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Crystal engineering of co-crystals and their relevance to pharmaceutical forms

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Crystal engineering of co-crystals and their relevance to pharmaceutical forms
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Shattock, Tanise R
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Supramolecular chemistry
Supramolecular synthon
Hydrogen bond
Supramolecular synthesis
Polymorphism
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ABSTRACT: The research presented herein focus upon crystal engineering of co-crystals with an emphasis upon the exploration of co-crystals in the context of delineation of the reliability of hydrogen bonded supramolecular synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthesis of co-crystals and the effect on polymorphism is also addressed. The application of the acquired knowledge is towards the crystal engineering of pharmaceutical co-crystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by the selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.
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Dissertation (Ph.D.)--University of South Florida, 2007.
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by Tanise R. Shattock.
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Crystal Engineering of Co-Crystals and their Relevance to Pharmaceutical Forms by Tanise R. Shattock 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. Edward Turos, Ph.D. Matthew L. Peterson, Ph.D. Date of Approval: July 16, 2007 Keywords: Supramolecular Chemistry, Supramolecular Synthon, Hydrogen Bond, Supramolecular Synthesis, Polymorphism Copyright 2007, Tanise R. Shattock

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Dedication For Joshua

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Acknowledgements The author would like to express sincere gratitude and appreciation to her mentor and supervisor Dr. Michael J. Zaworotko fo r his support over the years and for all the opportunities he has made available for he r professional growth and development. She would also like to thank Dr. Matt hew L. Peterson, Dr. Mohamed Eddaoudi and Dr. Edward Turos, her committee members; Dr. Vishweshwar Peddy, Dr. Joanna Bis, Jennifer McMahon, Gregory McManus, Mi randa Cheney, John J. Perry IV, Jason Perman and all members of the Zaworotko s Research Group for all their help and advice. Words cannot adequately express her h eartfelt appreciation to Nicholas and Joshua for their endless love, support, pa tience and understanding. Finally, she would like to acknowledge and thank her parents, her clos est family and friends for their constant support throughout the years of studies.

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i Table of Contents List of Tables ix List of Figures xi Abstract xvii Chapter 1. Introduction 1 1.1. Introduction 1 1.1.1. Supramolecular Chemistry 1 1.1.2. Intermolecular Interactions 2 1.1.3. Crystal Engineering 4 1.1.4. Supramolecular Synthons and the Cambridge Structural Database 5 1.1.5. Co-Crystal 8 1.1.6. Preparation of Co-Crystals 10 1.1.7. Pharmaceutical Co-Crystals 12 1.1.8. Polymorphism 21 1.1.9. Summary 23 1.2 References Cited 24

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ii Chapter 2. The Reliability of the Carboxylic acid-Aromatic Nitrogen Supramolecular Heterosynthon 39 2.1. Introduction 39 2.2. Results and Discussion 41 2.2.1. CSD Analysis 42 2.2.2.Features of Carboxylic Acid-A romatic Nitrogen Interaction 45 2.2.3. Crystal Structure Description 50 2.3. Conclusions 67 2.4. Experimental Section 69 2.4.1. Co-crystallization via grinding 69 2.4.2. Co-crystallization via solvent-drop grinding 69 2.4.3. Co-crystallization via melting 69 2.4.4. Co-crystallization via solution evaporation 69 2.4.5. Crystal structure determination 73 2.5. References Cited 77 Chapter 3. The Reliability of the Alcohol Aromatic Nitrogen Supramolecular Heterosynthon 83 3.1. Introduction 83 3.2. Results and Discussion 85 3.2.1. Cambridge Structural Database Analysis 85 3.2.2 Features of HydroxylAr omatic Nitrogen Interaction 87

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iii3.2.3. Crystal Structure Description 90 3.3. Conclusions 100 3.4. Experimental Section 104 3.4.1. Synthesis of Co-Crystals 104 3.4.1. Co-crystallization via grinding 105 3.4.2. Co-crystallization via solvent-drop grinding 105 3.4.3. Co-crystallization via melting 105 3.5. References Cited 108 Chapter 4. Delineating the Hierarchy of S upramolecular Heterosynthons: Carboxylic acid-Aromatic Nitrogen versus Alcohol-Aromatic Nitrogen 113 4.1. Introduction 113 4.2. Results and Discussion 117 4.2.1.CSD Analysis 117 4.2.2 Features of the O-H Narom interaction 119 4.2.3.Crystal Structure Descriptions 121 4.2.4 Methods of Preparation 145 4.3.Conclusions 147 4.4. Experimental Section 148 4.4.1.Syntheses 148 4.4.2. Single-crystal X-ray diffraction. 152 4.5. References Cited 156

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iv Chapter 5. Pharmaceutical Co-crystals of Stavudine 160 5.1. Introduction 160 5.2. Results and Discussion 162 5.2.1. Crystal Structure Description 163 5.3. Conclusions 169 5.4. Experimental Section 170 5.4.1 Synthesis 170 5.4.2. Single-crystal X-ray diffraction 171 5.5. References Cited 176 6. Summary and Future Directions 180 6.1.Summary 180 6.2. Future Directions 184 Appendices 188 Appendix 1. Experimental Data for (benzoic acid)2 1,2-bis(4-pyridyl)ethane 1 189 Appendix 2. Experimental Data for (benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene 2 192 Appendix 3. Experimental Data for benzoic acid 4,4-bipyridine, 3 195 Appendix 4. Experimental Data for sorbic acid 1,2-bis(4-pyridinium)ethane sorbate 4 199

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vAppendix 5. Experimental Data for (naproxen)2 trans-1,2-bis(4-pyridyl)ethylene 5 202 Appendix 6. Experimental Data for glutaric acid 1,2-bis(4-pyridyl)ethane, 6 205 Appendix 7. Experimental Data for glutaric acid trans-1,2-bis(4-pyridyl)ethylene, 7 208 Appendix 8. Experimental Data for oxalic acidtetramethylpyrazine, 8 211 Appendix 9. Experimental Data for isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 214 Appendix 10. Experimental Data for (trimesic acid)2 trans-(1,2-bis(4-pyridyl)ethylene)3, 11 217 Appendix 11. Experimental Data for trimesic acid 1,2-bis(4-pyridyl)ethane, 12 220 Appendix 12. Experimental Data for (1-naphthol)2 1,2-bis(4-pyridyl)ethane, 13 225 Appendix 13. Experimental Data for (1-naphthol)2 trans-1,2-bis(4-pyridyl)ethylene, 14 227 Appendix 14. Experimental Data for 4,4-biphenol 1,2-bis(4-pyridyl)ethane, 15 229 Appendix 15. Experimental Data for 4,4-biphenol trans-1,2-bis(4-pyridyl)ethylene, 16 231

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viAppendix 16. Experimental Data for hydroquinone trans-1,2-bis(4-pyridyl)ethylene, 17 233 Appendix 17. Experimental Data for hydroquinone tetramethylpyrazine, 18 235 Appendix 18. Experimental Data for (resorcinol)2 (TMP)3, 19 237 Appendix 19. Experimental Da ta for 2,7-dihydroxynaphthalene (TMP)2, 20 239 Appendix 20. Experimental Data for (3-hydroxybenzoic acid)2 pyrazine, 21 241 Appendix 21. Experimental Data for 4-hydroxybenzoic acid 1,2-bis (4-pyridinium)ethane 4hydroxybenzoate, 22 244 Appendix 22. Experimental Data for (4-hydroxybenzoic acid)2 tetramethylpyrazine, 23 247 Appendix 23. Experimental Data for 4-hydroxybenzoic acid 4-phenylpyridine, 24 249 Appendix 24. Experimental Data for (4-hydroxybenzoic acid)2 pyrazine, 25 251 Appendix 25. Experimental Data for 4-hydroxybenzoic acid)2 tetramethylpyrazine acetonitrile solvate, 26 254 Appendix 26. Experimental Data for 3-hydroxybenzoic acid phenylpyridine)2, 27 256 Appendix 27. Experimental Data for 3-hydroxybenzoic acid 1,2-bis(4-pyridyl)ethane, 28 259

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viiAppendix 28. Experimental Data for 3-hydroxybenzoic acid 4,4-bipyridine, 29 262 Appendix 29. Experimental Data for 3-hydroxybenzoic acid quinoxaline, 30 265 Appendix 30. Experimental Data for (3-hydroxybenzoic acid)2 (tetramethylpyrazine)3, 31 268 Appendix 31. Experimental Data for 6-hydroxy-2-naphthoic acid trans-1,2-bis(4-pyridyl)ethylene, 32 270 Appendix 32. Experimental Data for 4-hydroxybenzoic acid trans-1,2-bis (4-pyridyl)ethylene, 33 272 Appendix 33. Experimental Data for 3-hydroxybenzoic acid trans-1,2-bis(4-pyridyl)ethylene, 34 274 Appendix 34. Experimental Data for 3-hydroxypyridinium benzoate, 35 276 Appendix 35. Experimental Data fo r 3-hydroxypyridinium isophthalate, 36 279 Appendix 36. X-ray powder diffraction pa tterns of grinding and solvent drop grinding of isonicotinic acid 1-naphthol, nicotinic acid 1-naphthol, (nicotinic acid)2 4,4-biphenol, (isonicotinic acid)2 4,4-biphenol, (isonicotinic acid)3 phloroglucinol, (nicotinic acid)3 phloroglucinol, (isonicotinic acid)2 resorcinol, (nicotinic acid)2 resorcinol. 282 Appendix 37. Diffractograms of Melt Experiments 286 Appendix 39. Experimental Data for (stavudine)3 melamine, 37 298

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viiiAppendix 40. Experimental Data for stavudine 2,4,6-triaminopyrimidine hydrate, 38 301 Appendix 41. Experimental Data for stavudine2-aminopyridine, 39 303 Appendix 42. Experimental Data for stavudine4-hydroxybenzoic acid, 40 307 Appendix 43. Experimental Data for stavudine salicylic acid, 41 311 About the Author End Page

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ix List of Tables Table 1.1 Covalent and Noncovalent Interactions* 2 Table 1.2 Percentage Occurrence of hydr ogen bonding functional groups in APIs 14 Table 2.1. Percentage occurrence, distan ce ranges, and average distance for supramolecular synthons I-VI 43 Table 3.1 Geometric features of supramolecular homosynt hon V and supramolecular heterosynthon VI 86 Table 3.2 p Ka values of components used in co-crystals 13 20 88 Table 3.3 Crystallographic data and structure refinement parameters for co-crystals 13-20 102 Table 3.4 Melting points of co-crystals 13-20 and corresponding starting materials 106 Table 3.5 Geometrical parameters of intermolecula r interactions for co-crystals 13-20 107 Table 4.1 CSD statistics on supramolecular synthons that occur in structures cont aining only COOH, Narom, and OH 119 Table 4.2 p Ka data for 21-36 121 Table 4.3 Summary of supramol ecular synthons present in 21-36 145 Table 4.4 Melting point comparison for 21-36 147

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xTable 4.5 Hydrogen Bond Distances and Parameters for 21-36 154 Table 4.6 Hydrogen Bond Distances and Parameters for 21-36 (cont.) 155 Table 4.7 Crystallographic data and stru cture refinement parameters for compounds 21-36 156 Table 4.8 Crystallographic data and struct ure refinement parameters for compounds 21-36 (cont) 157 Table 5.1 Geometrical Features of Supramolecular Synthons 163 Table 5.2 Geometric Parameters of Intermolecular Interactions for (stavudine)3 melamine, 37 173 Table 5.3 Geometric Parameters of Intermolecular Interactions for 38-41 174 Table 5.4 Crystallographic Data and st ructure refinement parameters for compounds 37-41 175

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xi List of Figures Figure 1.1. Watson and Crick hydrogen bonding in DNA 3 Figure 1.2 Examples of supramolecular synthons: a) carboxyl ic acid homosynthon and b) carboxylic acidpyridine heterosynthon 5 Figure 1.3. Crystal stru cture of quinhydrone 8 Figure 1.4. Hydrogen bonded co-crystal st ructures in the CSD from 1985-2005 9 Figure 1.5. Co-crystal of sulfadimidin e and acetylsalicylic acid, VUGMIT 15 Figure 1.6. Co-crystal of barbital and N,N-bis(m-t olyl)melamine JICVIA10, sustained by 3-point recogniti on supramolecular heterosynthon 15 Figure 1.7. Crystal structure of carbamazepine sustained by amide dimer 16 Figure 1.8. Illustrate the co -crystal of carbamazepineacetylsalicylic acid sustained by the two point recognition acid-am ide supramolecular heterosynthon 17 Figure 1.9. The crystal structure of carbamazepinesaccharin co-crystal 18 Figure 1.10. Crystal struct ure of cis-itraconazolesuccinic acid co-crystals 20 Figure 1.11. The crystal structur e of fluoxetine hydrochloridesuccinic acid co-crystal sustained by char ge assisted carboxylic acid Clinteractions 20 Figure 2.1. Molecular components us ed in co-crystallization of 1-12 41

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xiiFigure 2.2. Supramolecular heterosynthons that can be formed between carboxylic acids and aromatic nitrogen 43 Figure 2.3. Histograms of contacts fo r: a) supramolecular homosynthon I b) ON contacts in supram olecular heterosynthon III 45 Figure 2.4. Histograms that pres ent the distribution of the CNC angle in a) neutral aromatic nitrogens and b) protona ted aromatic nitrogen moieties 47 Figure 2.5. Illustrate a) discrete thr ee component adducts of co-crystal 1 b) crystal packing in 1 51 Figure 2.6 Illustrate (a) Discrete adduct sustained by supramolecular heterosynthon III (b) packing between adjacent trimeric units. 52 Figure 2.7 Crystal packing of two component units in 3 53 Figure 2.8 Illustrates a discre te three component adduct in 4 54 Figure 2.9 Illustrates discrete adducts of (naproxen)2 trans-1,2-bis(4-pyri dyl)ethylene, 5 55 Figure 2.10 Crystal pack ing in (naproxen)2 trans-1,2-bis(4-pyridyl)ethylene, 5 55 Figure 2.11 Crystal packing in pure glutaric acid 56 Figure 2.12 Crystal struct ure of glutaric acid 1,2-bis(4-pyridyl)ethane 6 57 Figure 2.13 Crystal struct ure of glutaric acid trans-1,2-bis(4-pyridyl)ethylene, 7 58 Figure 2.14 Crystal pack ing of oxalic acid tetramethylpyrazine, 8 59 Figure 2.15 Crystal structur e of isophthalic acid1,2-bis(4-pyridyl)ethane, 9 60 Figure 2.16 Space filling views of a single (10,3)-a network of 12a 63 Figure 2.17 Schematic illustrations of the interpenetration in 12a 64 Figure 3.1 Molecular structures of com ponents used in co-crystallization of 13-20 85

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xiiiFigure 3.2 Histogram of hydrogen bonds of (a) homosynthon V and (b) heterosynthon VI retrieved from the CSD 87 Figure 3.3 Histograms representing the distribution of carbon-oxygen bond lengths in a) neutral aromatic hydroxyl mo ieties (b) neutral aliphatic hydroxyl moieties (c) deprotonated aromatic hydroxyl moieties and (d) deprotonated hydroxyl moieties 89 Figure 3.4 Crystal pack ing in 1-naphthol 90 Figure 3.5 Three component adducts pres ent in the crystal structure of 13 91 Figure 3.6 Crystal packing in 13 91 Figure 3.7 Three component adduct in the crystal structure of 14 92 Figure 3.8 Crystal packing in 14 92 Figure 3.9 Crystal struct ure of 4,4-biphenol 93 Figure 3.10 Crystal stru cture of 4,4-biphenol1,2-bis(4-pyridyl)ethane, 15 94 Figure 3.11 Crystal Pack ing in 4,4-biphenoltrans-1,2-bis(4-pyridyl)ethylene, 16 94 Figure 3.12 Crystal Packi ng in 16, viewed down the b -axis 95 Figure 3.13 Crystal structure of hydroquinone trans-1,2-bis(4-pyridyl)ethylene, 17 95 Figure 3.14 Crystal Packing in hydroquinone trans-1,2-bis(4-pyridyl)ethylene 17 96 Figure 3.15 Crystal structure of hydroquinone TMP, 18 97 Figure 3.16 S-shaped discrete unit in the crys tal structure 19 99 Figure 3.17 Discrete three component adduct of,7-dihydroxynaphthalene (TMP)2 20 100 Figure 4.1 Molecules used in Co -crystallization Experiments 117

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xivFigure 4.2 Possible supramolecular synthons that can form when OH, Narom and COOH are present in the same structure 118 Figure 4.3 Crystal packing in (3-hydroxybenzoic acid)2 pyrazine, 21 showing corrugated sheet 122 Figure 4.4 Interdigitation of independent 2D networks in the crystal structure of 21 123 Figure 4.5 Supramolecular synthon in 22 124 Figure 4.6 Crystal packing of 22 showing corrugated sheet 124 Figure 4.7 Crystal packing of adjacent 2D networks in 22 124 Figure 4.8 a) Eight membered molecular rectangular grid formed by si x 4-hydroxy benzoic acid and two TMP molecules. b) 2-dimensional herringbone network in the crystal st ructure of (4-hydroxybenzoic acid)2 TMP co-crystal 23 125 Figure 4.9 Crystal packing of adjacent 2D networks in 23 126 Figure 4.10 Crystal structur e of 4-hydroxybenzoic acid4-phenylpyridine 24 127 Figure 4.11 Crystal packing of 24 showing translationally related carboxylic acid dimer and face to face -stacked aromatic rings of adjacent 4-phenylpyridine 127 Figure 4.12 Crystal structure of (4-hydroxybenzoic acid)2 pyrazine, 25 showing centrosymmetric acid dimers and alc ohol-aromatic nitrogen heterosynthons 128 Figure 4.13 Crystal structure of (4-hydroxybenzoic acid)2 TMP acetonitrile solvate, 26 129 Figure 4.14 Crystal structur e of 3-hydroxybenzoic acid(4-phenylpyridine)2, 27 130 Figure 4.15 Crystal packing in 3-hydroxybenzoic acid .(4-phenylpyridine)2, 27 130 Figure 4.16 Crystal structur e of 3-hydroxybenzoic acid1,2-bis(4-pyridyl)ethane, 28 131

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xvFigure 4.17 Crystal Packing in 3-hydroxybenzoic acid4,4-bipyridine, 29 132 Figure 4.18 Crystal Packing in 3-hydroxybenzoic acid quinoxaline 30 133 Figure 4.19 Discrete 5-component adduct in the crystal structure of (3-hydroxybenzoic acid)2 (TMP)3, 31 133 Figure 4.20 Crystal structure of 6-hydroxynaphthoic acid trans-1,2-(bis(4pyridyl)ethylene 32 134 Figure 4.21 Crystal packing in 6-hydroxynaphthoic acidtrans-1,2-bis (4-pyridyl)ethylene, 32 135 Figure 4.22 Crystal packing in 4-hydroxybenzoic acidtrans1,2-(4-pyridylethylene, 33 showing translationally related zig-zag chains 136 Figure 4.23 Crystal packing in 3-hydroxybenzoic acid trans-1,2 (4-pyridyl)ethylene, 34 137 Figure 4.24 (a) Charge-assisted pyr idinium-carboxylate supramolecular heterosynthon IV in 35 (b) Crystal packing in 3-hydroxypyridinium benzoate, 35 139 Figure 4.25 Crystal packing in 3-hydroxypyridinium isophthalate 36 140 Figure 4.26 Crystal structures of th e polymorphic forms of 3-hydroxybenzoic acid: (a) Form I and (b) Form II 142 Figure 4.27 Chain motifs generated in 21-34 rationalized via synthons occurring in the pure carboxylic acid 143 Figure 5.1 Crystal structure of stavudine (Form I) 161 Figure 5.2 (a) Triangular four component supramolecular adduct in co-crystal 37 (b) Hexagonal packing of 3:1 co-cry stal of stavudine and melamine, 37 164

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xviFigure 5.3 Crystal Packing of 38 showing right handed helices formed through supramolecular hetero synthons VI and IX 165 Figure 5.4 Illustrates the supramolecula r synthons present in co-crystal 39 166 Figure 5.5 Hydrogen bonded infinite chains of stavudine molecules form terminal O HN hydrogen bonds with pyridyl moiety of 2-aminopyridine in co-crystal 39 166 Figure 5.6 Carboxylic acid-amide supram olecular heterosynthon in stavudine 4-hydroxybenzoic acid 40 167 Figure 5.7 Crystal packing of stavudine4-hydroxybenzoic acid, 40 168 Figure 5.8 Supramolecular synthon present in stavudine salicylic acid, 41 168

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xvii Crystal Engineering of Co-Crystals and their Relevance to Pharmaceutical Forms Tanise R. Shattock ABSTRACT The research presented herein focus upon cr ystal engineering of co-crystals with an emphasis upon the exploration of co-cryst als in the context of delineation of the reliability of hydrogen bonded supramolecula r synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthe sis of co-crystals and the effect on polymorphism is also addressed. The applic ation of the acquired knowledge is towards the crystal engineering of pharmaceutical co-c rystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by th e selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.

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1 1. Introduction 1.1. Introduction 1.1.1. Supramolecular Chemistry Supramolecular chemistry defined by Jean Marie Lehn as chemistry beyond the molecule is the organization of entities that results from the association of two or more chemical species held together by non-covalent interactions.1-7 Early inspiration for the construction of supramolecular entities was obtained from nature and focused upon the development of macrocyclic receptors for th e selective binding of alkali metal cations.8-23 The selective binding of a substrate by a molecular receptor involves molecular recognition, the so called lock and key concept enunciated by Emil Fischer.24 Consequently the principles of self-assem bly and molecular recognition are intimately associated paradigms of supramolecular chemistry. Supramolecular approach to synthesis offers an attractive alternative to traditional covalent synthesis, as a consequence the field of supramolecular chemistry has grown around Lehns analogy that supermolecules ar e to molecules and the intermolecular bond what molecules are to atoms and the covalent bond. 25

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2 1.1.2. Intermolecular Interactions The term non-covalent can be applied to a large range of intermolecular interactions26 including electrostatic interactions (ion-ion, ion-dipol e and dipole-dipole interactions), coordinative bonding (met al-ligand), hydrogen bonding, halogen bonding, stacking and Van der Waals forces. The utili zation of these interactions for directed self assembly requires an understanding of their strength, distan ce and directionality. Gaining a basic knowledge of these factors is a primary focus of this dissertation. A comparison of selected interactio ns is presented in Table 1.1. Table 1.1 Covalent and Non-covalent Interactions* Interaction Bond Energies (kJ/mol) Building blocks Products Features Covalent 200 400 Atoms Molecules H > T S MW: 1 1000 Da Hydrogen Bond Dipole-Dipole stacking Van der Waals 4 120 5 50 < 50 < 5 Molecules Supermolecules H T S MW: 1 100 kDa *Compiled from Steed, J. W.; Atwood, J. Supramolecular Chemistry Wiley J.; Chichester, 2000 Hydrogen bonding 27-29 is perhaps the most reliable design element in the directed self-assembly of small organic molecu les with hydrogen bond donor and acceptor functionalities. The ultimate example of a hydr ogen bonded array is provided by nature in the form of the double helix DNA, which is formed between complementary base pairing of cytosine (C) and guanine (G); and adenine (A) and thymine (T).

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3 N N O N H N N H H H N N N O H H N N N N N H H H N N O O GC base pair AT base pair Figure 1.1. Watson and Crick hydrogen bonding in DNA Scientists have therefore been inspired by nature to construct supramolecular structures and materials utilizing hydroge n bonding. The formation of supramolecular assemblies directed by hydrogen bonds has long been studied with respect to molecular association both in solu tion and the solid state. 30-43 In the solid state the hydrogen bond has been employed as a design elem ent in the crystal engineering70 of small organic molecules. Halogen bonding is another paradigm that complements the hydrogen bond.44-45 A striking parallelism exists betw een the properties of these two interactions. Like hydrogen bonding, the halogen bond is a relatively str ong and directional non c ovalent interaction making it well suited for geometry based design. First reported over 140 years ago,46-47 the interaction is of the type B XY, where B represents a Lewis base, commonly nitrogen, oxygen, sulphur or sellinium with a non bonding elect ron pair and X, a halogen atom commonly iodine. Hassel in his pioneering work used the equivalent term halogen molecule bridge48 to describe these interactions how ever more recently halogen bonds of the type X : N have been called X-bonds.49 This interaction has been used to control

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4 polymorph interconversion 50 and ultimately the generation of numerous supramolecular solid-state structures.51-59 In the solid state the application of thes e interactions are in the generation of multi-component crystals with desired st oichiometry, architecture and ultimately properties. 1.1.3. Crystal Engineering A crystal can be viewed as a supramol ecule par excellence an assembly of molecules crafted by mutual recogniti on to an amazing level of precision.60 The sequence of events that lead to the formation of an organic crystal from solution is governed by thermodynamic and kinetic factors which are inte rtwined in ways that are still hard to understand. As a consequence crystal struct ure prediction via computational methods 61 still remains elusive.62-69 Crystal engineering is defined by Desiraju as the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties . 70 It deals most typically with entire ly new phases, sometimes, but not necessarily, involving well known molecules. Cr ystal engineering invol ves the design of crystals with well defined non-covalent connectivities and networks based upon preselected molecular components that possess specific functional groups.71-75 The term crystal engineering was initiall y introduced by Pepinski in 1955.76 This contemporary area of research however has its origins in Schmidts study of topochemical reactions of cinnamic acids.77 Technological advances in ha rdware, software and X-ray

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5 crystallographic techniques and the concomita nt availability of a large amount of high quality structural information triggered signi ficant activity in the-eighties and nineties. Pioneering works by Etter 78 and Desiraju 79 focused upon using the Cambridge Structural Database (CSD) 80 to analyze and inte rpret non-covalent bonding patterns in an effort to design functional solids. Crystal engineering represents a paradigm for the synthesis of new crystalline phases with pred ictable stoichiometry and architecture. 1.1.4. Supramolecular Synthons and the Cambridge Structural Database Supramolecular synthons79 are structure determining patterns81 or motifs78 that encode the molecular recognition informa tion during the crystallization process. Supramolecular synthons may be divided into two distinct categories: supramolecular homosynthons and supramolecular heterosynthons.82 Supramolecular homosynthons occur as a consequence of th e interaction between identical, complementary functional group as in the case of the carboxylic acid dimer 83-84 (Figure 1.2a) and the amide dimer. 85 Supramolecular heterosynthons result from the interaction be tween different but complementary functional groups. Examples of supramolecular heterosynthons include: carboxylic acidpyridine 82, 86-98 (Figure 1.2b), alcoholpyridine 99-120 and carboxylic acidamide. 121-130 Figure 1.2 Examples of supramolecular synthons: a) carboxylic acid homosynthon and b) carboxylic acidpyridine heterosynthon

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6 Supramolecular homosynthons typically exis t in single component crystals, even though their existence has also been observed in several crystals cont aining two different carboxylic acids.131-134 However when competing or multiple functional groups are present the formation of the supramolecular he terosynthon is more likely. Furthermore, if supramolecular heterosynthons form preferentially the know ledge can be utilized to design and ultimately generate multi-component crystals of structurally more complex molecules such as active pharmaceutical ingred ients (APIs). General trends observed in a series of relevant crysta l structures, in terms of the prevalence of specific supramolecular synthons as compared to others would therefore provide valuable insight for crystal engineering strategies toward the generation of novel multiple-component crystals. Analysis of existing crystal structures represents the first step in a crystal engineering experiment. As suc h, the systematic analysis of large numbers of related structures is a powerful research technique, cap able of yielding results that could not be obtained by any other method. 135 This is facilitated by the Cambridge Structural Database (CSD). The CSD is a depository of crystal structures of over 403,790 organic and organometallic compounds (ConQuest v1.9, January 2007 update) and has earned its status as one of the most inva luable research tools in crysta l engineering. The wealth of crystal structures archived within has aide d the evolution of th e field by allowing the supramolecular retrosynthesis 136 of numerous non-covalent c ontacts. This has facilitated the characterization of robust and reliable synt hons and the potential for the elucidation of new or perhaps overlooked interac tions from existing structures.

