide further evidence that cocrystals can change the physical and pharm acokinetic properties of an API. The greatest improvements in solubility and PK pr ofile were shown with meloxicam salicylic acid form III ( 5 ), however, due to the clinical warnings the meloxicam 1-hydroxy-2naphthoic acid cocrystal ( 1 ) would be taken further into clinical trials as the pharmacokinetic profile suggests that 1 will achieve similar efficacy after 30 mi nutes. 4.4. Materials and Methods 4.4.1. Materials Meloxicam was purchased from Jai Radhe Sales, India with a purity of 99.64% and was used without further purification. All other chemicals were supplied by SigmaAldrich and used withou t further purification.

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205 4.4.2. Synthesis of Compounds 1-7 Meloxicam was reacted with five cocrystal formers shown in Scheme 4.2. They were 1-hydroxy-2-naphthoic acid, gl utaric acid, L-malic acid, as pirin, and salicylic acid. The cocrystallization attempts resulted in se ven crystal forms. A ll of the crystal forms can be made from solvent-drop grinding and slurrying, however, only five crystal forms can be made from solu tion crystallization. Synthesis of meloxicam 1-hydroxy-2naphthoic acid cocrystal (1) – (a) solvent-drop grinding – 0.176 g (0.501 mmol ) meloxicam was ground together with 0.0957 g (0.508 mmol) of 1-hydroxy-2naphthoic acid and 40 l of tetrahydrofuran (THF) for 30 minutes in a ball-mill. 1 was generated in ca. 1 00% yield. (b) slurry – 0.700 g (1.99 mmol) meloxicam and 0.391 g ( 2.07 mmol)of 1-hydroxy-2-naphthoic acid were slurried in 3ml of THF overnight seal ed under ambient condi tions at ca. 250 rpm. The resulting solid was filtered and washed with THF. 1 was obtained in ca. 90% yield. (c) solution crystallization – 0.0176 g (0.0501mmol) meloxicam and 0.0095 g (0.505 mmol) of 1-hydroxy-2-naphthoic aci d dissolved in 10 ml of et hyl acetate and left to slowly evaporate. 1 was obtained in ca. 93% yield. Synthesis of meloxicam glut aric acid cocrystal (2) – (a) solvent-drop grinding – 0.179 g (0.511 mmol) meloxicam was ballmilled together with 0.0699 g (0.529 mmol) of glutaric acid and 40 l of chloroform for 30 minutes, producing 2 in ca. 100% yield. (b) slurry – 0.892 g (2.54 mmol) meloxicam and 0.351 g (2.66 mmol) of glutaric acid were slurried in 3 ml of ethyl acet ate overnight sealed under ambi ent conditions at ca. 250 rpm. The resulting solid was filtered a nd washed with ethyl acetate. 2 was made in ca. 96% yield. (c) solution crysta llization – 0.0194 g (0.0552 mmol ) meloxicam and 0.159 g (1.20

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206 mmol) of glutaric acid dissolved in 2 ml of ethyl acetate and left to slowly evaporate. 2 was isolated in ca. 89% yield. Synthesis of meloxicam L-malic acid cocrystal of a salt (3) – (a) solvent-drop grinding – 0.176 g (0.501mmol ) meloxicam was ground together with 0.0361 g (0.269 mmol) of L-malic acid and 40 l of THF for 30 minutes in a mechanical ball-mill. 3 was generated in ca. 100% yield. (b) slur ry – 0.897 g (2.55 mmol) meloxicam and 0.182 g (1.36 mmol) of L-malic acid were slurried in 3ml of THF overnight sealed under ambient conditions at ca. 250 rpm. The solid was filte red and washed with THF resulting in ca. 92% yield of 3 (c) solution crystallization – 0.0214 g (0.0609 mmol) meloxicam and 0.0416 g (0.301 mmol) of L-malic acid dissolved in 2 ml of a 1:1 mix of dioxane and ethyl acetate and left to slowly evapor ate. The resulting si ngle crystals of 3 were isolated in ca. 82% yield. Synthesis of meloxicam aspirin cocrystal (4) – (a) solvent-drop grinding – 0.182 g (0.517 mmol) meloxicam was ball-milled together with 0.0966 g (0.536 mmol) of aspirin and 40 l of chloroform for 30 minutes to obtain 4 in ca. 100% yield. (b) slurry – 0.905 g (2.56 mmol) meloxicam a nd 0.452 g (2.51 mmol) of aspiri n were slurried in 3ml of THF overnight sealed under ambient conditio ns at ca. 250 rpm. The resulting solid was filtered and washed with THF. 4 was isolated in 96% yield. (c) solution crystallization 0.0232 g (0.0660 mmol) meloxicam and 0.110 g (0.611 mmol) of aspirin dissolved in 8 ml of ethyl acetate and left to slowly evaporate, generating single crystals of 4 (ca. 35% yield) concomitantly with mel oxicam form I and aspirin. Synthesis of meloxicam salicylic acid form III (5) – (a) solvent-drop grinding – 0.174 g (0.495 mmol) meloxicam was ball-m illed together with 0.0724 g (0.524 mmol)