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7 Etter et al proposed several hydrogen bonding ru les, one of which states: the best hydrogen-bond donor and the best hydrogen-bond acceptor will preferentially form hydrogen bonds to one another . 78, 137 The Etter rules describe anticipated hydrogen patterns for several well studi ed functional groups and have been used as a working model for the hierarchal app lication of these rules to th e non-covalent synthesis of supramolecular structures. Attempts to classify hydrogen bonded motif s were also addressed by Etter based upon a system of graph-set notation. 138 Hydrogen bonded pattern s are described as chains (C), dimers (D), rings (R), or in tramolecular hydrogen bonds (S). The number of donors (d) and acceptors (a) us ed in each motif are assi gned as subscripts and superscripts respectively and the number of at oms involved in the patt ern is indicated in parenthesis. For example, R2 2(8) graph set notation denotes an eight-membered ring with two hydrogen bond acceptors and two hydrogen bond donors, and is exemplified by the carboxylic acid dimer (Fig 1.2a). The utility of the graph-set notation lay in the evaluation of the frequency of a given hydrogen bonding pattern. However, information with respect to the types of proton donors and proton acceptors engaged in the pattern are not provided. Therefore the frequency of supramolecular synthon composed of specific hydrogen bond donors and acceptors can not be addressed via the graph-set notation system. The identification of reliable supramolecu lar synthons is the preliminary step in the design and analysis of multi-component crysta l structures and is one of the foci of the research presented herein.

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8 1.1.5. Co-Crystal The term and the definition of co-cryst al is a subject of topical debate. 139-141 Broad definition such as that given by Dunitz defines a co-c rystal as a crystal containing two or more components together.140 This definition includes molecular adducts, salts, solvates/hydrates, inclusion compounds, etc. More specific perspective taken by others 142-43 describes a co-crystal as a multiple component crysta l formed between compounds that are solid under ambient c onditions at least one component is molecular and forms a supramolecular synthon with the remaining components. That all components of a cocrystal ( co-crystal formers ) are solids under ambient conditions has important implications with respect to the stability of the co-crystal and its susceptibility for preparation in the solid-state. Analysis of the literature, reveal that co-crystals have been encountered under various terminolog ies, such as molecular compounds, 144 organic molecular compounds, 145 addition compounds, 146 molecular complexes, 147 and solidstate complexes.148 The prototypal co-crystal qu inhydrone formed between hydroquinone and quinone was first reported in 1844 by Whler149 however the crystal structure was not elucidated until the 1960s.150-151 Figure 1.3. Crystal structure of quinhydrone

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9 Although long known, co-crystals represen t a relatively unexplored class of compounds as compared to single component crystals or solvates. There are ca. 1,722 hydrogen bonded molecular co-cryst als (comprised of components that are solid at room temperature) which constitute less than 0.5% of all structures archived in the CSD, as compared to 42,589 hydrates (ca. 11%). Howe ver, based upon the increasing number of relevant literature, it is clear that there is ever-growing interest. 0 20 40 60 80 100 120 140 160 180 198419861988199019921994199619982000200220042006YearFrequency Figure 1.4. Hydrogen bonded co-crystal structures in the CSD from 1985-2005 The inherent physical properties of a mo lecule in part depend on its crystal structure. Towards this end the generation of multiple component crystals is therefore of great importance. Moreover, co-crystals by nature are composed of two or more component therefore the exploration of the competition occurring between supramolecular synthons may be afforded. As will become evident the CSD can be used to study the competition between supram olecular homosynthon and supramolecular heterosynthon. However there is not enough in formation to address the hierarchy of

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10 supramolecular heterosynthons in a competitive environment. Systematic studies involving the competition between three hydr ogen bonded moieties have only been undertaken in a few instances. 152-154 Competitive studies by Aakery et al focused on three distinct hydrogen bonding moieties: prim ary amide, pyridine, and carboxylic acid. The study involved co-crystals of iso -nicotinamide and a range of aromatic and aliphatic acids. The generated co-crystals reve aled consistent hydrogen bonding patterns comprised of two robust supramolecu lar synthons: carboxylic acidpyridine heterosynthon and self-complementary prim ary amide homosynthon. The reproducibility of the hydrogen bonded motifs suggests a domin ant tendency of formation of the acidpyridine heterosynthon ove r the acidamide he terosynthon, that is formed in acid and amide-containing compounds in the absen ce of pyridines. Studies conducted by Bis et al involved alcohol, cyano and aromatic nitrogen moieties. The study involved determining the relative tendency of fo rmation of alcohol-a romatic nitrogen supramolecular heterosynthon in the presen ce of competing cyano group. It was found that the alcohol-aromatic nitrogen heterosynt hon occurred reliably in the presence of the cyano moiety. 1.1.6. Preparation of Co-Crystals Co-crystals are usually prepared by ev aporation from a solution containing stoichiometric amounts of components (cocrystal formers). However sublimation, blending of powders, sonication, growth from melt, slurries and grinding of the components together are suitable methodologies Grinding 155-160 or milling of solids is usually carried out manually us ing a mortar and pestle or mechanochemically using a ball

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11 mill or a Wig L Bug Variables that arise are in the control of reaction conditions such as pressure exerted by the ope rator or the machine, grindi ng time and temperature. The aforementioned technique has profound implicat ions with respect to green chemistry161 which seeks to reduce and prev ent pollution via implementation of environment-friendly chemical processes. Solvent drop grinding 162-163 also referred to as kneading164 or more recently as liquid assisted grinding 165-166 is another promising method of preparation in which a small amount of suitable solvent is added to the ground mixture in order to accelerate co-crystallization. Jones et al ., have successfully shown that the addition of a small quantity of solvent enhances the kinetics of the solid state co-crystallization of cis cis cis -1, 3, 5-cyclohexanetricarboxylic ac id with pyridyl based molecules.167 Solventdrop grinding has also been utilized in pr omoting selective polymorph transformation and for polymorph control.168 The role of the solvent is sugge sted to act as a lubricant for molecular diffusion, a sort of solvent catalysis for the solid-state process, 164 as well as enhancing the opportunity for molecular collision 164 A number of factors contribute to the succe ssful synthesis and isolation of a cocrystal. A detailed understanding of the s upramolecular chemistr y of the functional groups present is a prerequisite for desi gning a co-crystal since it facilitates the appropriate selection of co-crystal formers. However when multiple functional groups are present in a molecule, as is often the case with APIs, th e CSD rarely contains enough information to address the hi erarchy of supramolecular synt hons. Solvent can also be critical in obtaining a particular co-crystal from solution and the relative solubilities of the components in a particular solvent also n eeds to be considered. Moreover, the role of

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12 solvent in the nucleation process remain s somewhat poorly understood even though strides are being made in this area. 169 The inherent change in physicochemical properties as a consequence of the introduction of another component into the crystal lattice a nd the existence of supramolecular synthons affords many potential applications of co -crystals. Notable applications of co -crystals include: non-covalent derivatization a term that was coined in the context of modifying the stability of Polaroid film 73 and the considerable interest these compounds have attracted w ith respect to pharmaceuticals.74-75, 129-130, 142, 170, 193-195 Co-crystals have also found applications in solid-state so lvent free synthesis116, 171, the formation of biomolecular complexes172 and may potentially act as precursors to the formation of 2D and 3D polymers. Moreover a recent publication reports that a variety of supramolecular synthons present within the co -crystal may act as precursors to a number of solid state condensation r eactions thereby affording solid state synthesis of organic molecules.173 The main emphasis of the research pr esented herein however focuses upon the application of co-crystals towards the generation of pharmaceutical co-crystals and developing strategies to accomplish this goal. 1.1.7. Pharmaceutical Co-Crystals Undesirable physicochemical properties, physiological barriers or issues of toxicity often limit the therapeutic benefit of drugs. This has motivated research in API form optimization and drug delivery system s for poorly soluble and poorly absorbed substances. For orally administered drugs, unl ess the substance has an aqueous solubility

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13 above 10 mg/ml over pH-range 1-7 potential absorption problems may occur. The European Pharmacopoeia reports that more than 40% of drug substances have aqueous solubility below 1 mg/ml. The primary method presently utilized in enhancing dissolution of these low solubility substances is the selection of a salt form for weak acids and bases 174-176 or covalent modificatio n. An apparently overlooked means to improve drug dissolution until recently is to make benefit of the reactive functionalities in the molecule and their interacti ons by hydrogen bonding. Crystalline self-assemblies provide a promising modality for improving physicochemical properties such as drug solubility, physical st ability, dissolution rate and bioavailability. The emergence of crystal engineering and the supramolecular design approach to modify APIs extends to these issues without changing the pharmacological benefit of the API. Traditional crystalline forms of APIs have been limited to salts, hydrates/solvates, polymorphs and the free acid or base form. 177 Hydrates/solvates are typically obtained as a result of adventitious uptake of wate r/solvent upon crystallization and like polymorphs they are difficult to be rationally designed. The possibility of dehydration/desolvation and subsequent forma tion of amorphous material, that may occur as a function of time and storag e conditions is also a concern. Pharmaceutical co-crystals are multiple component crystals that are formed between an API and at least one or more co-c rystal former that are solids under ambient conditions.74 This class of compound has gained mu ch interest over the past few years since they offer the potential to amend unde sirable physicochemical properties without covalent modification of the API. Moreover unlike salt forms of APIs, co-crystal formation is not restricted to an ionizable (acidic or basic) center on the API and can

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14 simultaneously address multiple functional groups on the API. A relative large number of non-toxic compounds with hydrogen bonding functionalities ex ist on the GRAS (generally regarded as safe) list that may act as co-crystal formers in comparison to the limited number of salt form ing counter-ions in use.174 The presence of multiple functional gr oups inherent to APIs affords the opportunity for the design of pharmaceutical co-c rystals. In fact an analysis of the top 100 prescription drugs178 reveal that 39% of pharmaceutica lly active ingredients contains at least one alcohol and 30% c ontain at least one carboxylic aci d, this is also consistent with the percentage alco hol and carboxylic acid mo ieties in the Merck Index.179 Consequently addressing the ability of th ese functional groups to form supramolecular synthons would be of great interest. Table 1.2 Percentage Occurrence of hydrog en bonding functional groups in APIs Functional Group Top 100 Prescription Drugs % CSD only Organics % Alcohol 39 20 3 amine 37 11 Carbonyl 35 14 Ether 33 27 2 amine 31 7 Carboxylic acid 30 6 Ester 22 20 Aromatic N 12 6 2 amide 11 9 Sulfonamide 3 1 Analysis of the 1722 co-crystals deposited in the CSD reveal that approximately 5% contain API molecules.180-192 Whereas, some of the examples are a result of

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15 serendipity, the first crystal engineered se ries of pharmaceutical co-crystals may be attributed to works of Caira et al involving the complexa tion of sulfonamide drugs193-195 and the extensive rese arch of Whitesides et al concerning supramolecular assemblies of barbiturates and melamine derivatives. 196-199 Figure 1.5. Co-crystal of sulfadimidine and acetylsalicylic acid, VUGMIT The crystal engineering approach to APIs based upon the use of reliable supramolecular heterosynthons is exemplified by seve ral series of co-crystals involving carbamazepine (CBZ),129-130 ibuprofen,82 piracetam,200 fluoxetine hydrochloride201 and itraconazole.202 CBZ had four reported polymorphs a nd two solvates. All forms of CBZ Figure 1.6. Co-crystal of barbital and N,N-bis(m-tolyl)melamine JICVIA10, sustained by 3-point recognition supramolecular heterosynthon

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16 for which structural data was available were sustained by the primary amide dimer (Fig 1.7.) and the peripheral H-bond donors and acceptor pairs remained unused. Figure 1.7. Crystal structure of carbamazepine sustained by amide dimer Two strategies based upon information obtained from a CSD analysis of the primary amide functional group was employed in designing co-crystals of CBZ. Strategy 1, involved breaking the amide dimer via th e introduction of a car boxylic acid moiety thereby, forming the acid-amide supramolecula r heterosynthon and strategy 2, utilized the peripheral NH2 H-bonding sites while keeping the amide dimer intact. The acidamide supramolecular heterosynthon exists in 47% of entries that contain both an acid and an amide. Both strategies were successf ully implemented to generate several cocrystals of CBZ.

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17 Figure 1.8. Illustrate the co-crystal of carbamazepine acetylsalicylic acid sustained by the two point recognition acid-amide supr amolecular heterosynthon. Figure 1.9. Crystal structure of (carbamazepine.)24,4-dipyridyl illustrates the intact amide dimer and H-bonding of 4,4-dipyrid yl to the peripheral N-H.

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18 Although we are unaware of any pharmaceu tical co-crystals that have been approved by the FDA, there have been seve ral reports related to their physicochemical properties. The CBZsaccharin co-crystal exhibits improved dissolution, chemical suspension and, bioavailability to that of the parent compound.203 Moreover based upon 1,200 high throughput screening experiments the co-crystal also appears to lack the relative propensity towards polymorphism as is seen in pure CBZ. 203 Figure 1.9. The crystal structure of carbamazepinesaccharin co-crystal 2-[4-(4-chloro-2-flourophe noxy)phenyl]pyrimidine-4-carboxamide is a sodium channel blocker with indications in the trea tment or prevention of surgical, chronic or neuropathic pain. The glutaric acid 2-[4-(4-chloro-2-flourophenoxy)phenyl]pyrimidine4-carboxamide co-crystal exhibits 18 fold greater intrinsic dissolution rate as compared to the parent API in a single dose dog exposure study.204 The co-crystal was also physically and chemically stable for storage under stress conditions of 40 C/75% relative humidity and 60 C for 2 months.

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19 Figure 1.11. Illustrates the hydrogen bonding interaction present in 2-[4-(4-chloro-2flourophenoxy)phenyl]pyrimidine-4-carboxamide glutaric acid co-crystal Theophylline, a drug used in the treatment of respiratory illnesses such as asthma, is known to convert between the crystallin e anhydrate and the monohydrous form as a function of relative humidity (RH). This re presents a challenge in the formulation process. A series of dicarboxylic acid co-c rystals of theophylline were subjected to relative humidity changes in an effort to evalua te their stability in relation to crystalline theophylline.205 None of the co-crystals in the stu dy converted into a hydrated form upon storage at high humidity Moreover the theophyllineoxalic acid co-crystal demonstrated superior humidity stability as compared to anhydrous theophylline and the other cocrystals exhibited comparable stability to the theophylline anhydrate. Similar studies involving a series of co-cry stals of caffeine and dicarboxy lic acids have also been undertaken.206 The relative stability profiles of the co-crystals differed from that of the crystalline caffeine in that no co-crystal hyd rate was found. Moreover the co-crystals that were unstable relative to RH dissoci ated into starting components. Dissolution studies of pharmaceutical co-c rystals of itraconazole, a highly water insoluble antifungal dr ug, with 1,4-dicarboxylic acids, i ndicate that the co-crystals achieve and sustain 4 to 20-fo ld higher concentrations as compared to the crystalline itraconazole. 202

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20 Figure 1.10. Crystal structure of cis-itraconazole succinic acid co-crystals A recent study involving co-crystals of fluoxetine hydrochloride (Prozac) an antidepressant, with several pharmaceutically accep table carboxylic acids illustrates the dependence of the co-crystal on the aqueous solubility of the utilized co-crystal former.201 Consequently it is possible to fine-tune th e dissolution rate the API. Additionally the solubility of the fl uoxetine hydrochloridesuccinic acid co-crystal is doubled as compared to the fluoxetine hydrochloride salt. Figure 1.11. The crystal structu re of fluoxetine hydrochloridesuccinic acid co-crystal sustained by charge assisted carboxylic acid Clinteractions L-883555 is a phosphodiesterase IV inhibitor with indication in the treatment of asthma and chronic obstructive pulmonary di sease. Non-stoichiometric, isostructural

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21 complexes of L-883555 and L -tartaric acid demonstrated mu ch higher bioavailability in rhesus monkeys as compared to the free base form of L-883555. 207 In particular the 2:1 co-crystal of L-883555L -tartaric acid exhibited bette r physical properties and was chosen as the viable solid form for safety assessment. The aforementioned studies illustrate th e potential impact of pharmaceutical cocrystals on the pharmaceutical industry in terms of both form and properties. 1.1.8. Polymorphism Polymorphism can be defined as the existe nce of more than one crystal structure of the same compound.208-210 This phenomenon was recognized as early as 1822.211 Polymorphs arise as a consequence of differe nt arrangements and/ or conformation of the same molecules in the crystal lattice and as su ch are classified primarily as structural or conformational polymorphs. The possibility of homosynthons or heterosynthons, the formation of n -point recognition, as well as slight changes in to rsion angles are factors that can lead to the phenomenon of polymor phism. The topical issue of polymorphism is now recognized as being a major scientific ch allenge quite apart from its chemical and legal implications in the pharmaceutical industry. Polymorphs may differ in packing, spectroscopic, thermodynamic, kinetic, surface and mechanical properties. The polymor phic form that crystallizes from solution depends on an inter-play of several factors. Th e factors include polarity of solvent, initial supersaturation and depending on the crystalliz ation method, the rate of cooling or the evaporation of the solvent. Impurities can also affect the potential for a polymorph crystallizing from solution.

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22 The inability to predict the existence of polymorphs or crystal structures in general, has important intellectual property a nd scientific implications. For example, the appearance of an undesired polymorph can invoke problems during the formulation process and lead to patent litigations.209, 212 On the other hand, a novel polymorph can offer an opportunity in terms of impr oved physicochemical properties and product development. Furthermore, since physicoch emical properties of a compound can differ critically from one form to another, induc ing and controlling a specific polymorph is of utmost importance. Polymorphism in organic compounds is perhaps exemplified by 5-methyl-2-(2nitrophenyl)amino] 3-thiophenecarbonitrile (R OY), which has been crystallized as seven polymorphic modifications.213-215 The system has been named ROY because to its red, orange and yellow crystal colors. The forms crystallize as yellow prisms, red prisms, orange needles, orange plates, yellow n eedles, orange red plates and red plates. From a pharmaceutical perspective the stab ility of the product, the ability to process and bioavailability ar e influenced by the physicochemi cal properties of the varied solid state forms. 216 The impact of polymorphism on dr ug behavior is perhaps illustrated by chloramphenicol palmitate (CAPP). CAPP is a broad-spectrum antibiotic known to crystallize in at leas t three polymorphic forms; and one amorphous form.217-218 The most stable form, A, is marketed. Form B, howev er, has an eightfold hi gher bioactivity than form A, creating the danger of fatal dosages when the unwanted polymorph is unwittingly administered because of altera tions in process or storage conditions. 218 The impact of polymorphism with intellectual property implications is exemplified by the case of ranitidine hydrochloride.219 GlaxoSmithKline entered a

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23 lengthy court case against Novopharm for allege d patent infringement based on its right to manufacture and market a different polym orphic form of Glaxo s best-selling antiulcer drug, Zantac. The polymorphic forms in question we re therapeutically equivalent. The existence of polymorphism implies th at kinetic factors are important during nucleation and growth and that the free energy differences between the different crystalline forms are small (<10KJmol-1). The phenomenon is still not entirely understood, however, recent literature reveal that the solv ent-drop grinding approach can be utilized as an efficient method to achieve selective transformati ons between specific polymorphs.168 1.1.9. Summary The research presented herein focuses on crystal engineering of co-crystals and pharmaceutical co-crystals. Particular emphasis is placed upon the exploration of cocrystals in the context of: delineati on of the reliability of hydrogen bonded supramolecular synthons and their hierarchies; exploring the viability of alternatives to solution based methods of preparation of co -crystals specifically melts, grinding and solvent drop grinding; and evaluation of the susceptibil ity of co-crystals towards polymorphism using the solvent-drop gri nding technique. The rational design and synthesis of pharmaceutical co-crystals accomplished by the judicious selection of cocrystal formers facilitated by analysis of exis ting crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.

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24 1.2 References Cited 1. Lehn, J. M., Struct. Bonding 1973 16 1. 2. Lehn, J. M., Pure Appl. Chem 1978 50 871. 3. Lehn, J. M. Science 1985 227 849. 4. Lehn, J. M.; Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D.; Vgtle, F. Comprehensive Supramolecular Chemistry ; Pergamon: Oxford, 1996 5. Vgtle, F. Supramolecular Chemistry ; Wiley, J.: New York, 1991 6. Lehn, J. M. Supramolecular Chemistry: Concepts and Perspectives ; VCH: Weinheim, 1995 7. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry Wiley, J.; Chichester, 2000 8. Curtis, N. F.; House, D. A. Chemistry & Industry, 1961 708. 9. Caulder, D. L.; Raymond, K. N. Acc. Chem. Res ., 1999 32 975. 10. Curry, J. D.; Busch, D. H. J. Am. Chem. Soc ., 1964, 86 592. 11. Jager, E.-G. Z. Chem ., 1964 4 437. 12. Antonisse, M. M. G.; Reinhoudt, Chem Commun ., 1998 443. 13. Pedersen, C. J. J. Am. Chem. Soc ., 1967 89 7017. 14. Pedersen, C. J., Angew. Chem. Int. Ed. Engl ., 1988 27 1021. 15. Cram, D. J.; Dewhirst, K. C. J. Am. Chem. Soc ., 1959 81 5963. 16. Cram, D. J.; Bauer, R. H. J. Am. Chem. Soc ., 1959 81 5971. 17. Cram, D. J.; Bauer, R. H.; Allinger, N. L.; Reeves, R. A.; Wechter, W. J.; Heilbronner, E. J. Am. Chem. Soc ., 1959 81 5977.

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25 18. Cram, D. J. Angew. Chem. Int. Ed. Engl 1988 27 1009. 19. Ehrlich, P. Studies on Immunity ; Wiley: New York, 1906 20. Wolf, K. L.; Wolff, R. Angew. Chem. 1949 61 191. 21. Cram, D. J.; Cram, J. M. Science 1974 183 803. 22. Pedersen, C. J. J. Am. Chem. Soc. 1967 89 7017. 23. Dietrich, B. ; Lehn, J. M.; Sauvage, J. P. Tetrahedron Lett. 1969 2889. 24. Fischer, E. Ber. Deutsch. Chem. Ges. 1894 27 2985. 25. Lehn, J. M. Angew. Chem. Int. Ed. 1990 29 1304. 24. 26. Maitland, G. C.; Rigby, E. B.; Smith, E. B.; Wakeham, W. A. Intermolecular Forces: Their Origin and Determination ; Oxford University Press: Oxford, 1981 27. Jeffrey, G. A. An Introduction to Hydrogen Bonding. ; Oxford University Press: Oxford, 1997 28. Jeffrey, G. A.; Saenger, W. Hydrogen Bonding in Bi ological Structures ; Springer: Berlin, 1991 29. Pauling, L. The Nature of Chemical Bond ; Cornell University Press: New York, 1948 30. Whitesides, G. M.; Simanek, E. E.; Mathia s, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995 28 37. 31. Prins, L. J. ; Reinhoudt, D. N.; Timmerman, P. Angew. Chem. Int. Ed. 2001 40 2383. 32. Rotello, V. M.; Viani, E. A.; Deslongc hamps, G.; Murray, B. A.; Rebek, J. J. Am. Chem. Soc. 1993 115 797.

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26 33. Hirschberg J. H. K. K.; Brunsveld, L.; Ramzi, A.; Vekemans Jajm; Sijbesma, R. P.; Meijer, E. W. Nature 2000 407 167. 34. Lehn, J. M.; Mascal, M.; Decian, A.; Fischer, J. J. Chem. Soc. 1990 479. 35. Amaya, T.; Rebek, J. J. Am. Chem. Soc. 2004 126 14149. 36. Biros, S. M.; Ullrich, E. C.; Hof, F.; Trembleau, L.; Rebek, J. J. Am. Chem. Soc. 2004 126 2870. 37. Karle, I. L.; Ranganathan, D.; Haridas, V. J. Am. Chem. Soc. 1997 119 2777. 38. Zafar, A.; Geib, S. J.; Hamuro, Y.; Carr, A. J.; Hamilton, A. D. Tetrahedron 2000 56 8419. 39. Yang, J.; Fan, E. K.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1993 115 5314. 40. Rebek, J. Angew. Chem., Int. Ed. Engl. 1990 29 245. 41. Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992 114 4010. 42. Fan, E.; Vanarman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993 115 369. 43. Steiner, T. Angew. Chem. Int. Ed. 2002, 41 48. 44. Metrangolo, P.; Resnati, G. Chem. Eur. J 2001 7, 2511-2519. 45. Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res 2005 38, 386-395. 46. Guthrie, F., J. Chem Soc ., 1863 16 239. 47. Remses I., J. F., Am. Chem. J 1896 18 90. 48. Hassel, O.; Stromme, K. O. Nature 1958 182 1155.

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27 49. Pennington, William T.; Harris, Jeffrey L.; Hanks, Timothy W Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23-27, 2003 INOR-598. 50. Bailey, Rosa D.; Grabarczyk, M.; Hanks, T. W.; Pennington, William T J. Chem. Soc., Perkin Trans. 2 1997 2781 51. Crihfield, A.; Hartwell, J.; Phelps, D.; Wa lsh, R. B.; Harris, J. L.; Payne, J. F.; Pennington, W. T.; Hanks, T. W. Crystal Growth Des 2003 3 313. 52. Walsh, R. B.; Padgett, C. W.; Metran golo, P.; Resnati, G.; Hanks, T. W.; Pennington, W. T. Crystal Growth Des. 2001 1 165. 53. Cardillo, P.; Corradi, E.; Lunghi, A.; Valdo Meille, S.; Messina, T. M.; Metrangolo, P.; Resnati, G. Tetrahedron 2000 56 5535. 54. Romaniello, P.; Lelj, F J. Phys. Chem. A. 2002 106 9114. 55. Metrangolo, P.; Resnati, G.; Pilati, T.; Liantonio, R.; Meyer, F J. Polymer Science 2006 2007, 45 1. 56. Saha, B. K.; Nangia, A.; Jaskolski, M. CrystEngComm 2005 7 355. 57. Metrangolo, P.; Pilati, T.; Resnati, G. CrystEngComm 2006, 8 946. 58. Guardigli, C.; Liantonio, R.; Lorenza Mele, M.; Metrangolo, P.; Resnati, G.; Pilati, T. Supramolecular Chemistry 2003 15 177. 59. Neukirch, H.; Guido, E.; Liantonio, R.; Metr angolo, P.; Pilati, T.; Resnati, G. Chem. Commun., 2005 1534. 60. Dunitz, J. D. The Crystal as a Supramolecular Entity .; Desiraju, G.R.; Ed.; John Wiley and Sons: Chichester, 1996 61. Gdanitz, R. J. Curr. Op. Solid State Mater. Sci. 1998 3 414.

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28 62. Gavezzotti, A. Acc. Chem. Res. 1994 27 309. 63. Ball, P. Nature 1996 381 648. 64. Desiraju, G. R. Nature Mater. 2002 1 77. 65. Dunitz, J. D. Chem. Commun. 2003 545. 66. Lommerse, J. P. M.; Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J. D.; Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Mooij, W. T. M.; Price, S. L.; Schweizer, B.; Schmidt, M. U.; Van Eijck, B. P.; Verwer, P.; Williams, D. E. Acta Crystallogr. B 2000 56 697. 67. Gavezzotti, A.; Filippini, G. J. Am. Chem. Soc. 1995 117 12299. 68. Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J. D.; Dzyabchenko, A.; Erk, P.; Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Lommerse, J. P. M.; Mooij, W. T. M.; Price, S. L.; Scheraga, H.; Schweizer, B.; Schmidt, M. U.; Van Eijck, B. P.; Verwer, P.; Williams, D. E. Acta Crystallogr. B 2002 58 647. 69. Day, G. M.; Motherwell, W. D. S.; Amm on, H. L.; Boerrigter, S. X. M.; Della Valle, R. G.; Venuti, E.; Dzyabchenko, A.; Dunitz, J. D.; Schweizer, B.; Van Eijck, B. P.; Erk, P.; Facelli, J. C.; Bazt erra, V. E.; Ferraro, M. B.; Hofmann, D. W. M.; Leusen, F. J. J.; Liang, C.; Pantel ides, C. C.; Karamertzanis, P. G.; Price, S. L.; Lewis, T. C.; Nowell, H.; Torrisi, A.; Scheraga, H. A.; Arnautova, Y. A.; Schmidt, M. U.; Verwer, P. Acta Crystallogr. 2005 B61 511. 70. Desiraju, G. R. Crystal Engineering: the Design of Organic Solids ; Elsevier: Amsterdam, 1989 71. Panunto, T. W.; Urbanczyk-Lipkowska, Z.; Johnson, R.; Etter, M. C. J. Am. Chem. Soc. 1987 109 7786.

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29 72. Russell, V. A.; Evans, C. C.; Li, W. J.; Ward, M. D. Science 1997 276 575. 73. Taylor, L. D.; Warner, J. C. US 5338644 A 19940816 Cont. of US 5,177,262. 74. Zaworotko, M. J Cryst. Growth Des 2007 7 4. 75. Almarsson, .; Zaworotko, M. J. Chem. Commun. 2004 1889. 76. Pepinsky, R. Phys. Rev. 1955 100 971. 77. Schmidt, G. M. Pure Appl. Chem. 1971 27 647. 78. Etter, M. C. Acc. Chem. Res. 1990 23 120. 79. Desiraju, G. R. Angew. Chem. Int. Ed. 1995 34 2311. 80. Allen, F. H. ; Kennard, O. Chem. Des. Autom. News 1993 8 31. 81. Allen, F. H.; Motherwell, W. D. S.; Rait hby, P. R.; Shields, G. P.; Taylor, R. New J. Chem. 1999 23 25. 82. Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodrguez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003 186. 83. Leiserowitz, L. Acta Crystallogr. 1976 B32 775. 84. Etter, M. C. J. Am. Chem. Soc. 1982 104 1095. 85. Leiserowitz, L.; Schmidt, G. M. J. J. Chem. Soc. 1969 2372. 86. Krishnamohan Sharma, C. V.; Zaworotko, M. J. Chem. Commun ., 1996, 2655. 87. Arora, K. K.; Pedireddi, V. R. J.Org. Chem ., 2003, 68 9177. 88. Smolka, T.; Schaller, T.; Sustmann, R.; Blaser, D.; Boese, R. J. Prakt. Chem ., 2000, 342 465. 89. Olenik, B.; Smolka, T.; Boese, R.; Sustmann, R. Cryst. Growth Des 2003 3 183. 90. Shan, N.; Bond, A. D.; Jones, W. Cryst. Eng ., 2002 5 9. 91. Chatterjee, S.; Pedireddi, V. R.; Rao, C. N. R. Tet. Lett 1998 39 2843.

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30 92. Zhang, J.; Wu, L.; Fan, Y. J. Mol. Struct., 2003 660 119. 93. Aakery, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002 124 14425. 94. Batchelor, E.; Klinowski, J.; Jones, W. J. Mater. Chem., 2000 10 839. 95. Shan, N.; Batchelor, E.; Jones, W. Tet. Lett ., 2002 43 8721. 96. Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2002 2 325. 97. Bond, A. D. Chem. Commun. 2003, 250. 98. Etter, M. C.; Adsmond, D. A. J. Chem. Soc. 1990 589. 99. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst Growth Des. 2006 6 150. 100. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr ., 2003 C59 o481. 101. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm 2000 2, 96. 102. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999 C55 2133. 103. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999 C55 1890. 104. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999 C55 430. 105. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J. ; Liu, C.; Xu, S.; Li, Y.; Bai, C. Cryst. Growth Des ., 2005 5 1889. 106. Friscic T.; MacGillivray L. R Chem. Commun ., 2003 1306. 107. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters 2004 6 4647.

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31 108. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999 C55 2133. 109. Lavender, E. S.; Ferguson, G.; Gl idewell, C. Acta Crystallogr., 1999 C55 430. 110. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr ., 1999 B55 591. 111. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc ., 2006 128 2806. 112. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry 1999 10 429. 113. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr ., 2005 B61 46. 114. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth Des ., 2006 6 1048. 115. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular Pharmaceutics 2007 4 401. 116. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; J. Am. Chem. Soc., 2000 122 7817. 117. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des. 2002 2 7. 118. Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm 2003 5 164. 119. Papaefstathiou, G. S.; MacGillivray, L. R. Org. Lett. 2001 3 3835. 120. Haung, K, -S.; Britton, D.; Etter, M. C.; Byrn S.R. J. Mater. Chem ., 1997 7 713. 121. Aakeroey, C. B.; Beatty, A. M.; He lfrich, B. A.; Nieuwenhuyzen, M. Cryst. Growth Des ., 2003 3 159. 122. Aakeroy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm ., 2004 6 19..

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32 123. Aakeroy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed 2001 40 3240. 124. Aakeroy, C. B.; Desper, J.; Elisabeth, E.; Helfrich, B. A.; Levin, B.; Urbina, J. F. Zeit. fuer Kristallogr ., 2005 220 325. 125. Edwards, M. R.; Jones, W.; Motherwell, W. D. S. CrystEngComm 2006 8 545. 126. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des ., 2003 3 783. 127. Leiserowitz, L.; Nader, F. Acta Crystallogr. 1977 33 2719. 128. Videnova-Adrabinska, V.; Etter, M. C. J. Chem. Crystallogr. 1995 25 823. 129. Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D. B.; Rodrguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003 3 909. 130. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005 220 340. 131. Goud, B. S.; Reddy, P. K.; Panneerselvam, K.; Desiraju, G. R. Acta Crystallogr. 1995 C51 683. 132. Desiraju, G. R.; Sarma, J. A. R. P. J. Chem. Soc. 1983 45. 133. Aakery, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm 2004, 6 19. 134. Vishweshwar, P.; Beauchamp, D. A.; Zaworotko, M. J. Cryst. Growth Des ., 2006 6, 2429. 135. Allen, F. H.; Allen, Frank H.; Shields, Gregory P.; Taylor, R.; Raithby, P. R. Chem. Commun ., 1998 1043. 136. Desiraju, G. R. ed. The Crystal as a Supramolecular Entity: Perspectives in Supramolecular Chemistry 2, Wiley and Sons, Chichester, 1996 137. Etter, M. C. J. Phys. Chem. 1991 95 4601.

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33 138. Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr. B46, 1990 256. 139. Desiraju, G. R. CrystEngComm 2003 5 466. 140. Dunitz, J. D. CrystEngComm 2003 5 506. 141. Childs, S. L.; Stahly, G. P.; Park, A. Molecular Pharmaceutics 2007 4 323. 142. Almarsson, O; Bourghol Hickey, M.; Peterson, M.; Zaworotko, M. J.; Moulton, B.; Rodriguez-Hornedo, N. PCT Int. Appl. WO 2004078161, 2004 143. Aakery, C. B.; Salmon, D. J. CrystEngComm 2005 7 439. 144. Ling, A. R.; Baker, J. L. J. Chem. Soc. 1893 63 1314. 145. Anderson, J. S. Nature 1937 140 583. 146. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1931 53 2784. 147. Vanniekerk, J. N.; Saunder, D. H. Acta Crystallogr. 1948 1 44. 148. Hall, B.; Devlin, J. P. J. Phys. Chem. 1967 71 465. 149. Whler F. Annalen 1844 51 153. 150. Sakurai. Acta Crystallogr. 1965 19 320. 151. Sakurai, T. Acta Crystallogr. 1968 B 24 403. 152. Aakery, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002 124 14425. 153. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003 3 783 154. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular Pharmaceutics 2007 4, 401. 155. Etter, M. C.; Frankenbach, G. M. Chem. Mater. 1989 1 10. 156. Etter, M. C.; Frankenbach, G. M.; Bernstein, J. Tetrahedron Lett. 1989 30 3617.

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34 157. Etter, M. C.; Urbanczyklipkowska, Z.; Ziaebrahimi, M.; Panunto, T. W. J. Am. Chem. Soc. 1990 112 8415. 158. Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991 113 2586. 159. Etter, M. C.; Reutzel, S. M.; Choo, C. G. J. Am. Chem. Soc. 1993 115 4411. 160. Trask, A. V.; Jones, W. Topics in Current Chemistry 2005 254, 41. 161. Anastas, P.; Warner, J. C. Green Chemistry: Theory and Practice ; Oxford University Press: London, 1998 162. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002 2372. 163. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun ., 2004 890. 164. Braga, D.; Giaffreda, S .L.; Grepioni, F.; Pettersen, A.; Maini, L.; Curzi, M.; Polito, M. Dalton Trans. 2006 1249. 165. Friscic, T.; Fabian, L.; Burley, J. C. ; Jones, W.; Motherwell, W. D. S. Chem. Commun ., 2006 5009. 166. Friscic, T.; Trask, A. V.; Jones, W.; Motherwell, W. D. S. Angew. Chem., Int. Ed 2006 45 7546. 167. Trask, A. V.; Shan, N.; Motherwell, W. D. S.; Jones, W.; Feng, S.; Tan, R. B. H.; Carpenter, K. J. Chem. Commun ., 2005 880. 168. Shan, N.; Toda, F.; Jones, W. Chem. Commun ., 2002 2372. 169. Rodriquez-Hornendo, N.; Murphy D. J. Pharm. Sci. 1999 88 651. 170. Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci ., 2006 95, 499. 171. MacGillivray, L. R. CrystEngComm 2002 4 37.

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35 172. Paul, D.; Suzumura, A.; Sugimoto, H.; Teraoka, J.; Shinoda, S.; Tsukube, H. J. Am. Chem. Soc ., 2003 125 11478. 173. Cheney, M. L.; McManus, G. J.; Perman, J. A.; Wang, Z.; Zaworotko, M. J. Crystal. Growth Des. 2007 7 616. 174. Stahl, P. H.; Nakano, M. Pharmaceutical Aspects of the Drug Salt Form, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use; Ed. Stahl, P. H. and Wermuth, C. G, W iley-VCH/VCHA: New York, 2002 175. Gould, P. L. Int. J. Pharm. 1986 33 201. 176. Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. J. Pharm. Sci. 1977 66 1. 177. Haleblian, J. K. J. Pharm. Sci. 1975 64 1269. 178. Web Page, http://www.rxlist.com/top200.htm 179. Merck Index version. 13.4. 180. 5% API CSD refcodes of 32 co-crystals of barbital: AEPDEB, AMIWUO, BARAPY10, BARBAM, BARBUR, BARHMP, BARIMZ10, BARMPN, BIGCUP, CAFBAR20, EADBAR10, HIBJ UX, HIBKEI, JICTIY, JICTOE, JICTUK, JICVAS, JICVEW, JICVIA, JICVOG, JICVUM, JUBRAZ, KEGPUH, KUFPIK, MUDSAF, MUDSEJ, MUDS IN, PIYGEJ, QQQEUV, QQQFVA, WETSOD, WETTUK. 181. CSD refcodes of 14 co-crystals of sulfonamide drugs: GEYSAE, SACCAF, SANAPY, SMZTMP, SORWEB, SORW IF, STHSAM, SULTHE, VIGVOW, VUGMIT, VUGMOZ, XEXCAE, XEXCEI, YOSMOI. 182. CSD refcodes of 8 co-crystals of phenathiazine: BUNRAD, DAPXUN, LENGOA, NIWCEB, PHNSNB10, PHTNBA, PTZPMA, PTZTCQ.

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36 183. CSD refcodes of 9 co-crystals of carbamazepine: UNEYOB, UNEYKH, UNEZAO, UNEZES, UNIBIC, TAZRAO, XAQQUC, XAQRAJ, XAQRIR. 184. CSD refcodes of 9 co-crystals of theophylline: CSATEO, DUXZAX, SULTHE, THOPBA, ZEXTIF, XEJXEQ, XEJXAM, XEJWUF, XEJXIU. 185. CSD refcodes of 6 co-crystals of caffeine: CAFSAL, DIJVOH, DIJVUN, SACCAF, VIGVOW, EXUQUJ. 186. CSD refcodes of 2 co-crystals of fluribuprofen: HUPPEN, HUPPIR. 187. CSD refcode of the co-crystal of ibuprofen: HUPPAJ. 188. CSD refcode of the co-cryst al of itraconazole: IKEQEU. 189. CSD refcode of the co-crystal of diphenylhydantoin: DPHPZL. 190. CSD refcode of the co-crystal of naproxen: YOCZUL. 191. CSD refcodes of 3 co-crystals of fl uoxetine hydrochloride: RAJFAK, RAJFEO, RAJFIS. 192. CSD refcodes of 2 co-crystals of piracetam: DAVPAS, DAVPEW. 193. Caira, M R. J. Chem. Crystallogr ., 1994 24 695. 194. Caira, M. R. J. Crystallogr. Spectros. Res ., 1992 22 193. 195. Caira, M. R. J. Crystallogr. Spectros. Res ., 1991 21 641. 196. Zerkowski, J. A.; MacDonald, J. C.; Whitesides, G. M. Chem. Mater. 1997 9 1933. 197. Zerkowski, J. A.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1994 116 4305. 198. Zerkowski, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994 116 4298.

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37 199. Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992 114 5473. 200. Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J. Chem. Commun ., 2005 4601. 201. Childs S. L.; Chyall L. J.; Dunlap J. T.; Smolenskaya V. N.; Stahly B. C.; Stahly G. P. J. Am. Chem. Soc. 2004 126 13335. 202. Remenar, J. F.; Morissette, S. L.; Pete rson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, J. Am. Chem. Soc. 2003 125 8456. 203. Hickey, M. B.; Peterson, M. L.; Scoppettu olo, L.A.; Morrisette S.L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M.J.; Eur. J. Pharm. Biopharm. 2007 accepted manuscript. 204. McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; ODonnell, E.; Park, A. Pharm. Res. 2006 23 1888. 205. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm 2006 320 114. 206. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Crystal Growth Des 2005 5 1013. 207. Variankaval, N.; Wenslow, R.; Murry, J.; Hartman, R.; Helmy, R.; Kwong, E.; Clas, S.-D.; Dalton, C.; Santos, I. Crystal Growth Des. 2006 6 690. 208. McCrone, W. C. Polymorphism. In Physic s and Chemistry of the Organic SolidState; Interscience: New York, 1965 209. Bernstein, J. Polymorphism in Molecular Crystals ; Clarendon Press: Oxford, United Kingdom, 2002 210. Threlfall, T. L. Analyst 1995 120 2435.

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38 211. Mitscherlich, E. Ann. Chim. Phys. 1822 19 350. 212. Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Pharm. Res. 2001 18 859. 213. Chen, S.; Guzei, I. A.; Yu, L. J. Am. Chem. Soc. 2005 127 9881. 214. Yu, L. Stephenson, G. A.; Mitchell, C. A. Bunnell, C. A.; Snrek, S. V.; Bowyer, J.; Borchardt, T. B.; Stowell, J. G.; Byrn S. R. J Am. Chem. Soc 2000 122 585. 215. Mitchell, C.A.; Yu, L.; Ward, M.D. J. Am. Chem. Soc. 2001 123 10830. 216. Grant D. J. W. Polymorphism in Pharmaceutical Solids: Theory and origin of polymorphism Brittain H.G.ed., Marcell Dekker Inc. New York 1999 1. 217. Kaneniwa, N.; Otsuka, M. Chem. Pharm. Bulletin 1985 33 1660. 218. Bernstein, J. Prog. Clin. Biol. Res 1989 289 203. 219. Wu, V.; Rades, T.; Saville, D. J. Pharmazie 2000 55 508.

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39 2. The Reliability of the Carboxylic Acid -Aromatic Nitrogen Supramolecular Heterosynthon 2.1. Introduction Carboxylic acids represent one of the most ubiquitous functional groups in crystal engineering. They possess a hydrogen bond donor as well as an acceptor site and are therefore self complementary. Carboxylic ac ids are known to self associate to form centrosymmetric dimers I and catemers II .1 A search of the Cambridge Structural Database (CSD)2-5 reveals that there are 7148 crystal st ructures that cont ain at least one carboxylic acid. Of this number 1683 ( 23%) entries exhibit the acid dimer I whereas 125 (1.7%) crystal structures exhibit the catemer motif II Based upon the analysis ca. 25% of the total 7148 crystal structur es that contain a carboxylic ac id are involved in forming either I or II O O H O O H I O O H O O H O O H II Analysis of the remaining 75% of carboxylic acid containing compounds not involved in forming homosynthon6 I or II reveals that they are engaged in interactions

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40 with different complementary functional groups i.e they are involved in forming a variety of supramolecular heterosynthons.6 Functional groups that were found to interact with carboxylic acids include: aromatic N (defined in the searches as six membered aromatic ring containing at least one unprotonated nitrogen), 1 and 2 amides, carbonyls, phoshonyls, alcohols, chlorides, bromides, etc. In an effort to further investigate the occurrence of supramolecular homosynthon6 I and II, entries containing carboxylic acids devoid of competing hydrogen bond donors and/or acceptors were analyzed. There are 452 crystal structures containing at least one carboxylic acid in the absence of competing functional groups 422 entries (93 %) exhibit supramolecular homosynthon I as compared to 30 structures (7%) that form supramolecular homosynthon II suggesting that I is favored over II In this chapter, the presented research is focused on the ability of carboxylic acids and aromatic nitrogen to form reliable carboxy lic acid-aromatic nitrogen supramolecular heterosynthon III In order to form a co-crystal between a carboxylic acid and an aromatic nitrogen, the basic assumption is that the initial components must engage in the formation of supramolecular heterosynthon III that can compete successfully with the carboxylic acid homosynthon, otherwise a mixt ure of starting material results. The second part of the study involve s evaluating alternative methods such as grinding, solvent drop grinding7 and melts towards synthesis of co-cry stals and to screen the obtained cocrystals for polymorphism8 using the solvent-drop grind technique. The application of the knowledge obtained from the series of experime nts is the rational de sign and synthesis of new multiple-component crystals that contain structurally more complex molecules such as active pharmaceutical ingredients (APIs).

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41 2.2. Results and Discussion A series of mono, di and tricarboxylic acids were co-crystallized with a set of aromatic nitrogen based molecules (Figure 2.1). Single crystal of the following multicomponent crystals were isolated: (benzoic acid)2 1,2-bis(4-pyridyl)ethane, 1 ; (benzoic acid)2 trans-1,2-bis(4pyridyl)ethylene, 2; benzoic acid 4,4-bipyridine, 3 ; Sorbic acid 1,2-bis(4-pyridinium)ethane sorbate, 4 ; (naproxen)2 trans-1,2-bis(4-pyridyl) ethylene, 5; glutaric acid 1,2-bis(4-pyr idyl)ethane, 6, ; glutaric acid trans-1,2-bis (4-pyridyl)ethylene, 7 ; oxalic acid tetramethylpyrazine, 8 ; isophthalic acid 1,2-bis (4-pyridyl)ethane, 9 ; (trimesic acid)2 ( trans-1,2-bis(4-pyridyl)ethylene)3, 11 ; (trimesic acid)2 1,2-bis(4-pyridyl)ethane)3 Form I, 12a and (trimesic acid)2 1,2-bis (4-pyridyl)ethane)3 Form II, 12b N N C H3 C H3 CH3 CH3 N N N N COOH COOH HOOC COOH HOOCCOOH HOOC COOH HOOC COOH HOOCCOOH COOH O N N tetramethylpyrazine (TMP) 1,2-bis(4-pyridyl)ethane trans-1,2-bis(4-pyridyl)ethylene benzoic acid isophthalic acid trimesic acid glutaric acid sorbic acid oxalic acid naproxen 4,4'-bipyridine Figure 2.2.1. Molecular components used in co-crystallization of 1-12

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42 2.2.1. CSD Analysis Searches were conducted using the 2006 release of the CSD using Conquest version 1.9, with the January 2007 update. Fi lters placed on the searches include 3D coordinates determined, R factor < 7.5% a nd only organics. The visualization package Mercury 1.5 was used to anal yze the retrieved entries. For each supramolecular synthon consider ed, initial contact distance well beyond the sum of the Van der Waals radii of the hydrogen bond donor and the acceptor atoms were applied. Contact limits for each inter action was subsequently determined from distance distribution plots. Based on visual inspection of the resulting histogram and subsequent structural analysis of selected entries, the lower an d higher cut offs for hydrogen bonds distances were determined. In order to distinguish protonated arom atic nitrogen from neutral aromatic nitrogen specific restrictions were applied to the CSD searches. For neutral aromatic nitrogen, the nitrogen atom was defined to be uncharged and the number of bonded atoms was set to 2. In the case of protonated ar omatic nitrogen, hydrogen atoms were placed on the aromatic nitrogen, the char ge was set to +1 and the number of bonded atoms was set to 3. For carboxylate anion the carbon atom was drawn bonded via any/unspecified bonds to two oxygen atom, the number of bonded at om for each oxygen atom was set to one and no charge was specified. There are four supramolecular synthons th at can be expected when a carboxylic acid and an aromatic nitrogen containing mo lecule occur within the same crystal structure: carboxylic acid supramolecular homosynthon I or II ; carboxylic acid-pyridine supramolecular heterosynthon III ; and the charge assisted form of III i.e.

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43 supramolecular heterosynthon IV (Figure 2.2). As will become clear, both statistical analysis and experimental data indicate that the formation of supramolecular heterosynthon is favored to that of supramolecular homosynthons I and II O O H N O O N+ H III IV Figure 2.2.2. S upramolecular heterosynthons that can be formed between carboxylic acids and aromatic nitrogen: carboxylic ac id-aromatic nitrogen heterosyntho n III and pyridinium-carboxylate heterosynthon IV A CSD analysis of compounds that contain at least one carboxylic acid and an aromatic nitrogen moiety was conducted in order to determine the occurrence of the supramolecular heterosynthon III. The percentage occurrence and hydrogen bond distances of supramolecular synthons I-IV are presented in Table 2.1. Table 2.1. Percentage occurrence, distance ranges and average distance for supramolecular synthons I-VI The CSD contains 684 crystal structures with both a carboxy lic acid and an aromatic nitrogen containing compound. 447 en tries (ca. 65%) exhi bit supramolecular heterosynthon III as compared to 32 crystal stru ctures (ca. 5%) that display the Number of entries Distance range [] Mean ( ) [] Synthon I 1683/ 7148 (23%) O-HO 2.50-3.00 2.65(3) Synthon II 125/7148 (1.7%) O-HO 2.50-3.00 2.70(9) Synthon III 447/684 (65%) O-HN 2.50-2.90 2.65(3) Synthon IV 365/368 (99%) N+-HO2.40-3.00 2.67(9)

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44 carboxylic acid supramolecular homosynthon I or II. It should be noted that there are 11 structures that exhib it both carboxylic acid homos ynthon and heterosynthon III due to the presence of multiple carboxylic acid moieties. In the remaining structures that do not exhibit III, the carboxylic acid f unctionality forms hydrogen bonds with other competitive proton donors or acceptors such as amines, amides, water molecules, chloride ions etc. The histogram (F igure 2.3) reveal that the COO-H Narom hydrogen bond distances for III occur within the ra nge of 2.50 2.90 (average 2.65(3) ). The same search was performed in the absence of other strong donors and/or acceptors e.g. alcohols, 1 and 2 amides, 1 and 2 sulfonamides, imidazoles, carbonyls, nitriles, nitrocompounds, phosphine oxides, chloride ions, bromide ions and water molecules. The number of structures cont aining both carboxylic acid and aromatic nitrogen in the absence of other competing donor and or accep tor moieties is 109. In this subset, the percentage occurrence of III increases to 95% (104/109). It should be noted that duri ng the course of this work several reports have been published regarding the use of III as a design element in crystal engineering.6,9-29 The observation of the robustness of supramolecular synthon III based upon the CSD analysis is consistent with the experimental resu lts of the new compo unds presented herein.