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207 of salicylic acid and 40 l of ethyl acetate for 30 minutes. 5 was synthesized in ca. 100% yield. (b) slurry – 0.876 g (2.49 mmol) me loxicam and 0.350 g (2.53 mmol) of salicylic acid were slurried in 2 ml of THF overni ght sealed under ambient conditions at ca. 250 rpm. The resulting solid was filtered and washed with THF. 5 was isolated in ca. 84% yield. (c) solution crys tallization – 0.0226 g (0.0643 mm ol) meloxicam and 0.0787 g (0.570 mmol) of salicylic acid was dissolved in 8 ml of a 6:2 mixture of ethyl acetate and dioxane, respectively, and left to slow ly evaporate. Single crystals of 5 (ca. 33% yield) grew concomitantly with meloxi cam form I and salicylic acid. Synthesis of meloxicam salicylic acid form I (6) – (a) solvent-drop grinding – 0.177 g (0.504 mmol) meloxicam was ball-m illed together with 0.0675 g (0.489 mmol) of salicylic acid and 40 l of THF for 30 minutes. 6 was made in ca. 100% yield. (b) slurry – 0.871 g (2.47 mmol) meloxicam and 0.3 52 g (2.55 mmol) of salicylic acid were slurried in 2 ml of methanol overnight se aled under ambient conditions at ca. 250 rpm. The resulting solid was filtered and washed with methanol. 6 was obtained in ca. 91% yield. Synthesis of meloxicam salicylic acid form II (7) – (a) solvent-drop grinding – 0.175 g (0.498 mmol) meloxicam was ball-m illed together with 0.0705 g (0.510 mmol) of salicylic acid and 40 l of chloroform for 30 minutes, generating 7 in ca. 100% yield. (b) slurry – 0.869 g (2.47 mmol) meloxicam and 0.356 g (2.58 mmol) of salicylic acid were slurried in 2 ml of ch loroform overnight sealed unde r ambient conditions at ca. 250 rpm. The resulting solid was filtered and washed with chloroform. 7 was isolated in ca. 89% yield.

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208 4.4.3. Crystal Form Characterization Single-Crystal X-ray Diffraction : Single crystals were obtained for five compounds. Attempts to crystallize 6 and 7 did not afford crystals suitable for single crystal X-ray crystallographic analys is. Single crystal analysis for 1-3 was performed on a Bruker-AXS SMART APEX CCD diffractom eter with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low-temperature device while 4 and 5 was collected using a Cu K radiation ( = 1.54178 ). Data for 1, 2 was collected at 100 K. Data for 35 was collected at 293 K. Lattice parameters were determined from least-squares analysis, a nd reflection data were integrated using SAINT.69 Structures were solved by direct methods and refined by full matrix least squares based on F2 using the SHELXTL package.70 All non-hydrogen atoms were refined with anisotropic displacement para meters. All hydrogen atoms bonded to carbon, nitrogen, and oxygen atoms were placed geomet rically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. Hydrogen atoms bonded to methyl groups were placed geometrically and refined with an isotropic displacement parameter fixed at 1.5 times Uq of the carbon atoms. Powder X-Ray Diffraction (PXRD) : 1-7 were characterized by a D-8 Bruker Xray Powder Diffractometer using a Cu K radiation ( = 1.54178 ), 40kV, 40mA. Data was collected over an angular range of 3 to 40 2 value in continuous scan mode using a step size of 0.05 2 value and a scan speed of 1.0 /min. Calculated PXRD : Calculated PXRD diffractograms were generated from the single crystal structures us ing Mercury 1.5 (Cambridge Cr ystallographic Data Centre, UK) for the following complexes: 1-5 for comparison to the bulk sample.

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209 Differential Scanning Calorimetry (DSC) : Differential Scanning Calorimetry was performed on a Perkin Elmer Diamond DSC with a typical scan range of 25 C – 280 C, scan rate of 10 C/min, and nitrogen purge of ca. 30 psi. Fourier Transform Infrared Spectroscopy (FT-IR) : FT-IR analysis was performed on a Perkin Elmer Spectrum 100 FT-IR spectrometer equipped with a solidstate ATR accessory. Ultraviolet-Visible Spectroscopy (UV/Vis) : UV/Vis analysis was performed on a Perkin Elmer Lambda 25 UV/Vis spectrophotometer. High Performance Liquid Chromatography (HPLC) : Analysis was performed on an HPLC system (Perkin Elmer Instru ments LLC) comprising the following units: a series 200 Gradient Pump; a 785A UV/VIS Det ector; a series 200 Autosampler; an NCI 900 Network Chromatography Interface and a 6 00 Series Link. The system was operated by a Total Chrome Workstation. The sample hol der temperature was kept at 4 C with a flow rate of 1 mL/min. The column wa s a Microsorb-MV 300-5 C-18 (250 x 4.6 mm x 1/4”). The mobile phase consisted of a mixture of phosphate buffer (pH 3.0) with methanol (1/1, v/v). The phosphate bu ffer was prepared from 50 mmol/L Na2HPO3 water solution with pH-contro lled HCl titration. 4.4.4. Solubility and Dissolution Study Dissolution profiles and thermodynamic sol ubility were obtained for five crystal forms ( 1-5 ) in pH 8 phosphate buffer at 37 C. The study was conducted using excess free flowing solid, stirring with a magnetic st ir bar at a rate of ca. 250-300 rpm. The solids were sieved to achiev e a particle size between 53-75 m. Aliquots were taken out

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210 after 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150, 180, and 240 minutes and filtered with 0.45 m filters. The resulting solution was processed and the concentration of meloxicam was measured using a UV/Vis spectrophotometer. The experiment was repeated twice to allow for statistical analysis. 4.4.5. Animal Pharmacokinetic (PK) Study Six crystal forms ( 1-6 ) were submitted for pharmacokinetic analysis via a single dose oral gavage administration to Sprague-Daw ley rats (225-250 g). The rats were preimplanted with jugular vein catheters for withdrawing of blood samples. The animals were allowed water ad libitum and fasted overnight before drug administration. The crystal forms were administered a dosage of 10 mg/kg of meloxicam or meloxicam cocrystal, in the suspension vehicle of a 5% PEG and 95% methyl cellulose aqueous solution. After dosing, 2 ml of blood was withdrawn at 0, 15, 30, 45, 60, 120, and 240 minutes. The blood samples were processed and analyzed by HPLC according to the literature procedure.71 Table 4.6. Hydrogen bond distances and parameters Compound Hydrogen Bond d(H...A)/ d(D...A)/ / 1 N-H O 2.09 2.935(6) 161.7 O-H N 1.76 2.596(6) 170.9 O-H O 2.59 3.075(5) 118.3 O-H O 1.85 2.585(5) 145.8 O-H O 1.87 2.603(5) 145.1