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45 0 10 20 30 40 50 60 702.52.62.72.82.93O-HO hydrogen bonds ( )Number of entries a) 0 10 20 30 40 50 60 2.52.62.72.82.93 O-HN H-bond distance ( )Number of entries b) Figure 2.2.3. Histograms of contacts for: a) supramolecular homosynthon I b) ON contacts in supramolecular heterosynthon III 2.2.2. Features of Carboxylic Ac id-Aromatic Nitrogen Interaction The difference in p Ka of the carboxylic acid and the aromatic nitrogen base is often used as an indicator to determine whether neutral COO-H Narom hydrogen bond or proton transfer results [ p Ka = p Ka (base)p Ka (acid)]. In the pharmaceutical industry the rule of thumb for salt formation is a p Ka difference greater than 2 or 330 and is typically used as a criterion for selecting counter ions for salt formation. Johnson and Rumon31

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46 however suggests a limit they re port that a difference of pKa < 3.75 affords neutral COOH Narom interactions whereas pK a >3.75 results in proton transfer. The formation of the carboxylic acid-aromatic nitrogen hydrogen bond has also been rationalized in terms of the hydrogen bond rules formulated by Etter.32 It is well known that the geometrical f eatures of a neutral carboxylic acid group are different from those of a carboxylate anion.33 Carboxylate anions te nd to have similar C-O bond distances whereas a neutral carboxylic acid have two distin ctly different C-O distance.34 Neutral carboxylic acids are known to have average C=O and C-O bond distances of 1.21(2) and 1.31(2) respec tively whereas deprotonated carboxylate has average C-O bond distances of 1.25(2) .35 The CNC angle in aromatic nitrogen moieties are also known to be sensitive to protonation,75-78 and the cationic form exhibits higher values than that of the corresponding neutral molecules. A graphical representation of the CNC angle distribut ion in both protonated and unprotonated aromatic nitrogens are presented in Figure 2.4. The average CNC angle encountered in 4649 neutral aromatic nitrogen is 117(2) In comparison, the set of 963 cationic aromatic nitrogen exhibits higher CNC angles with an average value of 122(2) The structural features of the bond distances and bond angles are used in the analys is of the presented series of compounds.

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47 0 500 1000 1500 2000 2500 3000 350095 97 99 101 103 105 107 109 111 113 115 117 119 121 123 125 127 129 131 133 135 137 139 MoreC-N-C AngleNumber of Entrie s a) 0 100 200 300 400 500 600112 114 116 118 120 122 124 126 128 130 132 134 136C-N-C AngleNumber of Entrie s b) Figure 2.2.4. Histograms that present the distribution of the CNC angle in a) neutral aromatic nitrogens and b) protonated aromatic nitrogen moieties The p Ka values of the components in volved in the formation of 1-12 are presented in Table 2.2. The difference in p Ka of the base and the acid ranges from -0.93 to 3.15 and the co-crystals obtained from this study a ppear consistent with Johnson and Rumons

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48 observation. There is an exception however in the case 4 which is sustained by both III and IV and the p Ka difference between the initial components is 1.54. Table 2.2. pKa values of the components of 1-12 Melting point is still regarded as a poorly understood phenomenon however it is typically considered to arise as a conseque nce of the dissociati on of the solid state molecular assembly.36 Melting point alternation and i nversion of melting point involving co-crystals of homologous seri es of dicarboxylic acids and nalkyl carboxylic acid have been reported in the literature.37-40 Melting points of the co-crystals involving Co-crystal pKa of acid pKa of component 2 pKa [pKa(base)-pKa (acid)] (Benzoic acid)2 1,2-bis(4-pyridyl)ethane, 1 4.2 6.13 1.93 (Benzoic acid)2 trans-1,2-bis(4pyridyl)ethylene, 2 4.2 5.50 1.30 Benzoic acid 4,4-bipyridine, 3 4.2 3.27 -0.93 (Sorbic acid)2 1,2-bis(4-pyridyl)ethane, 4 4.59 6.13 1.54 (Naproxen)2 trans-1,2-bis(4pyridyl)ethylene, 5 4.84 5.50 0.66 Glutaric acid 1,2-bis(4-pyridyl)ethane, 6 4.33 6.13 1.80 Glutaric acid trans-1,2-bis(4pyridyl)ethylene, 7 4.33 5.50 1.17 Oxalic acid tetramethylpyrazine, 8 1.38 2.88 1.50 Isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 3.53 6.13 2.60 (Trimesic acid)2( trans-1,2-bis(4pyridyl)ethylene)3, 11 2.98 5.50 2.52 (Trimesic acid)2 1,2-bis(4-pyridyl)ethane)3, 12 2.98 6.13 3.15

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49 dicarboxylic acids n = 2-6 carbon atoms show alte rnation of even series having a higher melting point than odd members whereas inversion of the melting point alternation is observed within the latter series of co-crystals as compared to the pure n-alkyl carboxylic acids. Attempts to make correlation between the melting point of the obtained co-crystals and that of the initial com ponents yielded no general conclusions. As is evident from Table 2.3, the melting points of co-crystals 6 and 7 were higher than th at of both starting materials whereas co-crystals 1 3 and 5 had melting points lower than that of the initial components. 2 9 8 11 and 12 all exhibited melting points that were between that of the co-crystal formers. Table 2.3. Melting points of co-crystals 1-12 and corresponding starting materials Co-crystal M. pt of cocrystal M. pt of component 1 M. pt of component 2 (benzoic acid)2 1,2-bis(4-pyridyl)ethane, 1 80-81 121-123 107-110 (benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene, 2 128-129 121-123 150-153 benzoic acid 4,4-bipyridine, 3 99-102 121-123 111-114 sorbic acid 1,2-bis(4-pyridinum)ethane sorbate, 4 110-112 134-135 107-110 (naproxen)2trans-1,2-bis(4-pyridyl)ethylene, 5 135-137 152-154 150-153 glutaric acid1,2-bis(4-pyridyl)ethane, 6 130-132 95-98 107-110 glutaric acid trans-1,2-bis(4-pyridyl)ethylene, 7 180-186 95-98 150-153 oxalic acidtetramethylpyrazine 8 139-142 189-190 84-86 isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 212-222 341-343 107-110 (trimesic acid)2 ( t-1,2-bis(4-pyridyl)ethylene)3, 11 228-234 378-380 150-153 (trimesic acid)2(1,2-bis(4-pyridyl)ethane)3, 12 182-186, 298300 378-380 107-110

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502.2.3. Crystal Structure Description The crystal structure of benzoic acid form s discrete adducts that are sustained by centrosymmetric carboxylic acid dimer I, 41 also coded as R2 2 (8), graph set notation. Cocrystallization of benzoic acid and 1,2-bis( 4-pyridyl)ethane results in insertion of a molecule of 1,2-bis(4-pyridyl )ethane between the carboxylic acid dimer. The crystal structure of (benzoic acid)2 1,2-bis(4-pyridyl)ethane 1 reveals discrete 2:1 suppramolecular adducts sust ained by symmetric COOH Narom supramolecular heterosynthon III. In addition to IR sp ectroscopic evidence, the neutral nature of III is supported by structural data: the C-O and C=O bond distance within 1 is 1.316 and 1.220 respectively and the C-N-C bond a ngle within the pyridyl ring is 117.56 The COOH Narom hydrogen bond distance (D: 2.5983(19) ) occurs within the expected range for carboxylic acid-aroma tic nitrogen interactions (T able 2.1). The benzoic acid molecules are coplanar with respect to th e pyridyl rings of 1,2bis(4-pyridyl)ethane resulting in planar three component adducts. Such discrete adducts are related by translation and are connected via weak C-H O and hydrophobic interactions to generate a supramolecular sheet. Such organization stack as shown in Fi gure 2.5a and further stabilization of the structure is afforded by stacking between adjacent pyridyl rings the centroid to centroid di stance of which is 3.55.

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51 (a) (b) Figure 2.2.5. Illustrate a) discrete three component adducts of co-crystal 1 b) crystal packing in 1 The asymmetric unit of (benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene 2 consists of one molecule of benzoic acid and a half molecule of trans-1,2-bis(4pyridyl)ethylene and adopts the space group P21/ c The components form centrosymmetric three component discrete adducts sustained by supramolecular heterosynthon III (D: 2.622(2) ]. The C-O and C=O bond distances of 1.320 and 1.217 respectively and the C-N-C angle of 117.19 support the neutral nature of III. The supramolecular trimer in 2 is planar the dihedral a ngle between the carboxylic acid

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52 group and the pyridyl ring is 0.64 The structure is also stabilized by interaction between adjacent rings (Figure 2.6) a) b) Figure 2.2.6 Illustrate a) Discret e adduct sustained by supramolecu lar heterosynthon III b) packing between adjacent trimeric units. Co-crystallization of a 2:1 molar ratio of benzoic acid and 4,4-bipyridine resulted in the 1:1 co-crystal of benzoic acid4,4-bipyridine 3 The crystal structure of 3 consists of two molecules of benzoic acid a nd two molecules of 4,4 -bipyridine. The cocrystal forms two componen t adducts sustained by supramolecular heterosynthon III [D1: 2.668(3) D2: 2.655(3) ]. The dimeric pairs align in an alternating fashion parallel to the b axis. The dihedral angles between the planes of the pyridyl rings in the two independent 4,4-bipyidine molecules are 37.30 and 35.16 and in contrast to 1 and 2 the

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53 hydrogen bonded adducts are not planar. The pl ane of the carboxylic acid is slightly twisted with respect that of the interacting pyri dyl ring of the 4, 4-bipyidine molecule (25.49 and 21.75 ). The neutral nature of III is supported by structural information: the C-O and C=O bond distances are 1.316 and 1.203; 1.309 and 1.206 respectively and the corresponding C-N-C angles are 116.50 and 116.70 Figure 2.2.7 Crystal packing of two component units in 3 The crystal structure of 4 contains one molecule of sorb ic acid, a sorbate ion and a half molecule of 1,2-bis(4-pyridyl)ethane as well as a half 1,2-bis(4-pyridinium)ethane ion in the asymmetric unit. The crystal structure of 4 reveals discrete noncentrosymmetric 2:1 adducts that is sustai ned by either supramolecular heterosynthon III or IV. Analysis of the C-O and C=O bond distances within 4 reveal lengths of 1.322 and 1.208 ; 1.257 and 1.247 respectively and corresponding C-N-C bond angles of 115.96 and 117.29

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54 Figure 2.2.8 Illustrates a discrete three component adduct in 4 Naproxen is a non-steroidal an ti-inflammatory drug that used in the treatment of mild to moderate pain, fever and inflamma tion and is marketed under the trade-name Aleve Naproxen is sustained by th e carboxylic acid catemer motif II.42 Cocrystallization of naproxen with trans-1,2-bis(4-pyridyl)ethylen e resulted in the formation of co-crystal 5 The asymmetric unit of 5 contains two molecules of naproxen and one molecule of trans-1,2-bis(4-pyr idyl)ethylene. Analysis of the crystal structure reveals discrete non-centrosymmetric three co mponent adducts that are sustained by supramolecular heterosynthon III (D1: 2.678(7), D2:2.876(7) ). Such discrete adducts stack along the b axis as shown in Figure 2.10, and stacking between the trans-1,2bis(4-pyridyl)ethylene molecules in adjacent adducts is observed. The centroid to centroid distance for the stacking is 3.400 The C-O and C=O bond distances of the ca rboxylic group within the structure are 1.331 and 1.224 respectively for molecule 1; 1.311 and 1.213 for molecule 2 and the C-N-C angles within trans-1,2bis(4-pyridyl)ethylen e are 117.46 and 117.10 respectively.

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55 Figure 2.2.9 Illustrates discrete adducts of (naproxen)2 trans-1,2-bis(4-pyridyl)ethylene, 5 Figure 2.2.10 Crystal packing in (naproxen)2 trans-1,2-bis(4-pyridyl)ethylene, 5 The crystal structure of glutaric acid is sustained by carboxylic acid dimer I to generate infinite chains that are translationally related.43 Adjacent chains are connected via O O contact to generate 2D sheets as s hown in Figure 2.11. Insertion of the 1,2bis(4-pyridyl)ethane molecules between the ac id dimers of glutar ic acid (GLURAC03) occurs within 6 to generate extended chains sustained by acid-aromatic nitrogen supramolecular heterosynthon III.

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56 Figure 2.2.11 Crystal packing in pure glutaric acid The crystal structure of glutaric acid 1,2-bis(4-pyridyl)ethane 6 contains two independent molecules each of 1,2-bis( 4-pyridyl)ethane and glutaric acid. 6 is sustained by supramolecular heterosynthon III. The COOH Narom hydrogen bonds occur within the expected range based upon the CSD analysis. Adjacent infinite chains stack parallel to the b axis in an ABAB fashion as show n in Fig. 2.12. There are ancillary C-H O interactions between the carbonyl oxygen and the C-H groups adjacent to the aromatic nitrogen in the ring which further stab ilize the structure and the COOH group lies generally coplanar with the pyridyl ring (C-O-N-C torsion angle is 3.37 and 6.00 ). The C-O and C=O bond distance within 6 are 1.320 and 1.197; 1.314 and 1.201; 1.316 and 1.199; 1.326 and 1.194 respectively. The C-N-C angles within the two independent molecule s of 1,2-bis(4-pyridyl)ethane are 116.97 117.26 and 116.75 117.19 thus supporting the neutral nature of the interaction.

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57 Figure 2.2.12 Crystal structure of glutaric acid 1,2-bis(4-pyridyl)ethane 6 The 1:1 co-crystal of glutaric acidtrans-1,2-bis(4pyridyl)ethylene 7 is sustained by supramolecular heterosynthon III. As is seen in 6 extended chains are generated via symmetric COO-H Narom hydrogen bond [2.612(3) 175.3 ]. Auxiliary C-H O hydrogen bond contributes to III and helps maintain co-planarity of the carboxylic group and the pyridyl ring. Adjacent in finite chains stack orthogonal to -1 1 0 plane and are connected by weak C-H O interaction to generate 2D sheets. Weak CH O interactions also connect chains between adjacent layers. The neutral nature of 7 is supported by structural information: th e C-O and C=O bond distances are 1.316 and 1.212 respectively and the C-N-C angle is 118.09

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58 Figure 2.2.13 Crystal structure of glutaric acid trans-1,2-bis(4-pyridyl)ethylene, 7 Oxalic acid crystallizes in orthorhombic and monoclinic modifications.44 The polymorph forms carboxylic acid catemer II and generate supramolecular sheets whereas the metastable modification consists of mo lecules of oxalic acid linked through dimer I that extend to generate in finite hydrogen bonded chains. Oxalic acid co-crystallizes with TMP in the molar ratio 1:1 to yield crystals of oxalic acidtetramethylpyrazine (TMP), 8 The crystal structure of 8 consists of molecules of oxalic acid and TMP residing on centers of inversion. 8 is sustained by heterosynthon III [D1: 2.7156(19) ] to generate infinite chains. Such translationally related chains are connected via weak C-H O interactions to generate supramolecular sheets. The C-O and C=O bond distance within 8 is 1.317 and 1.196 respectively and the corresponding C-N-C bond angle is 119.75 The dihedral angle between the plane of the oxalic acid and TMP is 53.18 The deviation from planarity may be attributed to the presence of the methyl groups on the TMP mol ecule which acts as a source of steric hindrance.

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59 Figure 2.2.14 Crystal packing of oxalic acid tetramethylpyrazine, 8 The crystal structure of isophthalic acid1,2-bis(4-pyridyl)ethane, 9 contains one molecule of isophthalic acid and two half molecules of 1,2-bis(4-pyridyl)ethane in the asymmetric unit. Co-crystal 9 is sustained by supramolecular heterosynthon III [D1: 2.6470(18), D2: 2.5840(18)] to generate extended zi g-zag chains. As is seen in XUNGIW, 45 the co-crystal of isophthalic acid an d 4,4-bipyridine translationally related chains align parallel to each other forming planar supramolecular 2D sheets via weak CH O hydrogen bonds. The C-O and C=O bond distances are 1.306 and 1.214 ; 1.318 and 1.210 respectively; a nd the C-N-C bond angle of 116.98 and 117.81 supports the neutral nature of III. As is seen in 1 2 3 4 5 6 and 7 auxillary C-H O interactions stabilize III and the COOH is relatively planar to the pyridyl ring, the C-O-N-C torsion angles within 9 are 7.80 and 10.22

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60 Figure 2.2.15 Crystal structure of isophthalic acid1,2-bis(4-pyridyl)ethane, 9 As is anticipated when a molecule with one hydrogen bond donor is cocrystallized with a molecule containi ng two hydrogen bond acceptor, discrete hydrogen bonded structures results as in the case of 1 2 3 4 and 5 Stoichiometric 2:1 ratios of carboxylic acid to aromatic nitrogen are obser ved in structures invol ving monoacids with aromatic nitrogen having two acceptor sites in all cases except that of benzoic acid and 4,4-bipyridine. However the solvent drop gr inds of the 2:1 mole ratio yields a consistently different X-ra y powder diffraction pattern th an is observed for the 1:1 stoichiometry suggesting the possibilit y of a 2:1 co-crystal as well. Extended chains are observed in co-crystals 6 7 8 and 9 In all cases the ratio of the acid and the aromatic n itrogen is 1:1 and the molecu les are linked by supramolecular heterosynthon III or IV. The geometry of the resulting chains reflects the geometry of the linking acids in a predictable fa shion. Two types of chains are seen, linear chains for cocrystals 6 7 and 8 while zig-zag in the case of 9 In these structures weak C-H O hydrogen bonds link parallel chains to create supramolecular sheets.

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61 The multiple component crystals thus far discussed are all sustained by supramolecular heterosynthons III or IV to generate predominantly strong hydrogen bonded 0D and 1D motifs. However, depending on the multiplicity of the acceptors and donors in the crystal structure, and the resulting geometry of the molecules 2D and 3D hydrogen bonded networks may also be generated. In fact, in 1977 Wells catalogued network structures in crystals46 in a manner that has facil itated the crystal engineering47 of a wide range of infinite 2D and 3D networks.4850 The topology or connectivity of a given network is represented in terms of the general symbol (n, p) where n is the number of nodes in the smallest closed circuit in th e network and p is the number of connections to neighboring nodes that radiate from any centre or node.51 The use of either noncovalent or metal-ligand coor dination bonds means that such networks are modular, i.e., sustained by complementary combin ations of molecules or ions,52 thereby allowing the generation of classes of compound once a prototype has been established. Trimesic acid (benzene-1, 3, 5-tricarboxylic acid, TMA) forms hexagonal (6, 3) networks that are sustained by carboxylic acid homosynthon I.53-54 The diameter of the hexagonal rings which consists of six mol ecules of TMA is 14 x 14. The resulting cavity is filled via interpenetration of di fferent chicken wire frameworks. As a consequence the -polymorph exhibits 4-fold inclin ed interpenetration. The 2:3 cocrystal of TMA and 4,4-bipyridine, 10 represents a prototypal55 (6,3) honeycomb network formed by two components. The co -crystal is sustained by supramolecular heterosynthon III whereby 4,4-bipyridine molecules act as spacers inserting between the acid dimer I thereby expanding the 14 14 TMA cavity to ca. 35 26. The hexagonal cavity is filled by 3-fold parallel interpenetration of independent networks.

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62 Co-crystallization of TMA and trans-1,2bis(4-pyridyl)ethylene results in the formation of the (TMA)2 (trans-1,2-bis(4pyridyl)ethylene)3, 11 There are two molecules of TMA and three molecules of trans-1,2-bis(4-pyridyl)ethylene in the asymmetric unit. Co-crystal 11 exhibits hexagonal (6, 3) netw orks that are sustained by supramolecular heterosynthon III. An expanded cavity size of 41 x 35 dimension is observed without changing the network topol ogy of pure TMA. As is seen in the prototypal co-crystal 3-fold para llel interpenetration is observed. a) b) Figure 2.16. Super honeycomb (6, 3) network (a) and Space filling view of triply parallel interpenetrated (b) nets of 11 The X-ray crystal structure of (TMA)2 (1,2-bis(4-pyridyl)ethane)3, 12a confirms the expected 2:3 stoichiometr y and the presence of supramolecular heterosynthon, III. However, 12a does not exist as a (6, 3) network. Rather, 12a forms a supramolecular isomer48 that is better known in the c ontext of coordination polymers, a (10, 3)-a network.46, 49 The scale of the molecular components means that the dimensions of the channels in the network are ca. 53 30 (Figures 2.17). A distinguishing feature of (10, 3)-a networks is the presence of 4-fold helices, all of the same handedness, that

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63 align parallel to the three cubic axes. 12a contains a set of three (10, 3)-a nets of the same handedness that triply interpenetrate as shown in Figure 2.18a. This set in turn interpenetrates with two other sets of th e same handedness, thereby generating 9-fold interpenetration along the b -axis (Figure 2.18b). Further interpenetration between oppositely handed sets of nets affords 18-fold interpenetration (Figure 2.18c). To our knowledge this is the highest level of interpen etration yet observed in a net, the previous record being 11-fold.56-57 (a) (b) Figure 2.2.16 Space filling views of a single (10,3)-a network of 12a: the ca. 53 30 channel viewed down the c -axis; a view orthogonal to the c -axis.

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64 (a) (b) (c) Figure 2.2.17 Schematic illustration s of the interpenetration in 12a : (a) A set of triply interpenetrated (10,3)-a nets; (b) 9-fold interpenetration each color represents a set of triply interpenetrated (10,3)-a nets; (c) The six sets of triply interpenetrated nets that afford overall 18-fold interpenetration The X-ray crystal structure of (TMA)2 (1,2-bis(4-pyridyl)ethane)3, 12b reveals that it exhibits the expected (6, 3) networ k with linear 1,2-bis(4-pyridyl)ethane molecules expanding the 14 14 TMA cavity to ca. 39 27 The prototypal structure of 10

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65 exhibited a similar expansion of ca. 35 26 .55 Three (6, 3) networks engage in parallel interpenetration as illustrated in Figure 3.19. The void left over after catenation is filled by interdigitation of TMA and 1,2-bis(4-pyridyl )ethane molecules from adjacent layers. Nangia and co-workers have observed similar behavior in another trigonal scaffold, cyclohexane-1,3 cis ,5 cis -tricarboxylic acid (CTA) and have generated a related series of super honeycomb networks.58-59 The network topology and mode of interpen etration in 2:3 co-crystals of CTA,2bis (4-pyridyl)ethane59 is closely related to that observed in 10, 11 and 12b It should also be noted that TMA 1,2-bis(4-pyridyl)ethan e salt structures have been reported 60-62 but they do not exhibit interpenetration. That 12a and 12b are indeed molecular co-crystals is supported by location of hydr ogen atoms in Fourier maps, examination of C O and C=O bond distances, C N C angles and IR spectroscopy. (a) (b) Figure 2.19 Super honeycomb (6,3) network (a) and Space filling view of triply parallel interpenetrated (b) nets of 12b

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66 The existence of (10,3) networks and s upramolecular isomerism in coordination polymers is well documented but to our knowle dge there exist only five neutral hydrogen bonded (10,3)-a nets that are built from organi c molecules and they are not yet known to be polymorphic.63-64 Robson and co-workers recently reported a series of noninterpenetrated (10,3)-a networks in [C(NH2)3][N(CH3)4][XO4](X= S, Cr, Mo).65 However to the best of our knowledge, 12a represents the firs t observation of a hydrogen bonded (10,3)-a network in a co-c rystal. Polymorphism in co-cry stals is also a relatively rare phenomenon, especially when compared to single component molecular crystals.65Indeed, only three previous examples of concomitant polymorphism in cocrystals have been reported and are a consequence of conformational effects.66-68 A number of methodologies were employed in the synt hesis of the presented series of co-crystals. Co-crystallization expe riments were attempted via slow evaporation, melting, grinding and solvent drop grinding tech niques. The latter synthetic approaches can be advantageous from a green chemistry perspective. Additionally, the solvent-drop grinding approach has been shown to be usef ul in addressing the issue of stoichiometry and polymorph control in co-crystals.7 Solvent-drop grinding results suggest that it is generally possible to find expe rimental conditions, under which a specific co-crystal form exists. With regards to the stoi chiometry and the crystal form 1 2 3 4 5 6 7 8 9 and 11 were reproduced using the af orementioned techniques. (TMA)2 (1,2-bis(4pyridyl)ethane)3 was found to exist in two polymor phic modifications. While solution crystallization afforded concomitant polymor phs form I (12a) and form II (12b), both grinding and solvent drop gri nding resulted in a mixture of starting materials.

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67 A screen for crystal forms of 1 9 and 11 was conducted via solvent drop grinding of co-crystal formers involving seven solven ts of different polarity. As determined by infrared spectroscopy and X-ray powder di ffraction, only one form was isolated for 1-9 whereas 11 was only obtained from solvent drop us ing dimethyl sulfoxide. The solvent drop grinding experiments tend to mirror th e co-crystals that were obtained from solution. A screen for crystal forms of 12 was conducted using seventeen solvents. Solvent drop grinding involvi ng isopropanol, chloroform, dichloromethane, cyclohexane, heptane, ethyl acetate, tetra hydrofuran, acetonitrile, isopropyl acetate, methanol, heptane, DMA and DMSO resulted in a mixture of star ting materials whereas solvent drop grinds involving toluene, acetone and yielded a new phase that was different from 12a and or 12b The utilization of solid state co-crystallization of 1-9 and 11 indicates that such methods are viable means for supramolecular synthesis of co-crystals. 2.3. Conclusions Hydrogen bonded supramolecular synthons in a series of co-crystals containing carboxylic acids and aromatic nitrogen have been studied using X-ray diffraction. The hydrogen bonding in these co-crystals support the st atistical analysis that indicate that the acid-pyridine supramolecular heterosynthon III is favored over the formation of the carboxylic acid supramolecular homosynthons I or II. Consequently the relative ranking of these supramolecular synt hons can be presented as: III>I>II. Co-crystal 12 exhibits concomitant polymorphism and one form exhibits the highest level of interpenetration yet observed in an organic or me tal-organic network. The observation of polymorphism in a co-crystal s is of topical interest given the growing

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68 relevance of pharmaceutical co-crystals.6, 9, 69-71 The existence of a (10, 3)-a network with such large dimensions and the inherent modularity of co-crystal s illustrates how cocrystals of TMA might be worthy of furt her investigation in the context of open framework networks especially as a recent study suggests that interpenetrated metalorganic networks are of interest in the context of hydrogen gas storage.70 The majority of APIs in the pharmaceutical industry tend to have low water solubility. Particle size reduction by milling or grinding is typically performed as a means of improving the dissolution rate and there ex ists a correlation between particle size reduction and bulk properties such as flowability, bulk density, mixing ability etc. That the co-crystals within the study and co-crystals in ge neral may be synthesized via grinding and solvent drop grindi ng has significant implication with respect to processing of these novel materials and green chemistry.

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692.4. Experimental Section All reagents were purchased from Aldric h and used without further purification. Single crystals of 1-12 were obtained via slow evaporati on of stoichiometric amounts of starting materials in appropriate solvents and were isolated from solution before complete evaporation of the solvents. 2.4.1. Co-crystallization via grinding: Stoichiometric amounts of the starting material s were ground with a mo rtar and pestle for ca.4 minutes. 2.4.2. Co-crystallization via solvent-drop grinding: Stoichiometric amounts of the starting material s were ground with a mo rtar and pestle for ca. 4 minutes with the addition of 10 L of solvent per 50 mg of co-crystal formers. 2.4.3. Co-crystallization via melting: Stoichiometric amounts of the starting materi als were heated until melt and the mixture was left to crystallize at ambient conditions. 2.4.4. Co-crystallization via solution evaporation: (Benzoic acid)2 1,2-bis(4-pyridyl)ethane, 1 : 1,2-bis(4-pyridyl)ethane (0.037g, 0.20 mmol) and benzoic acid (0.049g, 0.40mmol) was dissolved in a 1:1 ethanol/methanol solvent mixture (2 mL) After three days colorless crystals of 1 were obtained, m. pt: 110-112 (Benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene, 2 : To trans-1,2-bis(4pyridyl)ethylene (0.039g, 0.21mmol) was added benz oic acid (0.052g, 0.42 mmol) and

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70 2 mL of a 1:1 ethanol/methanol so lvent mixture. Colorless rods of 2 were observed within five days, m. pt: 80-81 Benzoic acid4,4-bipyridine, 3 : Benzoic acid (0.049g, 0.40mmol) and 4,4-bipyridine (0.032g, 0.20mmol) was dissolved in of acetonitril e (2 mL). The solution was allowed to slowly evaporate at room temperat ure to yield colorless blocks of 3, m. pt: 128-129 Sorbic acid 1,2-bis(4-pyridinium)ethane sorbate, 4 : Sorbic acid (0.022g, 0.20mmol) and 1,2-bis(4-pyridyl)ethane (0.018g, 0.10mmol) was dissolved in 1:1 ethanol/methanol solution (2 mL). The solution was allowed to slowly evaporate at room temperature to yield colorless crystals of 4 after three days, m. pt: 99-103 (Naproxen)2 trans-1,2-bis(4-py ridyl)ethylene, 5 : Naproxen (0.080g, 0.34mmol) and trans-1,2-bis(4-pyridyl)ethylene (0.03 2g, 0.17mmol) was dissolved in 1:1 ethanol/methanol solution (2 mL). The soluti on was allowed to slowly evaporate at ambient temperature to yield crystals of 5 m. pt: 135-137 Glutaric acid 1,2-bis(4-pyridyl)ethane, 6 : Slow evaporation of a 1:1 ethanol/methanol solution (2mL) containing gl utaric acid (0.027g, 0.20mmol) and 1,2-bis(4-pyridyl)ethane (0.034g, 0.20mmol) yielded colorless crystals of 6 after two days, m. pt: 130-132 Glutaric acidtrans-1,2-bis(4-py ridyl)ethylene, 7 : Glutaric acid (0.027g, 0.20mmol) and trans-1,2-bis(4-pyridyl )ethylene (0.036g, 0.20mmol) wa s dissolved in a 1:1 ethanol/methanol solution (2mL). Afte r two days, colorless crystals of 7 were obtained upon slow evaporation, m. pt: 180-186 Oxalic acid tetramethylpyrazine, 8 : Tetramethylpyrazine (0.015g, 0.11mmol) and oxalic acid (0.0095g, 0.11mmol) was dissolved in ethylacetate (2 mL) on heating. Upon slow evaporation colorless rods of 8 was obtained, m. pt: 139-142

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71Isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 : To 1,2-bis(4-pyridyl)ethane (0.048g, 0.26mmol) was added isophthalic acid (0.044g, 0.27mmol) and the solid mixture dissolved in DMSO (0.5mL). Colorless crystals of 9 were observed within four days, m. pt: 212-222 (Trimesic acid)2 ( trans-1,2-bis(4-pyridyl)ethylene)3, 11 : Trimesic acid (0.077mg, 0.37mmol) and trans-1,2-bis( 4-pyridyl)ethylene (0.100g, 0.55 mmol) was dissolved in DMSO (1 mL). After 3 days, small yellow bl ocks were obtained to yield co-crystal 11, m. pt: 228-234 (Trimesic acid)2 1,2-bis(4-pyridyl)ethane)3, 12 : Trimesic acid (0.030g, 0.14mmol) and trans-1,2-bis(4-pyridyl )ethylene (0.039g, 0.21mmol) was dissolved in DMSO (1mL) The solution was left to slow evaporate at room temperature. Colorless crystals of 12 were obtained within 3 days, m. pt: 182-186 298-300 Polymorphism Screen 1-12 were subjected to a preliminary polymorph screen using solvent drop grinding (as described above) with seven so lvents that exhibit a wide range of polarity: cyclohexane, toluene, chloroform, ethyl acetate, methanol dimethyl sulfoxide (DMSO) and water. A summary of the results obtained from dry grinding, solvent drop grinding and melts are presented in Table 2.4. In addition to the co -crystal, trace amounts of starting material was also observed in the case of 1 2 3 8 9 and 11

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72Table 2.4 Results obtained from solution crystallizat ion, grinding, solvent drop grinding and melting experiments All compounds were analyzed by infrared spectroscopy using a Nicolet Avatar 320 FTIR instrument. The purity of bulk samples was confirmed by X-ray powder diffraction analysis conducted on a Riga ku Miniflex Diffractometer using Cu K ( = 1.540562), 30kV, 15mA. The data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.02 2 and a scan speed of 2.0/min. The X-ray powder diffraction analysis of the powders obtained in the polymorphism screens for 1, 2, 3, 4 6 7 8 9 11 and 12 were collected on Bruker AXS D8 discover X-ray diffractom eter equipped with GADDSTM (General Area Diffraction Detection System), a Bruker AXS HI-STAR ar ea detector at a distance of 15.05 cm as Solution Grinding Solvent-drop grinding Melt 1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 7 7 7 7 7 8 8 8 8 8 9 9 9 9 n/a 11 11 starting material 11* n/a 12 12 starting material New form + starting material n/a

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73 per system calibration, a copper source, automated x-y-z stage, and 0.5 mm collimator. Data were collected over a 2 range of 2.0-37.0 at a step size of 0.02 2. The melting points were determined on a Mel-temp apparatus and are presented in Table 2.1. Differential Scanning Calorime try was performed using a TA instrument model 2140, 10 step/min. 2.4.5. Crystal structure determination Crystals 1-12 were examined under a microscope and suitable single crystals were selected for X-ray analysis. Data were collected on a BrukerAXS SMART APEX CCD diffractometer with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low temperature device. Data for 1, 4-5, 8-9, 11-12 were collected at 100 K whereas data for 2-3, 6-7 were collected at 298 K. Lattice parameters were determined from least square analysis, and reflection data were integrated using the program SAINT+ Version 6.22. Lorentz and polarization corrections were applied for diffracted reflections. In addition, the data was corrected for absorp tion using SADABS. Structures were solved by direct methods and refi ned by full matrix least squares based on F2 using SHELXTL74 software Version 6.10. All non-hydr ogen atoms were refined with anisotropic displacement parameters All H-atoms bonded to carbon atoms, except methyl groups, were placed geometrically a nd refined with an isotropic displacement parameter fixed at 1.2 times Uq for the atoms to which they were attached. H-atoms of methyl groups as well as N or O bonded prot ons were located from Fourier difference map and refined isotropically base d upon the corresponding N or O-atom

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74 (U(H)=1.2Uq(N, O)). Crystallographic data for 1-12 are presented in tables 2.4 and 2.5 and selected hydrogen bond distance s are presented in table 2.6. Table 2.4. Crystallographi c data and Parameters for 1-12 1 2 3 4 5 6 Formula C26H24N2O4 C26H22N2O4 C17H14N2O2 C24H28N2O4 C40H38N2O6 C17H18N2O4 Mol .wt. 428.47 426.46 278.30 408.48 642.72 314.33 Crystal system Triclinic Monoclinic Tr iclinic Monoclinic Triclinic Monoclinic Space group P-1 P2(1)/c P-1 C2/c P1 C2/c a/ 6.4357(17) 8.8678(13) 7.608(2) 25.377(5) 5.7645(16) 15.562(6) b / 6.8960(18) 4.9009(7) 11.454(3) 12.669(3) 7.607(2) 10.281(4) c / 12.412(3) 24.411(4) 16.423(5) 14.754(3) 19.109(5) 9.436(4) 79.037(5) 90 100.293(5) 90 84.851(5) 90 80.952(5) 99.524(3) 95.987(6) 98.68(3) 83.797(5) 92.357(7) 80.144(5) 90 90.521(5) 90 89.241(5) 90 V /3 528.4(2) 1046.3(3) 1399.8(7) 4689.1(4) 829.7(4) 1508.4(10) Dc/g cm-3 1.347 1.354 1.321 1.157 1.286 1.384 Z 1 2 4 8 1 4 2 range 3.38-52.74 3.38-49.42 2.54-49.42 4.40-49.58 2.16-50.20 5.24-52.74 Nref./Npara. 2102/145 1760/145 4679/ 379 3994/324 2928/433 1542/105 T /K 100(2) 100(2) 298(2) 298(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0516 0.0508 0.0638 0.0681 0.0611 0.0820 w R2 0.1385 0.1355 0.1649 0.1957 0.1474 0.2258 GOF 1.083 1.097 1.087 0.995 1.050 1.134 Abs coef. 0.091 0.092 0.088 0.079 0.087 0.100

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75 Table 2.5. Crystallographi c data and Parameters for 1-12 7 8 9 11 12a 12b Formula C17H20N2O4 C10H14N2O4 C20H18N2O4 C27H21N3O6 C54H48N6O12 C27H24N3O6 Mol .wt. 316.35 226.23 350.36 483.47 972.98 486.49 Crystal system Monoclinic Triclinic Tric linic Monoclinic Orthorhombic Monoclinic Space group P2(1)/c P-1 P1 P2(1)/n Pbca P2(1)/n a/ 12.295(3) 3.8081(9) 6.9526(17) 10.214(3) 19.270(3) 10.344(2) b/ 11.166(2) 8.3558(19) 7.4920(18) 12.391(3) 19.906(3) 12.313(2) c/ 24.421(5) 8.606(2) 17.118(4) 18.630(5) 25.249(3) 18.914(4) 90 81.950(4) 100.783(4) 90 90 90 97.102(4) 80.337(4) 90.162(4) 98.129(6) 90 94.309(4) 90 85.847(4) 101.822(4) 90 90 90 V / 3326.8(12) 266.97(11) 856.5(4) 2334.2(10) 9685(2) 2402.3(8) Dc/g cm-3 1.263 1.407 1.358 1.376 1.335 1.345 Z 8 1 2 4 8 4 2 range 3.34-52.74 4.84-52.74 2.42-52.74 3.96-52.74 3.22-49.42 3.96-49.42 Nref./Npara. 6760/415 1069/73 3417/235 4761/334 8249/650 4096/ 325 T/K 298(2) 100(2) 298(2) 100(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0844 0.0654 0.0514 0.0734 0.0557 0.0626 wR2 0.2321 0.1792 0.1405 0.1720 0.1262 0.1242 GOF 1.058 1.061 1.050 1.001 1.062 0.906 Abs coef. 0.091 0.110 0.096 0.099 0.096 0.096

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76Table 2.6. Selected Hydrogen Bo nd Distances and Parameters for 1-12 Hydrogen Bond d (HA) / D (DA)/ / 1 O-H N 1.68 2.5983(19) 175.0 2 O-H N 1.65 2.622(2) 170.9 O-H N 1.73 2.668(3) 171.2 3 O-H N 1.69 2.655(3) 171.3 O-H N 1.66 2.678(7) 172.9 5 O-H N 1.59 2.687(7) 158.1 O-H N 1.79 2.647(3) 174.9 O-H N 1.83 2.657(3) 156.2 O-H N 1.81 2.632(3) 174.2 6 O-H N 1.74 2.657(3) 155.4 7 O-H N 1.74 2.612(3) 175.3 8 O-H N 1.81 2.7156(19) 174.2 O-H N 1.74 2.6470(18) 173.7 9 O-H N 1.61 2.5840(18) 171.2 O-H N 1.63 2.623(4) 160.9 O-H N 1.57 2.597(4) 170.5 11 O-H N 1.66 2.622(4) 168.2 O-H N 1.64 2.601(3) 174.3 O-H N 1.67 2.622(3) 161.6 O-H N 1.59 2.621(3) 178.1 O-H N 1.33 2.553(3) 175.5 O-H N 1.64 2.625(3) 167.7 12a O-H N 1.62 2.607(3) 173.5 O-H N 1.50 2.596(4) 163.7 O-H N 1.56 2.605(4) 175.2 12b O-H N 1.51 2.614(4) 169.9

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772.5. References Cited 1. Leiserowitz, L. Acta Crystallogr., 1976, B32 775. 2. Allen, F. H.; Kennard, O. Chem. Des. Automation News, 1993, 8 31. 3. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res ., 1983, 16 146. 4. Allen, F. H. Acta Crystallogr., 2002, B58 380. 5. Allen, F. H, Taylor, R. Chem. Soc. Rev ., 2004, 33 463. 6. Walsh, R. B. D.; Bradner, M. W.; Fleishman, S.; Morales, L. A.; Moulton, B.; Rodriquez-Hernedo, N.; Zaworotko, M. J. Chem Commun., 2003, 186. 7. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372. 8. Bernstein, J. Polymorphism in Molecular Crystals ; Claredon Press: Oxford, United Kingdom, 2002. 9. Remenar, J. F.; Morissette, S. L.; Pete rson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. J Amer. Chem. Soc ., 2003, 125 8456. 10. Wheatley, P. S.; Lough, A. J.; Ferguson, G.; Glidewell, C. Acta Crystallogr. 1999, C55 1489. 11. Wheatley, P. S.; Lough, A. J.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 1486. 12. Nguyen, T. L.; Fowler, F. W.; Lauher, J. W. J. Amer. Chem. Soc 2001, 123, 11057. 13. Kane, J. J.; Liao, R..; Lauher, J. W.; Fowler, F. W. J. Amer. Chem. Soc 1995, 117 12003. 14. Chatterjee, S.; Pedireddi, V. R.; Rao, C. N. R. Tet. Lett., 1998, 39 2843.

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78 15. Pedireddi, V. R.; Chatterjee, S.; Ranganathan, A.; Rao, C. N. R Tetrahedron 1998, 54 9457. 16. Pedireddi, V. R. Cryst. Growth Des. 2001, 1 383. 17. Arora, K. K.; Pedireddi, V. R. J. Org. Chem ., 2003, 68 9177. 18. Garcia-Tellado, F.; Geib, S. J.; Goswami, S.; Hamilton, A. D. J. Amer. Chem. Soc 1991, 113 9265. 19. Lynch, D. E.; Smith, G.; Byriel, K. A.; Kennard, C. H. L Acta Crystallogr., 1994, C50, 1291. 20. Kumar, V. S.; Kuduva, S. S.; Desiraju, G. R. Acta Crystallogr., 2002, E58 865. 21. Bond, A. D. Chem. Commun ., 2003, 250. 22. Shan, N.; Bond, A. D.; Jones, W. Cryst Eng 2002, 5 9. 23. Shan, N.; Bond, A. D.; Jones, W. Tet. Lett., 2002, 43 3101-3104, 24. Olenik, B.; Smolka, T.; Boese, R.; Sustmann, R. Cryst. Growth Des 2003., 3 183. 25. Etter, M. C.; Adsmond, D. A.; Britton, D. Acta Crystallogr ., 1990, C46 933-4,. 26. Batchelor, E.; Klinowski, J.; Jones, W. J. Mater. Chem., 2000, 10 839. 27. Shan, N.; Batchelor, E.; Jones, W. Tet. Lett ., 2002, 43, 8721. 28. Smolka, T.; Schaller, T.; Sustmann, R.; Blaser, D.; Boese, R. J. Prakt. Chem ., 2000, 342 465. 29. Zhang, J.; Wu, L.; Fan, Y. J. Mol. Struct., 2003, 660, 119. 30. Stahl, P.H.; Wermuth, C. G. ed. Handbook of pharmaceutical salts: properties, selection, and use; Intern ational Union of Pure and Applied Chemistry, VHCA; Wiley-VCH: Weinheim, New York, 2002. 31. Johnson, S. L.; Rumon, K. A. J. Phys. Chem ., 1965, 69, 74.

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79 32. Etter, M. C. Acc. Chem. Res. 1990, 23 120. 33. Aakeroy, C. B.; Hussain, I.; Desper, J. Cryst. Growth Des 2006, 6 474-480. 34. Borthwick, P. W. Acta Crystallogr. 1980, B36 628 35. Bis, J. A.; Zaworotko, M. J. Crystal Growth Des ., 2005, 5 1169-1179. 36. Cotterill, R. M. J. J. Cryst. Growth, 1980, 48 582. 37. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Crystal Growth Des 2003, 3 783. 38. Bond, A. D. New J. Chem ., 2004, 28 104. 39. Bond, A. D. CrystEngComm., 2006, 8 333. 40. Smith, J. C.; Shenton, T. Tetrahedron, Supplement 1966, 7 45. 41. Sim, G. A.; Robertson, J. M.; Goodwin, T. H.; Acta Crystallogr ., 1955, 8 157. 42. Ravikumar, K.; Rajan, S .S.; Pattabhi, V.; Gabe, E. J. Acta Crystallogr ., 1985, C41 280. 43. CSD Refcodes: GLURAC, GLURAC02, GLURAC03, GLURAC04. 44. Thalladi, V. R.; Nsse, M.; Boese, R. J. Am. Chem. Soc. 2000, 122, 9227-923. 45. CSD Refcode: XUNGIW 46. Wells, A. F. Three-dimensional Nets and Polyhedra Wiley Interscience, New York, 1977. 47. Desiraju, G. R. Crystal Engineering. The Design of Organic Solids ; Elsevier: Amsterdam, 1989. 48. Moulton, B.; Zaworotko, M. J. Che m Rev 2001, 101 1629. 49. Batten, S. R.; Robson, R. Angew. Chem. Int. Ed. 1998, 37 1460. 50. Carluci, L.; Ciani, G.; Proserpio, D. M. Coord. Chem. Rev 2003, 246 247. 51. Janiak, C. Dalton Transactions 2003, 2781.

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80 52. Zaworotko, M. J. Chem. Soc. Rev 1994, 23 283. 53. Herbstein, F. H. in Comprehensive Supramolecular Chemistry ; MacNicol, D. D., Toda, F., Bishop, R., Eds.; Pergamon: Oxford, 1996; Vol. 6, pp 61 83. 54. Duchamp, D. J.; Marsh, R. E. Acta Crystallogr 1969, B25 5. 55. Sharma, C. V. K.; Zaworotko, M. J. Chem. Commun 1996, 2655. 56. Reddy, D. S.; Dewa, T.; Endo, K.; Aoyama, Y. J. Am. Chem. Soc 2000, 112 4436. 57. A compendium of interpenetration can be found at Dr. S. R. Battens web page: http://web.chem.monash.edu.au/Depa rtment/Staff/Batten/mainpage.htm 58. Bhogala, B.R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des 2002, 2 325. 59. Bhogala, B. R.; Nangia, A. Cryst. Growth Des 2003, 3 60. Paz, F. A. A.; Bond, A. D.; Khimyak, Y. Z.; Klinowski, J. New J. Chem 2002, 26 381. 61. Paz, F. A. A.; Klinowski, J. CrystEngComm 2003, 5 238. 62. Boldog, I.; Rusanov, E. B.; Sieler, J. ; Blaurock, S.; Domasevitch, K. V. Chem. Commun 2003, 740. 63. Denner, L.; Luger, P.; Buschmann, J. Acta Crystllogr 1988, C44 1979. 64. Abrahams, S. C.; Collin, R. L.; Lipscomb, W. N. Acta Crystallogr 1951, 4 15. 65. Abrahams, B. F.; Haywood, M. G.; Hudson, T. A.; Robson, R. Angew. Chem. Int. Ed 2004, 43 6153. 66. The CSD contains only 24 polymorphic co -crystals that are sustained by strong hydrogen bonds and data has been depos ited on only 9 of these compounds. 1623

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81 polymorphic single component crystals ex ist. Vishweshwar, P.; McMahon, J.A.; Zaworotko, M.J. Crystal Engineering of Phar maceutical Co-crystals. In Frontiers in Crystal Engineering, Eds. Tiekink, E.; V ittal, J. J. 2005, Wiley, Chichester, UK. 67. Bowes, K. R.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystllogr. 2003, B59 277. 68. Trask, A.V.; Motherwell, W.D.S.; Jones, W. 2004, 890. 69. McMahon J.A.; Bis, J.A.; Vishweshwar, P.; Shattock, T.R; McLaughlin, O.L.; Zaworotko, M. J. Zeit. Fr Krist. 2005, 220 340. 70. Almarsson, O; Bourghol Hickey, M.; Peterson, M.; Zaworotko, M. J.; Moulton, B.; Rodriguez-Hornedo, N. PCT Int. Appl. WO 2004078161, 2004. 71. Fleischman, S. G.; Kuduva, Srinivasan S. ; McMahon, J. A.; Moulton, B.; Walsh, Rosa D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des 3, 909919, 2003. 72. Kesanli, B.; Cui, Y.; Smith, M. R.; Bittner, E. W.; Bockrath, B. C.; Lin, W. Angew. Chem. Int. Ed. 2005, 44 72.Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110 2135. 73. SADABS [Area-Detector Absorption Correc tion]. Siemens Industrial Automation, Inc.: Madison, WI, 1996. 74. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997. 75. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110 2135.

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82 76. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D. Acta Crystallogr. 2003, B59 794. 77. Mootz, D.; Wussow, H. G. J. Chem. Phys. 1981, 75 1517. 78. Mootz, D.; Hocken, J. Z. Naturforschung B J. Chem. Sci. 1989, 44 1239.

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83 3.1. Introduction Crystal Engineering is the rati onal design of functional solids.1 Consequently one of the main goals is to control the way in wh ich individual molecules self assemble in the solid state, allowing us to affect solid st ate reactivity and to design new functional materials. A pre-requisite in the design pro cess is the identificati on of reliable, robust supramolecular synthons since it affords a certain level of predictability with respect to anticipated pattern formation in the crystal structure and allo ws for the judicious selection of co-crystal formers. In a continuing e ffort to assess how functional groups selfassociate i.e form supramolecular homosynthons2 versus their interactions with different complementary groups to form supramolecula r heterosynthons, the system of alcohols and aromatic nitrogens were chosen. The st udy involved assessing the reliability of the alcohol homosynthon as compared to the alcohol-aromatic nitrogen heterosynthon. Alcohols represent one of th e most prevalent functiona l groups found in nature and in pharmaceuticals. They are self compleme ntary since they are capable of acting as both hydrogen bond donor and hydrogen bond accep tor. Self-association of alcohols mediated by hydrogen bonds has been studied3 and they are known to form chains, rings (pentemers, hexamers etc) or helices through O-H O hydrogen bonds. Of the 24,995 3. The Reliability of the AlcoholAromatic Nitrogen Supramolecular Heterosynthon

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84 entries that contain an al cohol group in the Cambridge Structural Database (CSD)4-7 6183 (ca. 25%) self associate via hydrogen bonds to form supramolecular homosynthon V. Alcohols are also capable of forming supr amolecular heterosynthons with a number of different complementary functional groups such as aromatic nitrogen, carbonyls, phosphonyls, sulfonyls, etc. The utilization of the alcohol-aromati c nitrogen supramolecular heterosynthon VI in crystal engineering is certainly not without precedence. In fact several examples of cocrystals8-24 based upon supramolecular heterosynthon VI exist in the CSD. VI has been utilized to build crystals with intricate supramolecular architectures25-31, to synthesize host-guest complexes, 31-38 for non-linear optics39 and as supramolecular template to direct topochemical reactions.40-41 In the present study, hydrogen bonded co -crystals formed between aromatic nitrogen and alcohols are investigated in the context of the reliabil ity of supramolecular synthons formed.

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85 N N C H3 C H3 CH3 CH3 OH O H OH OH O H OH OH OH OH N N N N tetramethylpyrazine (TMP) hydroquinone resorcinol 2,7-dihydroxynaphthalene 1-naphthol 4,4'-biphenol 1,2-bis(4-pyridyl)ethane trans-1,2-bis(4-pyridyl)ethylene Figure 3.1 Molecular structures of comp onents used in co-crystallization of 13-20 3.2. Results and Discussion 3.2.1. Cambridge Structural Database Analysis A statistical analysis of the CSD revealed the percentage of occurrence and the parameters of supramolecular synthons V and VI. For each supramolecular synthon considered, initial contact distances well be yond the sum of the Van der Waals radii of the acceptor and the donor atoms were applie d. Contact limits for each interaction was subsequently determined from histogram. Crys tal structures at the end of the bell curve (visual limits) were examined more closely in Mercury. The parameters used to define the searches were 3D-coordinates pr esent, only organics and R < 7.5%.

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86OH N OH O H C VI V C C Table 3.1 Geometric features of supramolecular homosynthon V an d supramolecular heterosynthon VI. Supramolecular Synthon Percentage Interaction Distance Range () Mean () V 6183/24994 (24.7%) O-HO 2.50-3.07 2.78(8) VI 682/1453 (46.9%) O-HNarom 2.50-3.00 2.77(8) There are 1453 entries that contain both an alcohol and an aromatic nitrogen containing molecule in the CSD. Of this number, 682 (47%) entries exhibit supramolecular heterosynthon VI as compared to 274 (19%) crystal structures that exhibit the alcohol homosynthon V. 517 of the 682 structures exhibiting VI were found to occur exclusive of the alcohol homosynthon. A further analysis revealed 208 structures in which an aromatic nitrogen and an alcohol are present in the absence of any other hydrogen bonding moieties. 203 of these st ructures (97%) exhibit heterosynthon VI as compared to 52 structures (26%) that exhibit V, suggesting that VI is favored over V even in the presence of competing functional groups. The alcohol-aromatic nitrogen heterosynt hon was found to occur within the range 2.50-3.00 with an average ON hydrogen bond distance of 2.77(8) see Table 3.1.