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211 2 O-H O 2.45 2.917(2) 115.9 O-H N 1.84 2.675(2) 174.2 N-H O 1.99 2.849(2) 165.1 O-H O 1.81 2.646(2) 176.0 O-H O 1.89 2.6226(18) 144.4 3 N-H O 2.08 2.90(3) 159.9 N-H O 2.05 2.89(3) 168.5 N-H O 1.85 2.70(3) 169.0 O-H N 1.92 2.73(3) 172.3 O-H O 2.42 2.90(3) 117.8 N-H N 2.23 2.67(3) 112.1 O-H O 1.86 2.59(3) 148.4 O-H O 2.49 2.92(2) 114.1 O-H O 1.98 2.67(3) 141.4 O-H O 2.32 2.81(2) 119.5 O-H O 2.51 3.04(3) 123.8 4 O-H O 1.85 2.568(2) 145.7 N-H O 2.01 2.856(3) 165.6 O-H N 1.85 2.665(3) 173.4 5 N-H O 2.14 2.975(5) 164.0 O-H N 1.84 2.627(5) 161.7 O-H O 1.84 2.556(4) 145.7 O-H O 1.97 2.678(5) 143.9

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212 4.5. References Cited (1) Aldridge, S., Chemistry World 2007, 4 64. (2) Peterson, M. L.; Hickey, M. B.; Zaworotko, M. J.; Almarsson, ., Journal of Pharmacy and Pharmaceutical Sciences 2006, 9 317. (3) Byrn, S. R.; Pfeiffer, R. R.; Stephenson, G.; Grant, D. J. W.; Gleason, W. B., Chemistry of Materials 1994, 6 1148. (4) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C., Journal of Pharmaceutical Sciences 1977, 66 1. (5) Khankari, R. K.; Grant, D. J. W., Thermochimica Acta 1995, 248 61. (6) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W., Advanced Drug Delivery Reviews 2001, 48 3. (7) Zaworotko, M.; Arora, K., Pharmaceu tical co-crystals: A new opportunity in pharmaceutical science for a long-known but little studied class of compounds. In Polymorphism in Pharmaceutical Solids 2nd ed.; Brittain, H. G., Ed. Informa Healthcare: 2009. (8) Aaltonen, J.; Alleso, M.; Mirza, S.; Koradia, V.; Gordon, K. C.; Rantanen, J., European Journal of Pharmaceutics and Biopharmaceutics 2009, 71 23. (9) Yin, S. X.; Grosso, J. A., Current Opinion in Drug Discovery & Development 2008, 11 771. (10) Pepinsky, R., Physical Review 1955, 100 971. (11) Desiraju, G. R., Crystal Engineering: The Design of Organic Solids Elsevier: 1989.

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213 (12) Schmidt, G. M. J., Pure and Applied Chemistry 1971, 27 647. (13) Almarsson, .; Zaworotko, M. J., Chemical Communications 2004 1889. (14) Ahmed, M.; Khanna, D.; Furst, D. E., Expert Opinion 2005, 1 739. (15) Thompson, J. P.; Sharpe P.; Kiani, S.; Owen-Smith, O., British Journal of Anaesthesia 2000, 84 151. (16) Roughan, J. V.; Flecknell, P. A., European Journal of Pain 2003, 7 397. (17) Engelhardt, G.; Homma, D.; Sc hlegel, K.; Utzmann, R.; Schnitzler, C., Inflammation Research 1995, 44 423. (18) Huang, K. S.; Britton, D.; Etter, M. C.; Byrn, S. R., Journal of Materials Chemistry 1997, 7 713. (19) Friš i T.; Fabian, L.; Burley, J. C.; Rei d, D. G.; Duer, M. J.; Jones, W., Chemical Communications 2008 1644. (20) Luger, P.; Daneck, K.; Engel, W.; Trummlitz, G.; Wagner, K., European Journal of Pharmaceutical Sciences 1996, 4 175. (21) Coppi, L.; Sanmarti, M. B.; Clavo, M. C. Crystalline Forms of Meloxicam and Processes for Thier Preparation and Interconversion. US 6,967,248 B2, 2005. (22) Stei, P.; Kruss, B.; Wiegleb, J.; Trach, V., British Journal of Rheumatology 1996, 35 (suppl. 1) 44. (23) Lehmann, H. A.; Baumeister, M.; Luetzen, L.; Wiegleb, J., Inflammopharmacology 1996, 4 105. (24) Davies, N. M.; Skjodt, N. M., Clinical Pharmacokinetics 1999, 36 115. (25) Bae, J. W.; Kim, M. J.; Jang, C. G.; Lee, S. Y., Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences 2007, 859 69.

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214 (26) Ghorab, M. M.; Abdel-Salam, H. M.; El-Sayad, M. A.; Mekhel, M. M., Aaps Pharmscitech 2004, 5 (27) Seedher, N.; Bhatia, S., Aaps Pharmscitech 2003, 4 Article 33. (28) Han, H. K.; Choi, H. K., European Journal of Pharmaceutics and Biopharmaceutics 2007, 65 99. (29) Defazio, S.; Cini, R., Journal of the Chemical Society-Dalton Transactions 2002 1888. (30) Bock, T.; Saegmueller, P.; Sieg er, P.; Tuerck, D. Meloxicam for Oral Administration. US 6,869,948 B1, 2005. (31) Struengmann, A.; Freudensprung, B.; Klokkers, K. New Pharmaceutical Compositions of Meloxicam with Improve d Solubility and Bioavailability WO 99/09988 A1, 1999. (32) Ki, H. M.; Choi, H. K., Archives of Pharmacal Research 2007, 30 215. (33) M. Peterson; M. Bourghol Hickey; M. Oliveira; O. Almarsson; Remenar, J. Modafinil compositions. US 2005267209 A1, 2005. (34) Remenar, J.; MacPhee, M.; Peterson, M.; Morissette, S. L.; Almarsson, . Novel Crystalline Forms of Conazoles and Me thods of Making and Using the Same. WO/2005/092884, 2005. (35) McNamara, D. P.; Childs, S. L.; Gior dano, J.; Iarriccio, A.; Cassi dy, J.; Shet, M. S.; Mannion, R.; O'Donnell, E.; Park, A., Pharmaceutical Research 2006, 23 1888. (36) Chen, A. M.; Ellison, M. E.; Peres ypkin, A.; Wenslow, R. M.; Variankaval, N.; Savarin, C. G.; Natishan, T. K.; Mathre, D. J.; Dormer, P. G.; Euler, D. H.; Ball, R. G.; Ye, Z. X.; Wang, Y. L.; Santos, I., Chemical Communications 2007 419.

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215 (37) Hickey, M. B.; Peterson, M. L.; Scoppett uolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M. J.; Almarsson, ., European Journal of Pharmaceutics and Biopharmaceutics 2007, 67 112. (38) Imamura, M. Cocrystal of C-Gl ycoside Derivative and L-Proline. WO 2007/114475 A1, 2007. (39) Annette Bak; Gore, A.; Yanez, E.; St anton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A., Journal of Pharmaceutical Sciences 2008, 97 3942. (40) E. Dova; J. M. Mazurek; Anker, J. Tenofovir disoproxil hemi-fumaric acid cocrystal. WO/2008/143500 2008. (41) Mohamed, S.; Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.; Price, S. L., Crystal Growth and Design doi:10.1021/cg9001994. (42) Bhogala, B. R.; Basavoju, S.; Nangia, A., Crystengcomm 2005, 7 551. (43) Stahl, P. H.; Wermuth, C. G., Handbook of Pharmaceutical Salts: Properties, Selection, and Use WILEY-VCH: Zurich, 2002. (44) Delori, A.; Suresh, E.; Pedireddi, V. R., Chemistry-a European Journal 2008, 14 6967. (45) Childs, S. L.; Stahly, G. P.; Park, A., Molecular Pharmaceutics 2007, 4 323. (46) Pedersen, C. J.; Frensdor.Hk, Angewandte Chemie-International Edition 1972, 11 16. (47) Himeno, Y.; Takeda, A.; Kawato, S.; Ninomiya, W. Process for preparation of acrylic acid or methacrylic acid. US 7,498,462, 2005.

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216 (48) Cram, D. J.; Cram, J. M., Accounts of Chemical Research 1978, 11 8. (49) Somasundaram, S.; Rafi, S.; Hayllar, J.; Sigthorsson, G.; Jacob, M.; Price, A. B.; Macpherson, A.; Mahmod, T.; Scott, D.; Wrigglesworth, J. M.; Bjarnason, I., 1997, 41 344. (50) Brittain, H. G.; Prankerd, R. J., In Profiles of drug substances, excipients, and related methodolgy Academic Press: 2007; p 369. (51) Allen, F., The Cambridge Structural Database: a quarter of a million crystal structures and rising. In Acta Crystallographica Section B 2002; Vol. 58, pp 380. (52) CSD version 5.30, November 2007 release including May 2009 update. Search parameters: organics only, no ions, 3D coordinates determined, R<7.5% (53) Etter, M. C., Accounts of Chemical Research 1990, 23 120. (54) Schultheiss, N.; Newman, A., Crystal Growth & Design 2009, 9 2950. (55) Stanton, M. K.; Bak, A., Crystal Growth & Design 2008, 8 3856. (56) Simamora, P.; Yalkowsky, S. H., Industrial & Engineering Chemistry Research 1994, 33 1405. (57) Katritzky, A. R.; Jain, R.; Lomaka, A.; Petrukhin, R.; Maran, U.; Karelson, M., Crystal Growth & Design 2001, 1 261. (58) Laurence, C.; Berthelot, M., Perspectives in Drug Discovery and Design 2000, 18 39. (59) Noyes, A. A.; Whitney, W. R., Journal of the American Chemical Society 1897, 19 930. (60) Hunter, C. A.; Sanders, J. K. M., Journal of the American Chemical Society 2002, 112 5525.

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217 (61) Lehn, J. M., Science 2002, 295 2400. (62) Lehn, J. M., Angewandte Chemie-International Edition in English 1988, 27 89. (63) Avdeef, A., Current Topics in Medicinal Chemistry 2001, 1 277. (64) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P., Journal of the Americ an Chemical Society 2004, 126 13335. (65) Shiraki, K.; Takata, N.; Takano, R.; Hayashi, Y.; Terada, K., Pharmaceutical Research 2008, 25 2581. (66) Stanton, M. K.; Tufe kcic, S.; Morgan, C.; Bak, A., Crystal Growth & Design 2009, 9 1344. (67) Good, D. J.; Rodriguez-Hornedo, N., Crystal Growth & Design 2009, 9 2252. (68) Parshad, H.; Frydenvang, K.; Liljefors, T.; Larsen, C. S., International Journal of Pharmaceutics 2002, 237 193. (69) Bruker SMART, SAINT-Plus, SADABS, XP and SHELXTL Madison, Wisconsin, USA, 1997. (70) Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997. (71) Aguilar-Mariscal, H.; Patino-Camacho, S. I.; Rodriguez-Silverio, J.; Torres-Lopez, J. E.; Flores-Murrieta, F. J., Methods and Findings in Ex perimental and Clinical Pharmacology 2007, 29 587.