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87 0 100 200 300 400 500 600 700 2.52.62.72.82.93 3 O-HO H-bond distance ()Frequency 0 10 20 30 40 50 60 70 80 90 2.52.552.62.652.72.752.82.852.92.953 O...N hydrogen bond distance () Frequency (a) (b) Figure 3.2 Histogram of hydrogen bonds of (a) ho mosynthon V and (b) heterosynthon VI retrieved from the CSD. 3.2.2 Features of HydroxylAr omatic Nitrogen Interaction Phenols (p Ka 8-11) are more acidic th an aliphatic alcohols (p Ka 15-17), consequently the O-H Narom hydrogen bonds formed between phenols and aromatic aromatic nitrogen are expected to be stronger than that form ed between aliphatic alcohols and aromatic nitrogen. Phenols and aromatic nitrogens can inte ract via neutral OH Narom interaction to form co-crystals or with proton transfer from the hydroxyl oxygen to the aromatic nitrogen to form organic salts.39 It has been suggested that proton transfer occurs when the difference in p Ka is greater than 2.95.39 The p Ka values in co-crystals 13 20 range from -3.27 to -7.45 (Table 3.2) and consequently the O-H Narom supramolecular synthons in these compounds woul d therefore be expected to be neutral rather than ionic.

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88 Table 3.2 p Ka values of components used in co-crystals 13-20 Structural parameters of ancillary groups, namely the C-N-C angle in the aromatic nitrogen and C-O bond length in the phenolic moie ties can be used to support the neutral or ionic nature of heterosynthon VI. The CNC angle in aromatic nitrogen is known to be sensitive to protonati on, the cationic form exhibits higher values (ca. 121 ) than that of the corresponding neutral counterpart (ca. 116 ).42-43 Histograms of carbon-oxygen lengths in neutral and ioni c hydroxyl moieties were generated using the CSD and are presented in Figure 3.2 (only good quality cr ystal structures: or dered, error-free, nonpolymeric with 3D coordinates determined and R< 7.5%). To distinguish neutral C-OH from ionic C-Ospecific restriction on the oxygen atoms were applied during the CSD searches. For neutral C-OH bond the hydrogen at om was defined to be bonded to the oxygen atom; the oxygen atom was defined to be uncharged, and the number of bonded atoms was set to 2. In the case of ionic C-Obond, the charge of the oxygen was set to -1 and the number of bonded atoms was set to 1. The 14,235 crystal structures that contain Co-crystal pKa of component 1 pKa of component 2 pKa 13 9.40 6.13 -3.27 14 9.40 5.50 -3.90 15 9.74 6.13 -3.61 16 9.74 5.50 -4.24 17 10.33 5.50 -4.83 18 10.33 2.88 -7.45 19 9.45 2.88 -6.57 20 9.14 2.88 -6.26

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89 neutral aliphatic hydroxyl mo ieties exhibit an average bond distance of 1.42(2) while the 5,150 entries that contain neutral arom atic nitrogen exhibit an average C-OH bond length of 1.36(2) There are 539 entries that contain aromatic deprotonated hydroxyl moieties which exhibit an average C-Obond of 1.27(4) while the 279 crystal structures that contain al iphatic deprotonated hydroxyl groups exhibit average C-Obond distance of 1.26(3) a) b) (c) (d) Figure 3.3 Histograms representing the distribution of carbon-oxygen bond lengths in a) neutral aromatic hydroxyl moieties (b) neutral aliphati c hydroxyl moieties (c) deprotonated aromatic hydroxyl moieties and (d) depr otonated hydroxyl moieties.

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90 The neutral nature of su pramolecular heterosynthon VI was confirmed by proton location in the difference Fourier map, and stru ctural parameters of the CNC angle in the aromatic nitrogen moieties and C O bond lengths in the phenolic moieties.44-45 3.2.3. Crystal Structure Description The crystal structure of 1-naphthol46-47 consists of molecules linked by homosynthon V into chains that run parallel to the b axis as shown in Figure 3.4. Figure 3.4 Crystal packing in 1-naphthol 1-naphthol co-crystallizes with 1,2-bis(4-pyr idyl)ethane in the 2:1 ratio to yield (1-naphthol)2 1,2-bis(4-pyridyl)ethane 13 The molecules interact through symmetric O-HNarom hydrogen bond [2.7206(15) 167.03 ] to form the expected 2:1 discrete adduct as shown in Figure 3.5. Such discrete un its interact in a zig-zag fashion through C-H interactions along the b axis and stacking between molecules of 1,2-bis(4pyridyl)ethane in adjacent disc rete trimers occurs along the c axis. The C-O bond distance in 13 is 1.351 and the C-N-C bond angle is 116.43 thus supporting the neutral nature of the interaction. The dihedral angl e between the planes of the naphthol ring and

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91 that of the pyridyl molecule is 66.28 Similar interactions are also observed in the isostructural co-crystal 14 Figure 3.5 Three component adducts present in the crystal structure of 13. Figure 3.6 Crystal packing in 13 In the crystal structure of (1-napthol)2 trans-1,2-bis(4pyridyl)ethylene 14 two molecules of 1-naphthol and one mol ecule of trans-1,2-bis(4-pyridyl)ethylene aggregate as discrete trimeric s upramolecular adducts through O-HNarom hydrogen bond [2.7350(13), 176.4 ]. As is observed in the previous co-crystal such discrete units interact in a zig-za g fashion through C-H interactions and further stabilization is

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92 afforded by stacking between molecules of trans-1,2-bis(4-pyridyl)ethylene. The C-O bond distance is 1.353 and the C-N-C bond angle is 116.57 The dihedral angle between the planes of the 1naphthol and trans-1,2-bis(4-pyr idyl)ethylene molecules in 14 is 63.38 Figure 3.7 Three component adduct in the crystal structure of 14 Figure 3.8 Crystal packing in 14

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93 Figure 3.9 Crystal structure of 4,4-biphenol 4,4-Biphenol is sustained by supramolecular homosynthon V to generate a 2D supramolecular sheet.48 Hydrogen bonded adducts formed between the combination of double donors such as biphenols and an equal number of acceptors such as diamines are anticipated to form chains with the two mo lecular components alternating along the chain as is observed in co-crystal 15 4,4-biphenol1,2-bis(4-pyridyl)ethane 15 crystallizes in a monoclinic system and is refined in centrosymmetric P21/c space group. Both molecules of 4,4-biphenol and 1,2-bis(4-pyridy l)ethane reside on centers of inversion. The 1:1 co-crystal is sustained by VI via symmetric O-HN H-bonding [2.7459(15), 165.5 ] to generate infinite zig zag chains.( Figure 3.10) The C-O bond distance is 1.361 and the C-N-C bond angle is 116.57 Molecules of 1,2-bis(4pyridyl)ethane can adopt different conformations as a consequence of the flexibility afforded by the central C-C bond; in 4,4-biphenol conformati onal degrees of rotation is afforded about the central C-C bonds and the hydroxyl group about th e C-O bonds. However molecules of 4,4biphenol and 1,2-bis(4-pyridyl )ethane in co-crystal 15 are planar.

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94 Figure 3.10 Crystal structure of 4,4-biphenol 1,2-bis(4-pyridyl)ethane, 15. In 4,4-biphenoltrans-1,2-bis(4-pyridyl)ethylene 16 molecules of 4,4biphenol and trans-1,2-bis(4-pyri dyl)ethylene reside on centers of inversion. As is seen in co-crystal 15 16 is sustained by supramolecular heterosynthon VI, via symmetric OH Narom H-bonding [2.7384(17) 165.0 ] to generate infinite zig zag chains. The neutral nature of the interac tion is supported by structural data: the C-O bond distance is 1.358 and the corresponding C-N-C angle in 16 is 116.66 Figure 3.11 Crystal Packing in 4,4-biphenol trans-1,2-bis(4-pyridyl)ethylene, 16

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95 Figure 3.12 Crystal Packin g in 16, viewed down the b -axis Co-crystallization of a 1:1 mole ra tio of hydroquinone and trans-1,2-bis(4pyridyl)ethylene results in the formation of hydroquinone trans-1,2-bis(4pyridyl)ethylene 17 Molecules of hydroquinone and tran s-1,2-bis(4-pyri dyl)ethylene reside on centers of inversion in 17 The resulting 1:1 co-c rystal is sustained by VI through symmetric O-H Narom hydrogen bonds [O N: 2.7053(18), 167.7 ] to form infinite chains (Figure 3. 5) similar to that seen in MEKWUU, the co-crystal of hydroquinone and 1,2-bis(4-pyridyl)ethane.15 The C-O bond distance in 17 is 1.369 and the C-N-C bond angle is 116.68 which supports the neutral nature of VI. Figure 3.13 Crystal stru cture of hydroquinone trans-1,2-bis(4-pyridyl)ethylene, 17.

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96 Figure 3.14 Crystal Packing in hydroquinone trans-1,2-bis(4-pyridyl)ethylene 17. Hydroquinone tetramethylpyrazine (TMP) 18 was crystallized in the monoclinic crystal system and refined in the P 21/ c space group. The asymmetric unit consists of a half molecule of TMP and a half molecule of hydroquinone. Both molecules reside on a crystallographic cen ter of inversion. In this 1: 1 co-crystal the hydroxyl groups of hydroquinone are hydrogen bonded to TMP via O-H Narom hydrogen bonds [O Narom: 2.76(2)] to generate infinite ch ains (Figure 3.15). Such chains are translationally related along the b axis The C-O bond distance in 18 is 1.369 and the C-N-C bond angle is 118.92 The hydrogen bond distance observed in this co-cry stal is consistent with values observed in other alcohol-aroma tic nitrogen structures (mean 2.78(2) ).

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97 Figure 3.15 Crystal stru cture of hydroquinone TMP, 18 The crystal structure of reso rcinol (RESORA03, RESORA13)49-50 is sustained by supramolecular homosynthon V. There are 16 chemically distinct co-crystals of resorcinol in the CSD,40, 51-58 in these structures resorcinol adopts three different conformations. Of the three possible conf ormation, resorcinol OH groups adopts two divergent motifs that may form linear chain a or zig zag chain b. The convergent OH motif c allows resorcinol to build discrete hydr ogen bonded adducts rather than infinite motifs (ABEKUN and TAHVII). This particular feature has found appl ication in forming discrete adducts in which olefins are br ought into close proximity such that 2+2cycloaddition is achieved upon photo-irradiation.40-41

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98 O O H H O O H H O O H H a c b Molecules of resorcinol in (resorcinol)2 (TMP)3 19, adopts conformation c. Surprisingly, co-crystal 19 crystallizes in 3:2 stoichiome try and exhibits discrete five component adducts rather than the expected 2:2 discrete adduct s or chains through OH Narom hydrogen bonds. While both hydroxyl groups of resorcinol molecules act as OH Narom donors, only one of the nitrogen in th e two exterior TMP molecules of the discrete units act as O-H Narom acceptor. The non-participating nitrogen atoms are involved in weak C-H Narom interactions with a di stance of 3.612 and 3.712. An analysis of the crystal structure revealed tw o independent S-shaped discrete units each consists of one independent molecule of re sorcinol and two independent TMP molecules, one of the TMP molecule reside on a center of inversion. The molecules in the discrete unit interact through O-H Narom hydrogen bonds [O Narom: 2.787(3) 2.816(3) ]. The O-H Narom hydrogen bonds in the other discrete unit are 2.777(3) and 2.824(3) Such independent discrete adduc ts are connected via weak C-H O hydrogen bond. TMP molecules within the five component adduc ts are involved in weak face to face stacking. The C-O bond distances within this structure are 1.362 1.369 1.363 and 1.371 ; the corresponding C-N-C angles are 119.21 119.06 119.22 and 119.24 respectively.

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99 Figure 3.16 S-shaped discrete unit in the crystal structure 19 The asymmetric unit of 2,7-dihydroxynaphthalene (TMP)2 20 consists of two molecules of TMP and a molecu le of 2,7-dihydroxynaphthalene. Similar to co-crystal 19 there is deviation from the expected 1:1 stoichiometry in co-crystal 20 The crystal structure reveals that 20 forms a 1:2 discrete unit in which each 2,7dihydroxynaphthalene molecule is linke d to two TMP molecules through O-H Narom hydrogen bonds of 2.806(3) and 2.733(3) (Figure 3.17). As in co-crystal 19 only one nitrogen atom on TMP is involved in O-H Narom hydrogen bonding. The other nitrogen atom is involved in weak C-H N interactions. The C-O bond distances are 1.363 and 1.362 and the corresponding C-N-C bond angles are 118.62 and 118.10 respectively. stacking is also observed 20 the centroid to centroid distance of which is 3.688.

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100 Figure 3.17 Discrete three component adduct of 2,7-di hydroxynaphthalene(TMP)2 20. Co-crystals 13-20 have been investigated in th e context of thei r reproducibility via grinding, solvent-drop grinding59 and growth from melts. It was observed that whereas solvent drop grinding for 4 minutes wa s efficient at produci ng the co-crystals or achieving partial conversion in most cases, the dry grinding approach did not always lead to conversion. As confirmed by PXRD and FTIR analysis, co-crystals 13, 14, 15, 16, 17, 18, 19 and 20 were reproduced via solvent drop grinding. 13 14 15 16 19 was obtained upon dry grinding for longer periods (8 minutes ) whereas a mixture of starting materials was obtained in the case of 18 19 and 20 Melt experiments also proved to be suitable methodology in obtaining 14 15 and 18 and a new phase was obtained from attempted melt to produce 13 3.3. Conclusions The study herein utilizes a series of co-c rystals to demonstrate that the alcoholaromatic supramolecular heterosynthon VI is favored to the alcohol homosynthon V. Co-

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101 crystals 13 20 are sustained by the alcohol-aro matic nitrogen supramolecular heterosynthon VI. This observation is consistent w ith the supramolecular heterosynthon persistency exhibited by the 203/208 (97%) of entries cont aining only these two moieties (no competing hydrogen bonding moiety) archived in the CSD. The hydrogen bond lengths in 13-20 correspond to the expected values of a typical O-H Narom interaction (Table 3.1) and the structural parameters(C-O lengths and C-N-C angles) of the ancillary groups suggest a neut ral character of VI. Co-crystals 13-20 can be reproduced with little or no solvent via solid-state synthesis.

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102Table 3.3 Crystallographic data and structu re refinement parameters for co-crystals 13-20 13 14 15 16 17 18 19 20 formula C32H28N2O2 C32H26N2O2 C12H11NO C24H20N2O2 C28H36N4O4 C14H18N2O2 C36H48N6O4 C26H32N4O2 Crystallization Solvent Ethanol Ethanol Ethanol Ethanol Methanol Aceton itrile Acetonitrile Aacetonitrile MW 472.56 470.55 185.22 368.42 292.33 246.30 628.80 432.56 crystal system Monoclinic Monoclinic Monoclinic Monoclinic Monoclinic Monoclinic Triclinic Monoclinic space group P 21/ c P 21/ c P 21/ c P 21/ c P 21/ c P 21/ c P -1 P 21/ c a () 6.961(15) 6.8699(7) 11.6591(16) 11.7712(19) 6.000(2) 7.566(2) 9.0768(11) 15.579(3) b () 25.182(5) 25.450(3) 5.9135(8) 5.9268(9) 17.265(6) 9.218(2) 11.7248(14) 8.5123(19) c () 7.7714(16) 7.6379(2) 14.087(2) 13.954(2) 7.062(2) 10.001(3) 17.443(2) 17.781(4) (deg) 90 90 90 90 90 90 98.097(2) 90 (deg) 111.272(4) 110.106(2) 107.618(2) 108.614(3) 92.296(6) 111.328(5) 98.195(2) 93.686(6) (deg) 90 90 90 90 90 90 106.019(2) 90 V /3 1270.9(5) 1254.0(2) 925.7(2) 922.6(3) 731.0(4) 649.7(3) 1734.1(4) 2353.19 Dc/g cm-3 1.235 1.246 1.329 1.326 1.328 1.259 1.204 1.221 Z 2 2 4 2 2 2 2 4 2 range 3.2452.74 5.90-52.74 3.66-52.74 3.66-56.76 5.72-52.74 5.789.92 2.40 52.74 2.62-52.74 Nref./Npara. 2587/163 2560/164 1897/127 2108/128 1493/100 1036/82 6924/415 4809/289 T /K 298(2) 298(2) 100(2) 173(2) 100(2) 100(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0455 0.0407 0.0423 0.0489 0.0428 0.0460 0.0656 0.0639 w R2 0.1196 0.1156 0.1027 0.1232 0.0990 0.1079 0.1593 0.1530 GOF 1.062 1.079 1.088 1.048 1.060 1.046 1.040 1.021 Abs coef. 0.077 0.078 0.085 0.085 0.088 0.085 0.080 0.079

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1043.4. Experimental Section 3.4.1. Synthesis of Co-crystals All reagents were purchased from Aldric h and used without further purification. Co-crystals 13 20 were prepared by dissolving st oichiometric amounts of starting materials in an appropriate solvent. Crysta ls were obtained by slow evaporation of the solvent at ambient temperature in an unmodi fied atmosphere and were isolated from solution before complete evaporation of the solvents. (1-Naphthol)2 1,2-bis(4-pyridyl)ethane, 13 : 1-Naphthol (0.035g, 0.24mmol) and 1,2bis(4-pyridyl)ethane (0.022g, 0.12mmol) was dissolved in et hanol. Slow evaporation of the solution yielded X-ray qua lity crystals, m. pt. 122-124 (1-Naphthol)2 trans-1,2-bis(4-py ridyl)ethylene, 14: 1-Naphthol (0.035g, 0.24mmol) and trans-1,2-bis(4-pyridyl )ethylene (0.021g, 0.12 mmol) was dissolved in 2 mL of ethanol. The solution was left to evaporate slowly at room temp erature, m. pt. 126-128 4,4-Biphenol1,2-bis(4-pyridyl)ethane, 15 : To 1,2-bis(4-pyridyl)ethane (0.035g, 0.19mmol) was added 4,4-bipheno l (0.035g, 0.19mmol). To the solid mixture was added ethanol (2 mL) and the solution was heated until dissolved. The solution was then allowed to slow evaporate in an unmodified atmosphere. After a few days, a precipitate was observed, collected and dried to give yellow blocks of 15, m. pt. 182-186 4,4-Biphenol trans-1,2-bis(4-pyridyl)ethylene, 16 : Slow evaporation of an ethanol solution containing trans1,2-bis(4-pyridyl)ethylen e (0.022g, 0.12mmol) and 4,4biphenol (0.023g, 0.12mmol) yielded yellow rods of co-crystal 16 after 3 day, m. pt. 235240

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105Hydroquinonetrans-1,2-bis(4-py ridyl)ethylene, 17 : Trans-1,2-bis(4-pyridyl)ethylene (0.028g, 0.15mmol) and hydroquinone (0.017g, 0.15mmol) was dissolved in methanol (2 mL). After a few days, brown blocks of 17 were obtained, m. pt. 196-198 Hydroquinonetetramethylpyrazine (TMP), 18 : Colorless crystals of 18 were obtained upon slow evaporation of an acetonitrile solu tion containing tetramethylpyrazine (0.022g, 0.17mmol) and hydroquinone (0.019g, 0.17mmol), m. pt. 185-190 (Resorcinol)2 (TMP)3, 19 : A 1:1 mixture of TMP ( 0.026 g, 0.19 mmol) and resorcinol (0.020 g, 0.19mmol) was dissolved in acet onitrile. Colorless crystals of 19 were obtained after two days upon slow evaporation at room temperature, m. pt. 134-137 2,7-dihydroxynaphthalene(TMP)2, 20 : Pale green crystals of 20 were obtained upon crystallization of 1:1 mixture of TM P (0.010g, 0.07 mmol) and 2,7-dihydroxynaphthalene (0.012 g, 0.07mmol) from acetonitrile solution. 3.4.1. Co-crystallization via grinding Stoichiometric amounts of the starting material s were ground with a mo rtar and pestle for ca.4 minutes. 3.4.2. Co-crystallization via solvent-drop grinding Stoichiometric amounts of the starting material s were ground with a mo rtar and pestle for ca. 4 minutes with the addition of 10 L of solvent per 50 mg of co-crystal formers. 3.4.3. Co-crystallization via melting Stoichiometric amounts of the starting materi als were heated until melt and the mixture was left to crystallize at ambient conditions.

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106 All compounds were analyzed by infrared spectroscopy using a Nicolet Avatar 320 FTIR instrument. The melting points were determined on a Mel-temp apparatus and are presented in Table 3.4. Table 3.4 Melting points of co-crystals 13-20 and corresponding starting materials 13 14 15 and 16 have melting points in between th at of the starting materials while 17 18 and 19 have melting point higher that that of both co-crystal formers. 3.4.2. Single Crystal X-ray Crystallography Co-crystals 13 20 were examined under a microscope and suitable single crystals were selected for X-ray diffraction. All si ngle crystal data was collected on a Bruker AXS SMART APEX CCD diffractometer with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low temp erature device. Data sets for cocrystals 15 17 18 19 and 20 were collected at 100K.Whereas data sets for 13 and 14 was collected at 298K and 16 at 173K. Lattice parameters were determined from least square analysis, and reflection data were in tegrated using the program SAINT. Lorentz Co-crystal M. pt of co-crystal M. pt of component 1 M. pt of component 2 (1-naphthol)21,2-bis(4-pyridyl)ethane, 13 122-124 96 107-110 1-napthol)2 trans-1,2-(bis(4-pyridyl)ethylene, 14 126-128 96 150-153 4,4-biphenol1,2-bis(4-pyridyl)ethane, 15 182-186 278 107-110 4,4-biphenoltrans-1,2-bis(4-pyridyl)ethylene, 16 235-240 278 150-153 Hydroquinone trans-1,2-bis(4-pyridyl)ethylene, 17 196-198 170 150-153 Hydroquinone tetramethylpyrazine (TMP ), 18 185-190 170 90 (Resorcinol)2 (TMP)3, 19, 134-137 110 90

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107 and polarization corrections we re applied for diffracted refl ections. In addition, the data was corrected for absorption using SADABS.60 Structures were solved by direct methods and refined by full matrix least squares based on F2 using SHELXTL.61 Non-hydrogen atoms were refined with anis otropic displacement parameters All H-atoms bonded to carbon atoms, except methyl groups, were plac ed geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq for the atoms to which they were attached. H-atoms of methyl groups as well as N or O bonded protons were located from Fourier difference map and refined isotr opically based upon the corresponding N or Oatom (U(H)=1.2Uq(N, O)). Crystallographic data for 13 20 are presented in Table 3.3 and selected hydrogen bond distan ces are listed in Table 3.5. Table 3.5 Geometrical parameters of intermol ecular interactions for co-crystals 13-20 Co-crystal Interaction d (HA) / d (DA)/ / 13 O-HN 1.78 2.7206(15) 176.0 14 O-H N 1.80 2.7350(13) 176.4 15 O-H N 1.86 2.7459(15) 165.5 16 O-H N 1.81 2.7384(17) 165.0 17 O-H N 1.79 2.7053(18) 167.7 18 O-H N 1.79 2.760(2) 166.6 O-H N 2.07 2.816(3) 153.7 O-H N 1.86 2.787(3) 156.9 O-H N 1.87 2.777(3) 176.8 19 O-H N 1.97 2.824(3) 156.6 O-H N 1.91 2.806(3) 178.5 20 O-H N 1.76 2.733(3) 160.0

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1083.5. References Cited 1. Desiraju, G. R.; Crystal Engineering: The Design of Organic Solids, Elsevier, Amsterdam, 1989. 2. Desiraju, G. R.; Angew. Chem. Int. Ed. Eng. 1995, 34, 2311 b) Walsh, R. B. D.; Bradner, M. W.; Fleishman, S.; Morales, L. A.; Moulton, B.; Rodriquez-Hernedo, N.; Zaworotko, M. J. Chem Commun., 2003, 186. 3. Taylor R.; Macrae, C.F.; Acta Crystallogr. 2001, B57, 815. 4. Allen, F. H.; Kennard, O. Chem. Des. Automation News 1993, 8 31. 5. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res ., 1983, 16 146. 6. Allen, F. H. Acta Crystallogr. B 2002, 58 380. 7. Allen, F. H, Taylor, R. Chem. Soc. Rev ., 2004, 33 463. 8. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst Growth Des. 2006, 6 150. 9. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr ., 2003, C59 o481. 10. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm 2000, 2 96. 11. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999, C55 2133. 12. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 1890. 13. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 430.

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109 14. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J. ; Liu, C.; Xu, S.; Li, Y.; Bai, C. Cryst. Growth Des ., 2005, 5 1889. 15. Friscic T.; MacGillivray L. R Chem. Commun ., 2003, 1306. 16. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters 2004, 6 4647. 17. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999, C55 2133-2136. 18. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 430432. 19. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr ., 1999, B55 591. 20. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc ., 2006, 128 2806. 21. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry 1999, 10 429. 22. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr ., 2005, B61 46. 23. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth Des ., 2006, 6 1048. 24. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular Pharmaceutics 2007, 4 401. 25. Benyen A.C.; Coupar, P. I.; Fergusaon, G. ; Glidewell, C.; Lough A. J.; Meehan, P.R.; Acta Crystallogr ., 1998, C54 1515. 26. Nguyen, T. L.; Scott, A.; Dinkelmeyer, B.; Fowler, F. W.; Laugher, J. W. New J. Chem. 1998, 22 129. 27. Birada, K.; Zaworotko, M. J.; J. Am. Chem. Soc ., 1998, 120 6431.