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218 Chapter 5 – Summary and Future Directions 5.1. Summary The field of supramolecular chemistry ha s grown dramatically since the early works of Jean-Marie Lehn, Donald Cram and others both in complexity and in scope. The subtopic crystal engineering has also grown alongside it from a [2+2] photodimerization topochemical reaction to ph armaceutical cocrystals with improved physicochemical properties. The research presen ted in this dissertat ion is a contribution to the current knowledge base of the crystal engineering of co crystals with a particular focus upon two separate applications: cocrys tal controlled solid-state synthesis and pharmaceutical cocrystallization. Cocrystal co ntrolled solid-state synthesis targets the cocrystal as the key intermediate stage that brings the two reactive components in close proximity such that the reaction can take plac e. Once the cocrystal is formed then the reaction can occur faster and with greater yield than trad itional solution methods. The cocrystal controlled solid-state synthesis of imides was targeted due to the potential for supramolecular heterosynthon formation with the primary amine and carboxylic acid anhydride starting materials. Three cocrystals: 1 2-methyl-4-nitroaniline 1,4,5,8naphthalenetetracarboxylic dianhydride, (2:1), 2 3-aminobenzoic acid 1,4,5,8naphthalenetetracarboxylic dianhydride, (2:1)), 3 (2-methyl-4-nitroaniline pyromellitic anhydride, (2:1))) were isolated and characte rized by single crystal analysis, DSC, FTIR,

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2191HNMR, and PXRD. Their transformations in the solid-state to their corresponding imides were closely monitored and the imides were also characterize d. Interestingly, the envisioned supramolecular synthon (amine -anhydride hydrogen bonding) did not occur, the cocrystals were instead sustained by system interactions of the aromatic rings that, in some cases, was determined to be charge -transfer interaction. The project concluded in an approximate 50% success rate of imide formation. Cocrystals were also studied in releva nce to pharmaceuticals. Lamotrigine and meloxicam were the targeted pharmaceuticals du e to their inherently low solubility but high bioavailability. The goal for both drugs was to improve the solubility by cocrystallizing with a pharmaceutically accepta ble cocrystal former. Additionally since meloxicam is a drug used for indications of acute pain, the goal was to reduce the time taken to reach the maximum con centration by at least half. Ten crystal forms were isolated for lamotrigine: lamotrigine methylparaben cocrystal form I (1:1) ( 1 ), lamotrigine methylparaben cocrystal form II (1:1) ( 2 ), lamotrigine nicotinamide cocrystal (1:1) ( 3 ), lamotrigine nicotinamide cocrystal monohydrate (1:1:1) ( 4 ), lamotrigine saccharin salt (1:1) ( 5 ), lamotrigine adipate salt (2:1) ( 6 ), lamotrigine malate salt (2:1) ( 7 ), lamotrigine nicotinate dimethanol solvate (1:1:2) ( 8 ), lamotrigine dimethanol solvate (1:2) ( 9 ), and lamotrigine ethanol monohydrate (1:1:1) ( 10 ). An underlying theme for the la motrigine cocrystals, salts, and solvates was the supramolecular synthon motifs. All of the crystal forms either hydrogen bonded to the exterior of the lamotrigine dime r or they broke the lamotrigine dimer. Crystal forms 1 5 6 and 8 break the lamotrigine dimer while 2 4 7 9 and 10 hydrogen bond to the exterior of the dimer.

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220 Solubility and dissolution measuremen ts were conducted on crystal forms 1-5 and pure lamotrigine in water and pH 1 HCl solution. 5 was the most soluble crystal form in water, however, it was the least solubl e in the pH 1 HCl solution. Instead, 2 exhibited the highest concentration in th e acidified solution. The average concentration for 2 and 4 in aqueous solution were similar to that of lamotrigine while 3 was similar to the maximum of lamotrigine. In the acidic media the concentrations for 2 3 4 and 5 all surpassed that of pure lamotrigine. The solubility of th e cocrystal former did not correlate to the solubility of the correspondi ng cocrystal. The animal pharmacokinetic data was gath ered via a single dose rat study. The area under the curve for the serum con centrations after administration of 5 was increased by 66% compared to lamotrigine. The other crystal forms, 3 and 4 however, resulted in a decrease in serum concentration by 37% and 26%, respectively. Analyzing the solubility and pharmacokineti c data in light of the original goal shows that the crystal forms of lamotrigine show great potential for an improved drug in clinical studies. 5 exhibits the greatest improvements in solubility and serum concentration thus 5 is the best candidate fo r further clinical studies. Pharmaceutical cocrystallizations of me loxicam afforded seven novel cocrystals: meloxicam 1-hydroxy-2-naphthoic acid cocrystal (1:1) ( 1 ), meloxicam glutaric acid cocrystal (1:1) ( 2 ), meloxicam L-malic acid cocrystal of a salt (1:1:1) ( 3 ), meloxicam aspirin cocrystal (1:1) ( 4 ), meloxicam salicylic acid cocrystal form III (1:1) ( 5 ), meloxicam salicylic acid cocrystal form II (1:1) ( 6 ), and meloxicam salicylic acid cocrystal form I (1:1) ( 7 ). Five of the seven resulting crystal forms were analyzed in terms of their crystal packing, solubility, diss olution rate, and pharmac okinetic properties.

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221 Crystal structures of cocrystals 1 5 were obtained from single crystal X-ray diffraction analysis of high quality single cr ystals grown from sl ow evaporation of a solution. Examination of th e crystal packing revealed the common motif of the meloxicam dimer and the two-point recognition carboxylic acid-azole/NH supramolecular synthon. The meloxicam dime r was only prevalent in crystal forms 1 4 while the carboxylic acid-azole/NH s upramolecular synthon sustained forms 1 5 The lack of the meloxicam dimer in 5 is unique and possibly co ntributes to the unique solubility and pharmacoki netic properties of 5 The dissolution profiles, conducted in pH 8 buffer, predicated the improved solubility of many of the cocrystals. 1 was the most soluble cocrystal while 2 was the least soluble cocrystal at the end of the 4 hour trial. However, due to the desire to improve the concentration in solution at the fa stest rate to decrease the onset of efficacy, the concentration after the first 15 minutes wa s the most crucial point. Examining of the concentrations at the early time points illustrated that 3 and 5 were the most soluble after 5 minutes but 3 quickly decreased in concentration while 5 maintained an elevated level. The solubility of the cocrystal former did not correlate to the of the corresponding cocrystal. The single dose rat pharmacokinetic study administered forms 1 5 7 and meloxicam. The area under the curves for the plasma concentrations of 2 3 and 6 were lower than pure meloxicam. Tw o hours into the 4-hour study 1 and 4 had achieved concentrations similar to meloxicam, 5 however, reaches therapeutic concentrations 15 minutes after administration.