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110 28. Wheatley, P. S.; Lough, A. J.; Ferguson. G.; Glidewell, C. Acta Crystallogr., 1999, C55 1489. 29. Ferguson, G.; Glidewell, C. Gregson, R. M.; Lavender, E.S. Acta Crystallogr ., 1999, B55 573. 30. Corradi, E.; Meille, S.V.; Messina, M.T.; Metrangalo, P.; Resnati, G. Angew. Chem. Int. Ed 2000, 39 1782. 31. Zakaria, C.M.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystallogr ., 2002, C58 o1. 32. Caira, M.R.; Horne, A.; Nassimbeni, L.R.; Toda, F. J. Mater. Chem ., 1997, 7 2145. 33. Ferguson G.; Glidewell C.; Lough, A.J.; McManus, G. D.; Meehan, P.R. J. Mater. Chem ., 1998, 8 2339. 34. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; CrystEngComm ., 1999, 1. 35. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; Chem. Commun.., 2001, 1034. 36. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des 2001, 1 272. 37. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des 2002, 2 7. 38. Hoger, S.; Morisson, D. L.; Enkelman, V. J. Am. Chem. Soc ., 2002, 124 6734. 39. Haung, K, -S.; Britton, D.; Etter, M. C.; Byrn S.R. J. Mater. Chem ., 1997, 7 713. 40. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; J. Am. Chem. Soc ., 2000, 122 7817. 41. MacGillivray, L. R. CrystEngComm 2002, 4 37. 42. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110 2135. 43. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D. Acta Crystallogr. B 2003, 59 794.

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111 44. Majerz, I.; Malarski, Z.; Sobczyk, L. Chem. Phys. Lett. 1997, 274 361. 45. Brzezinski, B.; Grech, E.; Malarski, Z.; Ro spenk, M.; Schroeder, G.; Sobczyk, L. J. Chem. Res. 1997, 151. 46. Rozycka-Sokolowska, E.; Marciniak, B.; Pavlyuk, V. Acta Crystallogr ., 2004, E60 o884. 47. Robinson, B.; Hargreaves, A. Acta Crys,tallogr ., 1964, 17 944. 48. Jackisch, M. A.; Fronczek, F. R.; Geiger, C. C.; Hale, P. S.; Daly, W. H.; Butler, L. G. Acta Crystallogr ., 1990, C46 919. 49. RESORA03: Fronczek, F. R. Private Communications 2001. 50. RESORA13: Bacon, G. E.; Jude, R. J. Z. Kristagr. Kristallgeom., Kristallphys ., Kristallchem., 1973, 138 19. 51. Papaefstathiou, G. S.; MacGillivray, L. R.; Organic Letters 2001, 3 3835. 52. Kawai, H.; Katoono, R.; Nishimura, K.; Matsuda, S.; Fujiwara, K.; Tsuji, T.; Suzuki, T. J. Amer. Chem. Soc ., 2004, 126 5034. 53. Pickering M.; Small, R. W. H. Acta Crystallogr ., 1982, B38, 3161. 54. Boldog, I.; Rosanov, E. B.; Sieler, J.; Domasevitch, K. V. New J. Chem 2004, 28 756. 55. Dideberg, O.; Dupont, L., Campsteyn, H. Acta Crystallogr 1975, B31 637. 56. Bosch, E., Schultheiss, N.; Rath, N., Bond, M. Cryst. Growth Des 2003, 3 263. 57. Barooah, N.; Sarma, R. J.; Baruah, J. B. Cryst. Growth Des 2003, 3 639. 58. Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm 2003, 5 164. 59. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20 2372.

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112 60. SADABS [Area-Detector Absorption Correc tion]. Siemens Industrial Automation, Inc.: Madison, WI, 1996. 61. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997

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113 4. Delineating the Hierarchy of Supram olecular Heterosynthons: Carboxylic acid-Aromatic Nitrogen versus Alcohol-Aromatic Nitrogen 4.1. Introduction Alcohols and carboxylic acids are functi onal groups that occur commonly in nature and are well represented in the Cambridge Structural Database (CSD.1-2 Moreover 65% of the top 100 prescription drugs3 and 35 % of those compounds possessing biological activity in the Merck Index4 contain at least one al cohol or carboxylic acid. However, despite the prevalence of alc ohols and carboxylic acids there are only 71 entries in the CSD that contains an alcohol, an acid and an aromatic nitrogen moiety in the same structure. As a result reliable in formation on the relative tendency of formation of the supramolecular heterosynthons base d upon existing crystallographic information could not be ascertained. A systematic st udy of the competition between carboxylic acids and alcohols for aromatic nitrogen was th erefore undertaken to determine whether a hierarchy exists with respect to the tendency of formation of the acid-aromatic nitrogen supramolecular heterosynthon III to that of the alcohol-aro matic nitrogen supramolecular heterosynthon VI. Each supramolecular heterosynthon in th e study has proven to be robust when compared to the tendency of formation of the corresponding supramolecular homosynthon. Whereby, the carboxylic acid -aromatic nitrogen supramolecular heterosynthon III is exhibited in 95% crystal struct ure containing only an acid and an

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114 aromatic nitrogen as compared to 6% of entries that exhibit the carboxylic acid homosynthon I or II. The alcohol-aromatic nitrogen supramolecular heterosynthon VI exists in 97% crystal structures compared to 17% entries that exhibit the alcohol homosynthon V for molecules comprised exclusively of alcohols and aromatic nitrogen. Competitive studies involving three moietie s have been previously conducted by Aakeroy et al5-6 and Bis et al .7 Aakery et al presented systematic studies of the competition between three distinct hydrogen bonding moieties: primary amide, pyridine, and carboxylic acid. The study involved co-crystals of iso -nicotinamide and a range of aromatic and aliphatic acids. The genera ted co-crystals revealed consistent hydrogen bonding patterns comprised of two robus t supramolecular synthons: carboxylic acidpyridine heterosynthon III and self-complementary amide homosynthon VIII. The reproducibility of the hydrogen bonded mo tifs suggests a dominant tendency of formation of the acidpyridine heterosynthon over the acidamide heterosynthon, that is formed in acid and amide containing compounds in the abse nce of pyridines.8-14 The latter study conducted by Bis et al involved alcohol, cyano and aromatic nitrogen moieties. The study involved determining the relative tendency of formation of alcoholaromatic nitrogen in the presence of co mpeting cyano group. It was found that the alcohol-aromatic nitrogen supramolecular heterosynthon VI occurred reliably in the presence of the cyano moiety. In the research presented herein co-cry stallization experiments were designed such that the co-crystal formers containe d different permutations of carboxylic acid, aromatic nitrogen and alcohol as shown in Sc heme 4.1. Co-crystal formers were selected based on the criteria that the molecules had th e functional group(s) of interest void of

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115 other competing hydrogen bond donors and/or acc eptors. These functional group(s) were also sterically accessible and not involved in intramolecular in teractions. The cocrystallization experiments were designed such that one co-crystal former contained two of the three moieties (eg. alc ohol and acid; or alcohol and ar omatic nitrogen; or acid and aromatic nitrogen) and the second possessed th e remaining moiety e.g aromatic nitrogen or carboxylic acid or alcohol. Accordingly indi vidual pairs of co-crystal formers were combined as follows: (1) a molecule possessing both an acid and an aromatic nitrogen with molecule containing a hydroxyl group; (2) molecules comprisi ng an alcohol and a carboxylic acid with those having aromatic nitrogen moieties and (3) molecules possessing an alcohol and an aromatic nitrogen with mol ecules containing a carboxylic acid. This approach is premised on the assumpti on that a co-crystal wi ll be favored if the synthon between the co-crystal formers is strong er than the interactions within the pure component. Consequently a co-crystal is not expected to be formed if a dominant supramolecular synthon already exists w ithin one of the pure components.

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116 Research Strategy utilized in th e competitive studies involving ca rboxylic acids, alcohols and aromatic nitrogens. Small organic molecules that contain al cohol, aromatic nitrogen, and carboxylic acid moieties used in this study are shown in Figure 4.1. Co-crystallizations of these chemicals afforded the following crys talline compounds: (3 -hydroxybenzoic acid)2 .pyrazine 21; 4-hydroxybenzoic acid1,2-bis(4-pyridinium)etha ne 4-hydroxybenzoate 22 ; : (4-hydroxybenzoic acid)2 tetramethylpyrazine (TMP) 23 ; 4-hydroxybenzoic acid 4-phenylpyridine 24 ; (4-hydroxybenzoic acid)2 pyrazine 25 ; (4-hydroxybenzoic acid)2 tetramethylpyrazine acetonitrile solvate 26 ; 3-hydroxybenzoic acid(4-phenylpyridine)2 27 ; 3-hydroxybenzoic acid1,2-bis(4-pyridyl)ethane 28 ; 3-hydroxybenzoic acid 4,4-bipyridine 29 ; 3-hydroxybenzoic acidquinoxaline 30 ; (3-hydroxybenzoic acid)2 (tetramethylpyrazine)3 31 ; 6-hydroxy-2-naphthoic acidtrans-1,2-bis(4-pyridyl)ethylene 32 ; 4-hydroxybenzoic acidtrans-1,2-bis(4pyridyl)ethylene 33 ; 3-hydroxybenzoic OH/COOH1 : 4-hydroxybenzoic acid N1: 4-phenylpyridine N/COOH1: nicotinic acid If Co-crystal forms OH Narom and or COOH Narom ? single crystal XRD If co-crystal forms: OH Narom dominant N/OH1: 3-hydroxypyridine If co-crystal forms: COOH Narom dominant COOH2: benzoic acid OH1: 1-naphthol

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117 acidtrans-1,2-bis(4-pyridyl)ethylene 34 ; 3-hydroxypyridinium benzoate 35 ; 3hydroxypyridinium isophthalate 36 N OH N OH OH COOH OH COOH N COOH N COOH COOH COOH COOH COOH HOOC HOOC COOH HOOCCOOH OH O H OH O H OH O H OH OH N N N N N N N N N N N 3-Hydroxypyridine 5-Hydroxyisoquinolone 3-Hydroxybenzoic acid 4-Hydroxybenzoic acid Nicotinic acid Isonicotinic acid Benzoic acid Sorbic acid Glutaric acid Isophthalic acid Trimesic acid 1-Naphthol 4,4'-Biphenol Resorcinol Phloroglucinol 4-Phenylpyridine Pyrazine 4,4'-Bipyridine 1,2-Bis(4-pyridyl)ethane Trans-1,2-bis(4-pyridyl)ethylene Tetramethylpyrazine Figure 4.1 Molecules used in Co-crystallization Experiments 4.2. Results and Discussion 4.2.1. CSD Analysis A number of supramolecular synthons are possible when all three moieties (carboxylic acid, alcohol, aromatic nitrogen) exist within the same crystal structure. The possibilities include: a ca rboxylic acid homosynthon I and/or II, carboxylic

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118 acidaromatic nitrogen supramolecular heterosynthon III, charge assisted verson of III i.e. IV, alcohol supramolecular homosynthon V, alcoholaromatic nitrogen supramolecular heterosynthon VI, alcoholcarbonyl supramolecular heterosynthon VII (Scheme 4.3). O O H O O H O O H O O H OH N OH O H O OH C O O H N O O N+ H O O H I II C VI V C C VII III IV C Figure 4.2 Possible supramolecular sy nthons that can form when OH, Narom and COOH are present in the same structure Of the 71 entries in the CSD that contai n all three moieties: 2 entries exhibit carboxylic acid homosynthon I or II, 9 entries contain alcohol homosynthon V, 41 structures exhibit carboxylic acid-aro matic nitrogen spramolecular synthon III and 20 entries exhibit alcohol-aromatic nitrogen supramolecular synthon VI. Furthermore there exists 10 structures that exhibit both III and VI. In the absence of competing hydrogen bond donors and/or acceptors the total number of entries containing these three moieties decreases to 11.15 Within this subset, GEHROB, SOFHIE and XAPMAC exhibit acidaromatic nitrogen heterosynthon III; MOBZUY exhibits both III and V; and HAKVEV and GUTSAP form acid dimer I and alcohol-aromatic nitrogen heterosynthon VI. The remaining structures BEQWAV, IDUBUF, VEFVEI, VEFVIM and WEPDIF exhibits both III and VI.

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119 Herein, a series of compounds that help to evaluate the rela tive hierarchy of III and VI is presented and analyzed in the contex t of supramolecular synthons formed. Table 4.1 CSD statistics on supramolecular synthons that occur in structures containing only COOH, Narom, and OH Moieties present in structure No. of structures Supramolecular synthon Structures with synthon DA [] Mean () [] COOH and Narom 109 COOHNarom OHO 104 (95%) 6 (5%) 2.50-2.90 2.65(3) OH and N 208 OHN O-H O 203 (97%) 52 (26%) 2.50-3.00 2.77(8) COOH, Narom and OH 11 COOHNarom (alc) OHN OHO 9 7 2 2.50-2.90 2.50-3.00 2.50-3.00 2.65(3) 2.77(8) 2.65(3) 4.2.2 Features of the O-HNarom interaction Structural information obtai ned from single crystal X-ray analysis can be used to determine the extent of proton transfer by analyzing proton locati on, bond distances of carboxylic or hydroxyl groups and C-N-C bond a ngles. Neutral carboxylic acids tend to have dissimilar C=O and C-O bond distances that average 1.21(2) and 1.31(2) 16 respectively whereas deprotonated carboxylat es have average C-O bond distances of 1.25(2).16 Likewise neutral phenolic alcohol gr oups have average CO bond lengths of 1.36(2). whereas the calculated average for ionic CObond length is 1.28(4).16 The C-N-C angle within the aromatic nitrogen mo iety is also known to be sensitive to protonation.16-20 and the cationic form typically e xhibits higher values (ca. 122(2) ) than that of the corresponding ne utral molecules (ca. 117(2) ). The structural features of the bond distances and bond angles are used in th e analysis of the pr esented series of compounds.

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120 In the pharmaceutical industry, it is genera lly accepted that the reaction of an acid and a base is anticipated to form a salt if the p Ka [p Ka (base)p Ka (acid)] is greater than 2 or 3.21 This criterion is often used as a guide when choosing appropr iate counterions for salt selection. With respect to neutral COOH Narom and charge-assisted N+-H -O hydrogen bonds, Johnson and Rumon22 suggests that a p Ka difference less than 3.75 affords neutral COOH N interactions whereas pKa greater than 3.75 results in proton transfer. In a recent article however the predictive utility of p Ka in the solid state is scrutinized.23 The authors report that although p Ka values tend to be reliable indicators of salt formation when p Ka >3, and likewise co-crystal formation is depicted when p Ka 0, there exists a salt-co-crystal continuum between p Ka range of 0 to 3. Within this range the reaction between an aci d and a base can result in sa lt or co-crystal formation or can contain shared proton s, or mixed ionization.23 Within the presented series of compounds, 21 25 and 30 all have p Ka 0, and based upon structural information and IR spectroscopy contain neutral components and therefore form co-crystals (Table 4.2). 23 24 27 28 29 31 32 33 and 34 have p Ka values ranging from 0.86 to 2.05 and also form co-crystals. 35 and 36 however form salts having p Ka of 4.31 and 4.98 respectively. Furthermore based upon the p Ka argument the yet isolated compounds within the series in which 3-hydroxy pyridine and 5-hydroxyisoquinoline are cocrystallized with carboxylic acids are exp ected to yield salts (See Appendices).

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121 Table 4.2 pKa data for 21-36 4.2.3. Crystal Structure Descriptions The asymmetric unit of 3-hydroxybenzoic acid pyrazine 21 consists of a half molecule of pyrazine and a molecule of 3-hydroxybenzoic acid. The resulting 2:1 cocrystal form trimeric adducts that are sustained by centrosymmetric COOH Narom pKa (acid) pKa (base) pKa [pKa (base)pKa (acid)] 21 4.08 0.10 1.00 0.30 -3.08 22 4.57 0.10 6.13 0.10 1.56 23 4.57 0.10 2.88 0.50 1.69 24 4.57 0.10 5.440.10 0.87 25 4.57 0.10 1.00 0.30 -3.57 26 4.57 0.10 2.88 0.50 1.56 27 4.08 0.10 5.440.10 1.36 28 4.08 0.10 6.13 0.10 2.05 29 4.08 0.10 3.27 0.26 0.81 30 4.08 0.10 0.590.28 -3.49 31 4.08 0.10 2.88 0.50 1.20 32 4.34 0.30 5.50 0.26 1.16 33 4.57 0.10 5.50 0.26 0.93 34 4.08 0.10 5.50 0.26 1.42 35 8.51 0.10 4.86 0.10 4.2 4.2 4.31 0.66 36 8.51 0.10 4.86 0.10 3.53 3.53 4.98 1.33

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122 supramolecular heterosynthon III. Such three component adducts are interconnected via alcohol-carbonyl supramolecular heterosython VII (Fig. 4.4) As a consequence, the overall hydrogen-bonding pattern in 21 can therefore be descri bed as a corrugated 2D network consisting of interconnected trimeric supramolecular adducts that align nearly perpendicularly with respect to each other. The dihedral angle between the planes parallel to the interacting trimeric adducts is 89.91 In addition to spectroscopic ev idence, the neut ral nature of III is supported by structural data: the C=O and the C-O bond distances are 1.228 and 1.313 respectively and the C-N-C angle within the aromatic nitrog en ring is 117.15 The COOH Narom hydrogen bond distance (D: 2.675(2) ) is with in the expected range for carboxylic acidaromatic nitrogen interactions and the dihedr al angle formed between the carboxylic acid group and the pyrazine ring is 9.60 Figure 4.3 Crystal packing in (3-hydroxybenzoic acid)2 pyrazine, 21 showing corrugated sheet

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123 Figure 4.4 Interdigitation of independent 2D networks in the crystal structure of 21 In the crystal structure of 4-hydroxybenzoic acid1,2-bis(4-pyridinium)ethane 4-hydroxybenzoate 22 there is ambiguity with regards to the location of the proton on one of the two crystallographically indepe ndent molecules of 4-hydroxybenzoic acid. The carbon-oxygen bond distance on this particul ar molecule of 4-hydroxybenzoic acid is 1.249 and 1. 283 and the associated C-N-C angle is 119.2 The O Narom hydrogen bond distance of 2.546(2) is si gnificantly shorter than the average distance for the acidaromatic nitrogen interaction [2.65 (3) ]. This suggest partial proton transfer in which the proton is shared between the Narom atom and the oxygen atom.24 The C=O and CO bond distances in the second independent mo lecule of 4-hydroxybenzoic acid are 1.237 and 1.308 respectively and the associated C-N-C angle is 117.68 The crystal structure of 22 is sustained by III and IV, alcohol-carbonyl supram olecular heterosynthon VII as well as alcohol-carboxylate supramolecula r heterosynthon. The basic hydrogen bonding components are the 1:1:1 adduct as shown in Figure 4.5, such adducts are connected via

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124VII to generate corrugated sheets along the bc plane (Figure 4.6). The supramolecular sheets stack along the a axis as shown in Figure 4.7. Figure 4.5 Supramolecular synthon in 22 Figure 4.6 Crystal packing of 22, showing corrugated sheet Figure 4.7 Crystal packing of adjacent 2D networks in 22

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125 The crystal structure of (4-hydroxybenzoic acid)2 TMP 23, is sustained by the carboxylic acid-aromatic nitrogen heterosynthon III [O N: 2.674(6) ] and the alcoholcarbonyl (acid) heterosynthon VII [O O: 2.68(5) ] hydrogen bond. As is observed in 21 and 22 the nitrogen atoms in TMP are hydrogen bonded to carboxylic acids via heterosynthon III. The hydroxyl group and carbonyl on adjacent 4-hydroxybenzoic acid molecules interacts via heterosynthon VII resulting in an eight component rectangular grid as shown in Figure 4.8a. The mol ecules interact to form a hydrogen bonded herringbone network with an angle of 110 be tween the planes of 4-hydroxybenzoic acid and TMP; and 78 between adjacent 4-hydroxybenzoic acid. The hydrogen bond distances are consistent with that observed from the CSD analysis. (a) (b) Figure 4.8 a) Eight membered molecular rectangular grid formed by six 4-hydroxy benzoic acid and two TMP molecules. b) 2-dimensional herringb one network in the crystal structure of (4hydroxybenzoic acid)2TMP co-crystal 23.

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126 Figure 4.9 Crystal packing of adjacent 2D networks in 23 21, 22 and 23 are related in terms of their compos ition, hydrogen bond motifs and packing modes. The difference in the molecula r structure of the components is not large enough to disrupt the 2D co rrugated packing mode. 4-hydroxybenzoic acid4-phenylpyridine 24, contains one molecule of each component in the asymmetric unit. Analysis of the crystal struct ure reveals discrete tetrameric units which are sustained by alcohol-aromatic nitrogen heterosynthon VI (D: 2.703 (3) ) as well as carboxylic acid homosynthon I (D: 2.630(3) ) as shown in Figure 4.10. The neutral nature of VI is supported by structural data: the C-O (alcohol) bond distance is 1.352 and the CNC angle within the aromatic nitrogen ring is 116.99 Stabilization of the structure is also afforded by face to face -stacking between neighboring 4-phenylpyridine molecules as shown in Figure 4.12. The centroid to centroid distances between the aromatic ri ngs are 3.684 and 3.862 The torsion angle

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127 between the benzyl ring and the pyridyl ri ng in the 4-phenylpyridine molecule is 41.06 and the dihedral angle formed by 4-ph enylpyridine and 4-hydroxybenzoic acid is 66.51 Figure 4.10 Crystal structure of 4-hydroxybenzoic acid4-phenylpyridine 24 Figure 4.11 Crystal packing of 24 showing translationally related carboxylic acid dimer and face to face -stacked aromatic rings of adjacent 4-phenylpyridine. The asymmetric unit of the (4-hydroxybenzoic acid)2 pyrazine 25 consists of one molecule of 4-hydroxyybenzoic acid lying in a general position and a half molecule of pyrazine lying on a center of inversion. Similar to that seen in HAKVEV and in the previous structuure, 24 is sustained by alcohol-aroma tic nitrogen supramolecular

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128 heterosynthon VI as well as carboxylic acid dimer I. The 4-hydroxybenzoic acid molecules interact with each othe r via 2-point recognition acid dimer I and the hydroxyl portion of the molecule is hydrogen bonded to the pyrazine mo lecule through O-H Narom hydrogen bonds to generate zig zag chains. Transl ationally related chains align parallel to the ab plane. The neutral nature of VI is supported by spectroscopi c evidence as well as structural data: the CO (alcohol) bond dist ance is 1.357 and the CNC angle within the aromatic nitrogen ring is 116.5(2) The OHNarom hydrogen bond distance (D: 2.7739(17) ) is within the expected range for hydroxylaromatic nitrogen interactions (Table 4.1) and the O-H O hydrogen bond of the centrosymmetric acid dimer is 2.6282 (15) Figure 4.12 Crystal structure of (4-hydroxybenzoic acid)2 pyrazine, 25, showing centrosymmetric acid dimers and alcohol-aromatic nitrogen heterosynthons. Surprisingly the acetonitril e solvate of co-crystal 23 does not exhibit the carboxylic acid-aromatic nitroge n supramolecular heterosynthon III and the alcohol-acid supramolecular heterosynthon VII, as seen in the unsolvated form. Rather the crystal structure of (4-hydroxybenzoic acid)2 TMP acetonitrile solvate 26 reveals infinite chains sustained by carboxylic acid dimer I and alcohol-aromatic nitrogen

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129 supramolecular heterosynthon VI. The O-H Narom hydrogen bond distance (D: 2.739(2) ) is within the expected range for alcohol-aromatic nitrogen interactions (Table 4.1) and the hydrogen bond distance of the centrosymmetr ic carboxylic acid dimer I is 2.617 The dihedral angle between th e 4-hydroxybenzoic acid and the TMP ring is 75.92 The acetonitrile molecule is within th e structure is not involved in any strong hydrogen bond interaction. Figure 4.13 Crystal structure of (4-hydroxybenzoic acid)2 TMP acetonitrile solvate, 26 The asymmetric unit of 3-hydroxybenzoic acid (4-phenylpyridine)2 27 contains one molecule of 3-hydroxybenzoic acid and two molecules of 4-phenylpyridine. The resulting 1:2 co-crystal is sustaine d by both supramolecular heterosynthon III (D: 2.596(2) ) and VI (D: 2.685(2) ) to generate di screte trimeric adducts. The observation of a C=O bond di stance of 1.220 and the C-O (acid) of 1.315 coupled with the C-N-C bond angle within the aromatic nitrogen molecule of 117.14 suggests a neutral acid-aromatic nitrogen hydrogen bond. The C-O (alcohol) bond distance of 1.349 and the C-N-C angle of 116.75 support the neutral nature of the alcoholaromatic nitrogen hydrogen bond. Adjacent trim eric adducts within the structure are

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130 involved in interactions wherein both face to face -stacking between adjacent 4phenylpyridine molecules and edge to f ace interaction betwee n the 3-hydroxybenzoic acid and the pyridyl molecule is observed. The centroid to centroid distances are 3.726 and 3.703 respectively. The dihedral angle be tween the pyridyl and benzyl ring within the 4-phenylpyridine molecules is 27.88 Figure 4.14 Crystal structure of 3-hydroxybenzoic acid.(4-phenylpyridine)2, 27 Figure 4.15 Crystal packing in 3-hydroxybenzoic acid.(4-phenylpyridine)2, 27.

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131 The 1:1 co-crystal of 3-hydroxybenzoic acid1,2-bis(4-pyridyl)ethane 28 is sustained by both carboxylic acid-aromatic nitrogen supramolecular heterosynthon III (D: 2.590(4)) and alcoholaromatic ni trogen supramolecular heterosynthon V (D: 2.663(4)) which alternate to generate in finite chains. The neutral nature of III and VI is supported by structural evidence: C=O and C-O bond distance of the carboxylic acid group is 1.219 and 1.325 ; the CNC angle within the aromatic nitrogen ring is 117.07 and 117.28 respectively and the C-O (alcohol ) bond distance was found to be 1.357 Face to face -stacking between pyridyl moieties in adjacent chains, the centroid to centroid distance of which are 3.793 and 3.721 is also observed in this structure. Figure 4.16 Crystal structure of 3-hydroxybenzoic acid1,2-bis(4-pyridyl)ethane, 28. The asymmetric unit of 3-hydroxybenzoic acid4,4-bipyridine 29 consists of one molecule of 3-hydroxybenzoic acid and one molecule of 4,4-bipyridine. The 1:1 cocrystal is sustained by both supramolecular heterosynthons III (D: 2.6881(19) ) and VI

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132 (D: 2.7898(19) ) to generate infinite chains. As is seen in 28 supramolecular heterosynthons III and VI alternate along the lengt h of the chains. The neutral nature of the in teractions is supported by st ructural evidence: the C=O and C-O bond distance of the carboxylic acid group is 1.216 and 1.325 respectively; the CNC angles within the arom atic nitrogen rings are 116.86 and 117.00 respectively and the C-O (alcohol) bond distance was found to be 1.356 The dihedral angle between the planes of the pyridyl rings in 4,4-bip yridine is 28.51 Figure 4.17 Crystal Packing in 3-hydroxybenzoic acid 4,4-bipyridine, 29 The crystal structure of 3-hydroxybenzoic acidquinoxaline 30 reveals infinite chains that are sustained by two supramolecu lar heterosynthons: carboxylic acid-aromatic nitrogen III and alcohol-aromatic nitrogen VI. As seen in 28 and 29 these interactions alternate along the length of the chain. Th ere are two independent molecules of each component in the asymmetric unit. The C=O and C-O bond distances of the carboxylic acid groups are 1.217 and 1.329 ; 1.214 and 1.335 respectively and the C-O (alcohol) bond distances was found to be 1.362 and 1.365 stacking is also observed within this structure.