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222 A consideration of the solubility and pharmacokinetic data for the meloxicam cocrystals led to the selection of 5 as the product that should be taken further into clinical trials. Unfortunately, there re mains a problem with marketing 5 as it is well known that meloxicam should not be taken with other NSAI D pain killers. With this in mind the next best crystal form, 1 would be selected for cl inical trial testing. 5.2. Future Directions The future for the field of crystal engineer ing is glowing bright The interest in developing solids as functional materials is pr ogressing rapidly as scie ntists are learning how to utilize the principles of crystal e ngineering and expand upon the existing synthetic methods for the design of novel materials. Th e advent of novel synthetic techniques such as cocrystal controlled solid-state synthesis, have been instrumental in the development of new molecules. Furthermore, with the facile generation of new molecules one can synthesize functional materials such as metalorganic frameworks that are currently being explored for applications such as hydrogen storage. Crystal engineering has within the last decade also had a major impact upon the pharmaceutical industry with a particular emphasis upon crys tal form and pharmaceutical cocrystals. Currently the physical properties of pharmaceutical cocrystals that result from the screening process are unpredictable. Pe rhaps with the knowle dge gained from the studies presented herein coupled with future studies will allow for the generation of a library that will facilit ate the estimation or possibly predict the solubility or maybe even the bioavailability of pharmaceutical cocrystals.

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223 The scientific literature surrounding pha rmaceutical cocrystals has also grown exponentially over the past decade containi ng many articles from major pharmaceutical companies as well as academic scientists. Furthermore, there are now more collaborations than ever between industry a nd academia resulting in fascinating science and influential papers. The conglomeration of industry and academia appears to be the wave of the future and cocrystals will cont inue to play a major role in crystal form development. The ability to control the pr operties of a crystal form still remains for futuristic development but as the future draws near Feynman’s dreams of possessing the ability to arrange the molecules exactly as we want them are growing one step closer to becoming the reality.

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224 Appendices

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225 Appendix 1. Experimental data for PA 1+AA1 (2-methyl-4-nitroaniline+NTCDA) IR and Powder X-ray diffractogram of heated and ground material and 1HNMR of imide

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226

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227 Appendix 2. Experimental data for PA1+ AA2 (2-methyl-4-nitroaniline+pyromellitic anhydride) IR and Powder X-ray diffractogram of heated and ground material and 1HNMR of imide

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228

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229

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230 Appendix 3. Experimental data for PA1+AA3 (2-methyl-4-nitroaniline+maleic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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231

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232

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233 Appendix 4. Experimental data for PA 1+AA4 (2-methyl-4-nitroaniline+phthalic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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234

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235

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236 Appendix 5. Experimental data for PA1+ AA5 (2-methyl-4-nitroaniline+3, 3’, 4, 4’biphenyltetracarboxylic dianhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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237

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238

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239 Appendix 6. Experimental data for PA2+AA1 (3-aminobenzoic acid+NTCDA) IR and Powder X-ray diffractogram of heated and ground material and 1HNMR of imide

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240

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241 Appendix 7. Experimental data for PA2+ AA2 (3-aminobenzoic acid+pyromellitic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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242

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243 1HNMR could not be obtained due to low solubility

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244 Appendix 8. Experimental data for PA2+AA3 (3-aminobenzoic acid+maleic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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245

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246

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247 Appendix 9. Experimental data for PA2+AA4 (3-aminobenzoic acid+phthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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248

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249

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250 Appendix 10. Experimental data for PA2+ AA5 (3-aminobenzoic acid+3, 3’, 4, 4’biphenyltetracarboxylic dianhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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251

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252 1HNMR could not be obtained due to low solubility

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253 Appendix 11. Experimental data fo r PA2+AA6 (3-aminobenzoic acid+1,8naphthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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254

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255 1HNMR could not be obtained due to low solubility

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256 Appendix 12. Experimental data for PA3+ AA2 (melamine+pyromellitic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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257 XPDS of heated material are not provided because the material was amorphous.

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258

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259 Appendix 13. Experimental data for PA3+AA3 (melamine+maleic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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260

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261

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262 Appendix 14. Experimental data for PA 3+AA4 (melamine+phthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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263

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264

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265 Appendix 15. Experimental data for PA4+AA1 (1,4-phenylenediamine+NTCDA) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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266

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267 1HNMR could not be obtained due to low solubility

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268 Appendix 16. Experimental data for PA 4+AA2 (1,4-phenylenediamine+pyromellitic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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269

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270

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271 Appendix 17. Experimental data for PA4+AA3 (1,4-phenylenediamine+maleic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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272

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273

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274 Appendix 18. Experimental data for PA4+AA4 (1,4-phenylenediamine+phthalic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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275

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276 1HNMR could not be obtained due to low solubility

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277 Appendix 19. Experimental data for PA 4+AA5 (1,4-phenylenediamine+3, 3’, 4, 4’biphenyltetracarboxylic dianhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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278

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279

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280 Appendix 20. Experimental data fo r PA4+AA6 (1,4-phenylenediamine+1,8naphthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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281

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282

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283 Appendix 21. Experimental data for PA5+AA1 (1,5-naphtha lenediamine+NTCDA) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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284 XPD of heated material not incl uded because the compound is amorphous.

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285

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286 Appendix 22. Experimental data fo r PA5+AA2 (1,5-naphthalenediamine+ pyromellitic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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287 XPD of heated material not incl uded because the compound is amorphous.

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288

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289 Appendix 23. Experimental data for PA 5+AA3 (1,5-naphthalenediamine+maleic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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290

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291

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292 Appendix 24. Experimental data for PA 5+AA4 (1,5-naphthalenediamine+phthalic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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293

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294

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295 Appendix 25. Experimental data for PA5+ AA5 (1,5-naphthalenedi amine+3, 3’, 4, 4’biphenyltetracarboxylic dianhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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296 XPD of heated material not incl uded because the compound is amorphous.

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297

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298 Appendix 26. Experimental data fo r PA5+AA6 (1,5-naphthalenediamine+1,8naphthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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299 XPD of heated material not incl uded because the compound is amorphous.

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300

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301 Appendix 27. Experimental data for PA6+AA3 (1-adamantylamine+maleic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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302

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303

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304 Appendix 28. Experimental data for PA6+AA4 (1-adamantylamine+phthalic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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305

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306

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307

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308 Appendix 29. Experimental data for PA7+ AA2 (triphenylmethyla mine+pyromellitic anhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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309

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310

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311 Appendix 30. Experimental data for PA7+AA3 (triphenylmethylamine+maleic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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312

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313

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314 Appendix 31. Experimental data for PA 7+AA4 (triphenylmethylamine+phthalic anhydride) IR, Powder X-ray diffractogram, and DS C of heated and ground material and 1HNMR of imide

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315

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316

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317 Appendix 32. Experimental data for PA7+ AA5 (triphenylmethylamine+3, 3’, 4, 4’biphenyltetracarboxylic dianhydride) IR, Powder X-ray diffractogram, and DSC of heated and ground material and 1HNMR of imide

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318

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319

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320 Appendix 33. Histograms for specified contacts between aminopyridine to carboxylic acid and aminopyridine to alcoho l moieties (comprised of entries in the CSD)

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321

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322 Appendix 34. Experimental data for lamotrigine methylparaben form I Powder X-ray diffractogram comparison of cocrystal to starting material 46810121416182022242628303234363840 0 50 100 150 200 250 300 350 400 2Theta (deg)Lamotrigine Methylparaben Calculated Lamotrigine methylparaben cocrystal form I An experimental PXRD is not shown because the crystallization results in multiple products in the same vial.

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323 Appendix 35. Experimental data for lamotrigine methylparaben form II Powder X-ray diffractogram, DSC, and IR for lamotrigine methylparaben form II 46810121416182022242628303234363840 40 60 80 100 120 140 160 180 200 220 240 260 Experimental Lamotrigine methylparaben form II cocrystal 2Theta (deg)Calculated Lamotrigine methylparaben form II cocrystal 4000.03600320028002400200018001600140012001000800650.0 18.2 25 30 35 40 45 50 55 60 65 70 75 80 85 90 96.7 cm-1 %T 3449.93 3324.77 3195.16 2945.93 2447.94 1867.62 1704.11 1656.48 1632.53 1604.07 59.23 155630 1532.96 1509.4 1467.9 1434.73 1411.73 1312.17 1286.2 1250.99 194.35 1170.66 1114.18 1055.27 969.69 849.23 810. 798. 786.7 770.91 755.98 3.98 721.32 694.75

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324 Appendix 36. Experimental data for lamotrigine nicotinamide cocrystal Powder X-ray diffractogram, DSC, and IR for lamotrigine nicotinamide cocrystal 46810121416182022242628303234363840 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 2Theta (deg)Lamotrigine Nicotinamide Lamotrigine nicotinamide cocrystal 4000.03600320028002400200018001600140012001000800650.0 38.7 45 50 55 60 65 70 75 80 85 90 95.0 cm-1 %T 31.3 331.60 3093.70 1686.60 66.7 1612.32 15513 1536.3 199.67 1653 13.9 108.29 139.25 1339.86 1295.7 1195.2 1153.53 1109.3 1055.6 1025.97 971.67 837.0 808.9 787.95 578 73892 707.96

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325 Appendix 37. Experimental data for la motrigine nicotinamide monohydrate Powder X-ray diffractogram, DSC, IR, and TGA for lamotrigine nicotinamide monohydrate 46810121416182022242628303234363840 100 200 300 400 500 600 700 800 900 1000 1100 1200 Experimental Lamotrigine nicotinamide cocrystal hydrate2Theta ( de g) Calculated Lamotrigine nicotinamide cocrystal hydrate

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326

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327 Appendix 38. Experimental data for lamotrigine saccharinate salt Powder X-ray diffractogram, DSC, and IR for lamotrigine saccharinate salt 46810121416182022242628303234363840 100 120 140 160 180 200 220 240 260 280 Experimental Lamotrigine saccharin salt2Theta (deg)Calculated Lamotrigine saccharin salt

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328 Appendix 39. Experimental data for lamotrigine adipate salt Powder X-ray diffractogram, DSC, a nd IR for lamotrigine adipate salt 46810121416182022242628303234363840 20 30 40 50 60 70 80 90 100 110 120 130 2Theta (deg)Calculated Lamotrigine adipate salt Experimental Lamotrigine adipate salt 4023.83600320028002400200018001600140012001000800644.1 26.7 30 35 40 45 50 55 60 65 70 75 80 85 90 95 97.9 cm-1 %T 3115.24 2965.02 2930.19 2864.42 2494.89 1874.56 1694.90 1656.45 1558.82 1462.33 1441.2 1407.28 1372.1 1323.2 1298.29 1276.29 1255.69 1193.60 1129.21 1056.98 1030.62 965.36 932.03 826.67 801.15 766.11 735.61 716.33 668.20

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329 Appendix 40. Experimental data for lamotrigine malate salt Powder X-ray diffractogram, DSC, and IR for lamotrigine malate salt 46810121416182022242628303234363840 50 100 150 200 250 300 350 400 450 Experimental Lamotrigine L-malate salt2Theta (deg)Calculated Lamotrigine L-malate salt 4000.03600320028002400200018001600140012001000800650.0 50.8 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94.6 cm-1 %T 3131.21 1663.15 1554.90 1439.86 1397.45 1331.99 1237.64 1192.83 1152.58 1113.43 10576 1037.90 979.19 923.36 879.15 790.22 73610 721.88 658.27

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330 Appendix 41. Experimental data for lamo trigine nicotinate dimethanol solvate Powder X-ray diffractogram, DSC, IR, and T GA for lamotrigine nicotinate dimethanol solvate 46810121416182022242628303234363840 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 Experimental Lamotrigine Nicotinate MeOH salt2Theta (deg)Calculated Lamotrigine Nicotinate MeOH salt

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331 4000.03600320028002400200018001600140012001000800650.0 13.4 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100.2 cm-1 %T 3312.85 2946.21 2813.43 1911.19 1665.61 1588.44 1547.21 1492.93 1438.08 141193 1381.53 1302.55 1195.09 153.51 1119.00 1092.12 10578 1048.2 1038.8 1026.40 1001.28 969.08 915.88 846.19 800.56 780.11 749.83 71883 703.56 65.72

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332 Appendix 42. Experimental data fo r lamotrigine dimethanol solvate Powder X-ray diffractogram, DSC, IR, and TGA for lamotrigine dimethanol solvate 46810121416182022242628303234363840 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 Experimental Lamotrigine methanol solvate 1:2 Calculated Lamotrigine methanol solvate 1:12 Theta (deg)Calculated Lamotrigine methanol solvate 1:2

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333 4000.03600320028002400200018001600140012001000800650.0 54.7 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98.5 cm-1 %T 3494.25 3362.78 3096.85 2820.90 1672.84 1614.96 1551.63 1496.67 1463.2 1430.37 1409.68 1327.14 1192.58 1160.41 1114.27 1053.63 1018.02 907.14 809.02 788.56 769.7 73825 721.64

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334 Appendix 43. Experimental data for lamotrigine ethanol hydrate Powder X-ray diffractogram, DSC, IR, and TGA for lamotrigine ethanol hydrate 46810121416182022242628303234363840 0 20 40 60 80 100 120 140 160 180 200 2Theta (deg)Calculated Lamotrigine ethanol hydrate Experimental Lamotrigine ethanol hydrate

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335 4000.03600320028002400200018001600140012001000800650.0 66.6 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 97.0 cm-1 %T 3330.51 3141.49 1664.38 1618.05 1522.95 497.18 1464. 1431.99 1408.33 1329.01 1195.25 1150.46 1116.86 1056.23 807.6 786.4 740.63

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336 Appendix 44. Histograms for specified co ntacts between carboxylic acid-azole, alcohol-azole, and primary amide-azol e compiled from entries in the CSD (a) (b) Acid homosynthon in the presence of azole Acid-azole supramolecular heterosynthon (c) (d) Alcohol homosynthon in the presence of azole Alcohol-azole supramolecular heterosynthon (e) (f) Amide homosynthon in the presence of azole Amide-azole supramolecular heterosynthon

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337 Appendix 45. Experimental data for me loxicam 1-hydroxy-2-naphthoic acid cocrystal Powder X-ray diffractogram, DSC, IR, and for meloxicam 1-hydroxy-2naphthoic acid cocrystal 46810121416182022242628303234363840 0 500 1000 1500 2000 Experimental Meloxicam 1-Hydroxy-2-naphthoic acid cocrystal2Theta (deg)Calculated Meloxicam 1-Hydroxy-2-naphthoic acid cocrystal

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338 Appendix 46. Experimental data for meloxicam glutaric acid cocrystal Powder X-ray diffractogram, DSC, IR, and for meloxicam glutaric acid cocrystal 46810121416182022242628303234363840 0 100 200 300 400 500 600 700 800 900 1 000 1100 Experimental Meloxicam Glutaric acid cocrystal2Theta (deg)Calculated Meloxicam Glutaric acid cocrystal

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339 Appendix 47. Experimental data for meloxi cam L-malic acid cocrystal of a salt Powder X-ray diffractogram, DSC, IR, and fo r meloxicam L-malic acid cocrystal of a salt 46810121416182022242628303234363840 0 200 400 600 800 1000 1200 1400 1600 Experimental Meloxicam L-Malic acid cocrystal2Theta (deg)Calculated Meloxicam L-Malic acid cocrystal

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340 Appendix 48. Experimental data for meloxicam aspirin cocrystal Powder X-ray diffractogram, DSC, IR, and for meloxicam aspirin cocrystal 46810121416182022242628303234363840 0 200 400 600 800 1000 1200 1400 1600 1800 Experimental Meloxicam Aspirin cocrystal 2Theta (deg) Calculated Meloxicam Aspirin cocrystal

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341 Appendix 49. Experimental data for melo xicam salicylic acid cocrystal form III Powder X-ray diffractogram, DSC, IR, and fo r meloxicam salicylic acid cocrystal form III 46810121416182022242628303234363840 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 Experimental Meloxicam Salicylic acid form III cocrystal2Theta (deg)Calculated Meloxicam Salicylic acid form III cocrystal

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342 Appendix 50. Experimental data for melo xicam salicylic acid cocrystal form I Powder X-ray diffractogram, DSC, IR, and fo r meloxicam salicylic acid cocrystal form I 46810121416182022242628303234363840 0 200 400 600 800 1000 1200 1400 Meloxicam:Salicylic acid form I Salicylic acid Meloxicam form I2Theta (deg)Meloxicam form III

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343 Appendix 51. Experimental data for melo xicam salicylic acid cocrystal form II Powder X-ray diffractogram, DSC, IR, and fo r meloxicam salicylic acid cocrystal form II 46810121416182022242628303234363840 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 Meloxicam:Salicylic acid form II Salicylic acid Meloxicam form I2Theta ( de g) Meloxicam form III

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About the Author Miranda Cheney received her Bachelors degree in Chemistry from the University of West Florida in 2004. In the fall of 2004 she entered the Ph.D. program at the University of South Florida and became a me mber of Dr. Zaworotkos research group. Under the guidance of Dr. Zaworotko, she deve loped the synthetic te chnique of cocrystal controlled solid-state synthesis. In 2007 she joined Thar Pharmaceuticals where her primary objective became the development of pharmaceutical cocrystals. She has since presented her research at regi onal, national, and internati onal conferences sponsored by the American Chemical Society and the Cana dian Society for Chemistry. Her work has also been published in Crystal Growth & Design and The Journal of Chemical Education Additionally, she is a co -inventor on eleven patent applications filed for cocrystal controlled solid-state synthe sis and pharmaceutical cocrystallization.