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133 Figure 4.18 Crystal Packing in 3hydroxybenzoic acid quinoxaline 30. The crystal structure of (3-hydroxybenzoic acid)2 (TMP)3 31 exhibits both acid-aromatic nitrogen III and alcohol-aromatic nitrogen VI supramolecular heterosynthons. Surprisingly 31 does not generate extended ch ains as is anticipated but rather forms discrete five component a dducts as shown in Figure 4.19. Consequently there are two nitrogen accepto r sites that are not involve d in any strong hydrogen bond interactions. These sites are however involved in weak C-H N interactions. Figure 4.19 Discrete 5-component adduct in the crystal structure of (3-hydroxybenzoic acid)2 (TMP)3, 31

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134 As seen in the previous co-crystal, 6-hydroxynaphthoic acid.trans-1,2-(4pyridyl)ethylene 32 is sustained by both supr amolecular heterosynthons III (D: 2.691(2) ) and VI ( D: 2.756). However unlike 29 30 and 31 heterosynthons III and VI, alternate in a different manner. Trans1,2-bis (4-pyridyl)ethylene molecule is hydrogen bonded at both nitrogen acceptor site s to carboxylic acids, then the subsequent trans-1,2-bis (4-pyridyl)ethylen e molecule in the chain is hydrogen bonded to alcohols. This sequence is repeated along the chain. The observed hydrogen bonds are symmetric about the trans-1,2-bis(4-pyr idyl)ethylene molecule. The C=O and C-O (acid) bond distances are 1.216 and 1.323 respectively. The C-N-C angle within th e pyridyl rings are 117.34 and 116.4 and the CO (alc) distance is 1.356 thus supporting th e neutral nature of the OHNarom hydrogen bonds. Figure 4.20 Crystal structure of (6-hydroxynaphthoic acid trans-1,2-(bis(4-pyridyl)ethylene 32

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135 Figure 4.21 Crystal packing in 6-hydroxynaphthoic acidtrans-1,2-bis-(4-pyridyl)ethylene, 32 The asymmetric unit of 4-hydroxybenzoic acidtrans-1,2-bis(4-yridyl)ethylene 33, consists of a molecule of 4-hydroxybenzoic ac id and two half mole cules of trans-1,2bis(4-pyridyl)ethylene. The resulting 1:1 co -crystal is sustaine d by both supramolecular heterosynthon III and VI. The components assemble in the alternate manner seen in 32 to generate zig-zag infinite chains. Molecules of trans1,2-bis(4-pyridyl)ethylene are hydrogen bonded at both Narom sites to carboxylic acids, th e subsequent trans-1,2-bis(4pyridyl)ethylene molecule in the chain is hydrogen bonded to alcohols and the sequence repeated along the chain. The C=O and C-O (acid) bond distances are 1.236 and 1.316 respectively. The C-N-C angle within th e pyridyl rings are 116.34 and 117.43 and the CO (alc) distance of 1.354 supports the ne utral nature of the OHNarom hydrogen bonds. stacking is also observed, which affords fu rther stabilization of this structure.

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136 Figure 4.22 Crystal packing in 4-hydroxybenzoic acidtrans-1,2-(4-pyridylethylene, 33 showing translationally related zig-zag chains. The crystal structure of 3-hydroxybenzoic acidtrans-1,2-bis(4pyridyl)ethylene 34, exhibits both supram olecular heterosynthon III and VI. The 1:1 cocrystal generates chains that hydrogen bond in a manner as seen in co-crystals 32 and 33 The C=O and C-O bond distances of th e carboxylic group are 1.222 and 1.328 respectively whereas the C O bond distance for the hydroxyl group is 1.361. The C-NC angle within the py ridyl rings are 117.03 and 116.65 thus supporting the neutral nature of III and VI.

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137 Figure 4.23 Crystal packing in 3-hydroxybenzoic acid trans-1,2 (4-pyridyl)ethylene, 34 The crystal structure of 3-hydr oxypyridine is sustained by O-H Narom supramolecular heterosynthon VI to generate extended chains.25 The 3-hydroxy proton is capable of adopting two conformations: anti planar or syn planar.26 (The anti planar conformation is seen in the pure form. N O H N O H anti planar syn planar There are twelve compounds in the CSD in which 3-hydroxypyridine is combined with a carboxylic acid.27 In the reported structures proton transfer result between the acid and the base to form organic salts. The 3-hydroxy group of the 3-hydroxypyridinium in IDUNIE, IDUNOK, IDUNUQ, JOJJUN, PA HZAA, VITXUR and YETLUE adopts

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138 anti planar conformation while the syn planar conformation is exhibited by IDUNEA, KUFBOC, OCAKAF and RACBED. Attempts to co-crystallize 3-hydroxypyrid ine and benzoic acid results in proton transfer between the acid and the aromatic nitrogen, thereby generating the chargeassisted hydrogen bonded salt of 3-hydroxypyridinium benzoate 35 The asymmetric unit consists of one ion of each component. The crystal structure exhibits 2-component adducts that is sustained by charge assi sted pyridinium-carboxyl ate supramolecular heterosynthon IV (Figure 4.25a). These adducts are connected orthogonally via alcoholcarboxylate interaction to generate infin ite chains. The 3-hydroxyl group of the 3hydroxypyridinium in 35 adopts the syn -conformation in this structure. The bond distances for the carboxylate group are 1.286 and 1.260 ; and the corresponding C-N-C angle is 121.41 The dihedral angle between the plane of the carboxylate group and that of the pyridinium ring is 8.05

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139 (a) (b) Figure 4.24 (a) Charge-assisted pyridinium-car boxylate supramolecular heterosynthon IV in 35 (b) Crystal packing in 3-hydroxypyridinium benzoate, 35 The asymmetric unit of 3-hydroxypyridinium isophthalate 36 consists of one 3-hydroxypyridinium ion and one isophthalate ion. Similar to that seen in OCAKAF,28 proton transfer is only observed at one s ite on the isophthalic acid molecule. 36 is sustained by the charge-assisted pyridinium-carboxylate heterosynthon IV, one point recognition charge assisted carboxylic acid (OH)-carboxylate interactions and alcoholcarboxylate heterosynthons. As a result of these three significant hydrogen bond interactions supramolecular sheets are generated as seen in Figure 4.25. The 3-hydroxyl group of the 3-hydroxypyridinium in 36 adopts the anticonformation in this structure.

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140 Figure 4.25 Crystal packing in 3-hy droxypyridinium is ophthalate 36 The crystal structures of isonicotinic acid and nicotinic acid are sustained by supramolecular heterosynthon III and generate extended chains.29-30 An analysis of the CSD yielded no examples of co-crystals cont aining isonicotinic acid. However there are five examples of organic salts involv ing the isonicotinate ion in the CSD31 (Refcodes: AWUDEB, HAFZIY, PAZHOO, SATLUV and YERXUP). The counter-ions in the aforementioned compounds are derived from mo lecules that are either more basic or acidic than isonicotinic acid. A similar observation is made in the case of nicotinic acid. Nicotinic acid forms several organic salts 32 and a co-crystal with 4-aminobenzoic acid. 33 Solution and solvent drop grinding34 attempts to co-crystallize isonicotinic acid and nicotinic acid with a series of alcohols re sulted in a mixture of starting materials as evidenced by XRPD. The negative results pe rhaps is suggesting that the carboxylic acidaromatic nitrogen supramolecular heterosyntho n in the pure nicotinic acids is more dominant than the alcohol-aromatic n itrogen heterosynthon that would exist if a co-crystal were to form.

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141 Rationalization of Crystal Structures 3-Hydroxybenzoic acid exists as two polymorphic modifi cations. Form I exhibits the commonly occurring carboxylic acid dimer I as well as the chain motif of the alcohol homosynthon V, to generate corrugated 2D sheets (Figure 4.26a and b). In the second polymorph the acid dimer motif is abandoned in favor of a new motif which consists of 1-point recognition alcohol homosynthon V and alcohol-carbonyl (acid) interaction VII, to generate a molecular tape (Fig 4.26b).35 This structural pair illustrates that the same compound can exist in both centrosymmetric and non-centrosymmetric structures and can perhaps help to explain why different supram olecular motifs are adopted in the structures containing 3-hydroxybenzoic acid.

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142 (a) (b) Figure 4.26 Crystal structures of the polymorphic forms of 3-hydroxybenzoic acid: (a) Form I and( b) Form II

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143 O O H O H O O H O H O O H O H N N O O H O H N N O O H O H O O H O H N O O H O H O O H O H O H O O H O O H O H O O H O H O O H O H N N N O O H O H Chain Type 1 b) a) Chain Type 2 Figure 4.27 Chain motifs generated in 21-34 rationalized via synthons occurring in the pure carboxylic acid. 4-Hydroxybenzoic acid is also known to be polymorphic, 36 there is however only one reported form in the CSD.37 The crystal structure of Form II of 4-hydroxybenzoic acid was determined by exploiting synchrotron X-ray microcrystal diffraction techniques. 38-39 The crystal structure of 4-hydroxybenzoic acid Form I exhibit carboxylic acid dimer I and alcohol homosynthon V. Similar to that seen in Form I of 3-hydroxybenzoic acid, the hydroxyl groups engage in forming homosynthon V, constructing chains that extend through the crystal. The reported crystal st ructure of Form II of 4-hydroxybenzoic acid also contains centrosymmetric carboxylic acid dimer I, however there is no interacton

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144 between adjacent hydroxyl groups as seen in Form I. Rather the hydroxyl group in Form II is involved in the formation of alc ohol-carbonyl supramolecular heterosynthon VIII, which serves to link adjacent dimers consequently generating a supramolecular sheet. It should also be noted that the co -crystals of 3-hydroxybenzoic acid with meta and para nicotinamide also exhibits different supramolecular synthons and crystal packing.5,40 LUNMEM the co-crystal of 3-hydro xybenzoic acid with isonicotinamide exhibits III and VIII and the hydroxyl group interacts with the carbonyl of the amide moiety. XAQQIQ exhibits alcohol-aromatic nitrogen VI and acid-amide 2-pt recognition supramolecular synthon X. These structures may perhaps also be rationalized based upon the crystal packing in the pure components. In summary, sixteen crystal structures were isolated in the study involving the competition between alcohol and car boxylic acid for aromatic nitrogen. 21 23 were sustained by carboxylic acid-aromatic nitrogen supramolecular heterosynthon III as well as alcohol-carbonyl(acid) synthon VII, 24-26 exhibited alcohol-aromatic nitrogen supramolecular heterosynthon VI and carboxylic acid dimer I. 27-34 exhibit both acidaromatic nitrogen III and alcohol-aromatic nitrogen VI supramolecular heterosynthons whereas 35 and 36 exhibited the charge-assisted pyridinium-carboxylate supramolecular heterosynthon IV. Of the eight structur e that exhibit both III and VI: 27 28 29 and 30 exhibit chain type 1 whereas 31 32 33 and 34 exhibit chain type 2 (Figure 4.27) The chain types observed and conseque ntly the crystal structures may be rationalized in terms of the synthons present in the pure carboxylic acids.

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145Table 4.3 Summary of supramolecular synthons present in 21-36 4.2.4 Methods of Preparation Co-crystallization experiments were a ttempted utilizing grinding, solvent-drop grinding and melting techniques. Solvent drop grinding and melt experiments of 3hydroxypyridinium benzoate 35 3-hydroxypyridinium isophthalate 36 3hydroxypyridine sorbic acid, (3 -hydroxypyridine)2 glutaric acid and (3-hydroxypyridine)3 trimesic acid yielded new phases as characterized by XRPD and DSC. Moreover grinding, solvent drop grind and melt afforded the same phase as obtained from solution in the case of 35 and 36 Solution co-crystallization attempts to obtain crystals of: 5-hydroxyisoquinoline benzoic acid, 5-hydroxyisoquinoline sorbic acid, (5-hydroxyisoquinoline)2 glutaric acid I O O H O O H III O O H N IV O O N+ H VI OH N C VII OH C O C 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

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146 and (5-hydroxyisoquinoline)2 isophthalic acid, were unsucce ssful. However as indicated by XRPD and DSC new phases were obtai ned upon solvent drop grinding and subsequent melting. Solution and solvent drop grinding attempts to obtain co-crystals of nicotinic acid and isonicotinic acid with carboxylic acids were unsuccessful; the IR spectroscopy and PXRD spectra of the solid obtained rev ealed a mixture of starting materials. 21 34 were also investigated in the contex t of their accessibility via grinding and solvent drop grinding methodologies. Initial 4-minute grinds and solvent drop grinds resulted in a mixture of st arting materials in most cases with the exception of 23 27 and 30 Co-crystals 21 23 28 29 30 and 31 were reproduced by solvent drop grinding. 29 30 and 31 was also obtained from the melt. Attempts to reproduce 21 22 23 and 25 from the melt resulted in the formation of new pha ses that differ from the isolated compounds and their respective starting materials. No proper theory on melting exists to date. However in general para isomers almost invariably have higher melting points than meta isomers the observation is a true solid state effect.41 The series of compounds presented all have melting points that occur in between that of the initial components and no general correlations with respect to melting points could be made between the co -crystals of 3-hydroxybe nzoic acid versus those of 4-hydroxybenzoic acid within this series of compou nds (Table 4.4).

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147 Table 4.4 Melting point comparison for 21-36 4.3. Conclusions In summary, the study presented herein invol ves a series of model co-crystals that adds to the limited information within the CS D related to the frequency of occurrence of supramolecular heterosynthon III in the presence of the competing alcohol functional group. That both III and VI occurs when an acid, an alcohol and an aromatic nitrogen are co-crystallized suggests that the COOHNarom III hydrogen bond is comparable to the OHNarom hydrogen bond VI. However the crystal stru ctures obtained may be rationalized based upon the synthons existing in the pure components. Single crystals of M. pt of compounds M. pt of component 1 M. pt of component 2 21 178 199-203 52-55 22 194-198 214-217 107-110 23 150-154 214-217 84-86 24 90-96 214-217 69-73 25 160-164 214-217 52-55 26 178-182 214-217 84-86 27 115-118 199-203 69-73 28 180-184 199-203 107-110 29 176-179 199-203 111-114 30 100-104 199-203 29-32 31 139-142 199-203 84-86 32 184-187 237-241 150-153 33 184-186 214-217 150-153 34 180-184 199-203 150-153

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1483-hydroxypyridinium benzoate, 35 and 3-hydroxypyridinium isophthalate 36, exhibit proton transfer between the carboxylic acid and the aromatic nitrogen and was sustained by charge assisted interaction IV. The charge assisted heterosynthon IV results perhaps as a consequence of the p Ka difference existing between the components. The negative results obtained within the series of com pounds involving isonicotinic acid and nicotinic acid with alcohols, coupled w ith the positive results obtained within the series involving OH/Narom with COOH suggests that the formation of the carboxylic acid-aromatic nitrogen supramolecular heterosynthon III appears to dominate over that of the alcoholaromatic nitrogen supramolecular heterosynthon VI. This conclusion is particular ly relevant to co-crystal s of APIs, since they are relatively complex molecules that often contain either OH or COOH moieties. Modification of the physicochemical properties that is associated with the co-crystal formation may lead to interesting opport unities toward new formulations for the improved performance of an API. 4.4. Experimental Section 4.4.1. Syntheses Reagents were purchased from Aldrich and used without further purification. Single crystals of compounds 21-36 were obtained via slow eva poration of stoichiometric amounts of starting materials in appropriate solvents and were isolated from solution before complete evaporation of th e solvents in all cases except 26 (3-Hydroxybenzoic acid)2 pyrazine, 21: To 3-hydroxybenzoic acid (0.015 g, 0.13 mmol) was added pyrazine (0.020 g, 0.13 mmol). The solid mixture was dissolved

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149 in chloroform (2ml) and the solution was left to evaporate slowly at room temperature. After 4 days colorless crystals of 21 mp = 178 C, were observed. 4-Hydroxybenzoic acid1,2-bis(4-pyridinium)eth ane 4-hydroxybenzoate, 22: To 4-hydroxybenzoic acid (0.026 g, 0.22 mmol) was added 1,2bis (4-pyridyl)ethane (0.020 g, 0.11 mmol) and the mixture dissolved in methanol (2 ml). The solution was allowed to evaporate at ambient temperature and after 8 days colorless crystals of 22, mp = 194-198 C, were obtained. (4-Hydroxybenzoic acid)2tetramethylpyrazine, 23: To 4-hydroxybenzoic acid (0.026 g, 0.22 mmol) was added tetramethylpyrazi ne (0.020 g, 0.11 mmol) and the solid mixture dissolved in methanol (2ml). The solution was allowed to evaporate to dryness to obtain crystals of 23, mp = 150-154 C. 4-Hydroxybenzoic acid4-phenylpyridine, 24: A solution of 4-hydroxybenzoic acid (0.015 g, 0.13 mmol) and 4-phenylpyrid ine (0.020 g, 0.13 mmol) in 2 mL of acetone/ethyl acetate (1:1) solvent mixture was le ft to evaporate at ambient conditions. After 3 days, colorless crystals of 24, mp = 90-94 C were obtained. (4-Hydroxybenzoic acid)2 pyrazine, 25: To 4-hydroxybenzoic acid (0.041g, 0.30 mmol) was added pyrazine (0.012g, 0.15mmol). The solid mixture was dissolved in acetonitrile (2 ml) and allowed to evaporate undisturbed at room temperature. After 4 days colorless crystals of 25 mp = 160-164 C, were observed. (4-Hydroxybenzoic acid)2tetramethylpyrazine acetonitrile solvate, 26: To 4hydroxybenzoic acid (0.026 g, 0.22 mmol) was added tetramethylpyrazine (0.020 g, 0.11 mmol) and the mixture was dissolved in 2 mL of acetonitrile. After 8 days colorless crystals of 26 mp = 178-182 C, were obtained.

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150 3-Hydroxybenzoic acid( 4-phenylpyridine)2, 27: To 3-hydroxybenzoic acid (0.015 g, 0.13 mmol) was added 4-phenylpyrid ine (0.020 g, 0.13 mmol) and 2 mL of 1:1 of acetone and ethyl acetate so lvent mixture. Slow evaporation of the solution afforded colorless crystals of 27, mp = 115-118 C after 3 days. 3-Hydroxybenzoic acid1,2-bis(4-pyridyl)ethane, 28: To 3-hydroxybenzoic acid (0.026 g, 0.22 mmol) was added 1,2bis(4-pyridyl)ethane (0. 020 g, 0.11 mmol) and the mixture was dissolved in 2 mL of acetone After 3 days colorless crystals of 28, mp =180-184 C, were observed. 3-Hydroxybenzoic acid 4,4-bipyridine 29 : To 3-hydroxybenzoic acid (0.031 g, 0.26mmol) was added 4,4-bipyridine (0.020 g, 0.13 mmol). The solid mixture was dissolved in 2 mL of methanol and the solution was left undi sturbed to evaporate under ambient conditions. After 12 days yellow needles of 29 mp = 176-179 C, were formed. 3-Hydroxybenzoic acidquinoxaline, 30: To 3-hydroxybenzoic acid (0.032g, 0.23mmol) was added quinoxali ne (0.030g, 0.23 mmol) and 2 mL of ethanol. After 2 days colorless crystals of mp = 100-104 C, were obtained. (3-Hydroxybenzoic acid)2 (tetramethylpyrazine)3, 31: To 3-hydroxybenzoic acid (0.020g, 0.14mmol) was added tetramethylpy razine (0.20 g, 0.14 mmol). The solid mixture was dissolved in 2 mL of acetonitr ile and the solution wa s left undisturbed to evaporate under ambient conditions. After 12 days yellow needles of 31 mp = 139-142 C, were formed. 6-Hydroxy-2-naphthoic acidtrans-1,2-bis(4-pyridyl)ethylene, 32: To 6-hydroxy2-naphthoic acid (0.025g, 0.13 mmol) was added 1,2bis (4-pyridyl)ethylene (0.024g,

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151 0.013 mmol). The solid mixture was dissolved in 2 mL of methanol. After 2 days colorless crystals of 32 mp = 184-187 C were observed 4-Hydroxybenzoic acidtrans-1,2-bis(4-pyridyl)ethylene, 33: To 4hydroxybenzoic acid (0.012g 0.12 mmol) was added trans-1,2bis (4-pyridyl)ethylene (0.023g, 0.13 mmol). The solid mixture was dissol ved in 2 mL of methanol. After 2 days colorless crystals of 33 mp = 184-186 C were observed. 3-Hydroxybenzoic acidtrans-1,2-bis(4-pyridyl)ethylene, 34: To 3hydroxybenzoic acid (0.013 g, 0.10mmol) was added trans-1,2bis (4-pyridyl)ethylene (0.018g, 0.10 mmol). The solid mixture was dissol ved in 2 mL of ethanol. After 2 days colorless crystals of 34 mp = 180-184 C were observed. 3-Hydroxypyridinium benzoate, 35: To 3-hydroxypyridine (0.020g, 0.21 mmol) was added benzoic acid (0.026g, 0.21 mmol) and 2 mL of a 1:1 methanol and ethanol mixture. The solution was left to evaporat e at ambient temperature and after 8 days colorless crystals of 35 were obtained. 3-Hydroxypyridinium isophthalate, 36: To 3-hydroxypyridine (0.025g, 0.26 mmol) was added isophthalic acid (0.022g, 0.13 mmo l) and the mixture was dissolved in 0.5 mL of dimethylsulfoxide. After 6 days colorless crystals of 36 were observed. Co-crystallization via grinding: Stoichiometric amounts of the starting materials were ground with a mortar and pestle for ca.4 minutes. Co-crystallization via solvent-drop grinding: Stoichiometric amounts of the starting materials were ground with a mortar and pestle for ca. 4 minutes with the addition of 10 L of solvent per 50 mg of co-crystal formers.

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152Co-crystallization via melting: Stoichiometric amounts of the starting materials were heated until melt and the mixture was left to crystallize at ambient conditions. All co-crystals were analyzed by infrared spectroscopy using a Nicolet Avatar 320 FTIR instrument. The purity of bulk samples was confirmed by X-ray powder diffraction. Co-crystals were analyzed on a Rigaku Miniflex Diffractometer using Cu K ( = 1.54056 ), 30 kV, 15 mA. The data was colle cted over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.02 2 and a scan speed of 2.0/min. Compounds and were analyzed on Bruker AXS D8 discover X-ray diffractometer equipped with GADDSTM (General Area Diffraction Detection System), a Bruker AXS HI-STAR area detector at a distan ce of 15.05 cm as per system calibration, a copper source, automated x-y-z stage, and 0.5 mm collimator. Data were collected over 2.1-37.0 2 range at a step size of 0.02 2. Melting points of 21 34 were determined on a MEL-TEMP apparatus, and the comparison of the melting points of 21-34 and the corresponding constituents is summarized in Table 4.4. 4.4.2. Single-crystal X-ray diffraction. The single crystal x-ray diffraction data were collected on a BrukerAXS SMART APEX CCD diffractometer with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX lo w temperature device. Data for 21 36 were collected at 100 K. Lattice parameters were de termined from least square analysis, and reflection data were integrated using th e program SAINT. Lore ntz and polarization corrections were applied for diffracted reflec tions. In addition, the data was corrected for absorption using SADABS.42 Structures were solved by direct methods and refined by

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153 full matrix least squares based on F2 using SHELXTL.43 Non-hydrogen atoms were refined with anisotropic displacement para meters. All H-atoms bonded to carbon atoms, except methyl groups, were placed geometri cally and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. N or O bonded protons, as well as H-atoms of methyl groups, were located from Fourier difference map and refined isotropically ba sed upon the corresponding N, O or C atom (U(H)=1.2Uq(N, O)). Crystallographic data for 21 36 are presented in Table 4.7. and 4.8. and selected hydrogen bond distances are li sted in Table 4.5 and 4.6.

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154Table 4.5 Hydrogen Bond Distan ces and Parameters for 21-36 Hydrogen Bond d (HA) / D (DA)/ / O-H N 1.74 2.675(2) 169.0 21 O-H O 1.82 2.7540(19) 176.5 O-H N 1.54 2.590(2) 173.5 O-H O 1.81 2.6455(19) 167.8 O-H N 1.72 2.546(2) 177.6 O-H O 1.90 2.7411(19) 171.6 22 N-H O 1.59 2.546(2) 177.8 O-H N 1.60 2.674(6) 168.2 23 O-H O 1.65 2.680(5) 154.2 O-H O 1.59 2.630(3) 170.4 24 O-H N 1.79 2.703(3) 167.0 O-H N 1.87 2.7739(17) 169.9 25 O-H O 1.76 2.6282(15) 169.6 O-H N 1.92 2.739(2) 163.7 26 O-H O 1.78 2.617(2) 175.4 O-H N 1.64 2.596(2) 166.6 27 O-H N 1.74 2.685(2) 169.3 O-H N 1.48 2.590(4) 172.4 28 O-H N 1.66 2.663(4) 167.8 O-H N 1.76 2.6881(19) 168.0 29 O-H N 1.81 2.7898(19) 175.0 O-H N 1.85 2.720(2) 170.0 O-H N 1.89 2.782(2) 170.6 O-H N 1.77 2.699(2) 169.5 30 O-H N 1.86 2.762(2) 163.1

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155Table 4.6 Hydrogen Bond Distances and Parameters for 21-36 (cont.) Hydrogen Bond d (HA) / D (DA)/ / O-H N 1.77 2.673(2) 177.2 31 O-H N 1.81 2.755(2) 162.2 O-H N 1.70 2.756(3) 176.7 32 O-H N 1.71 2.640(2) 172.5 O-H N 1.54 2.617(4) 168.8 33 O-H N 1.79 2.756(4) 163.8 O-H N 1.64 2.6482(16) 168.6 34 O-H N 1.80 2.7358(16) 174.8 N-H O 1.43 2.559(10) 176.1 O-H O 1.74 2.569(9) 169.0 35 N-H O 2.41 3.065(10) 115.1 O-H O 1.76 2.662(3) 165.8 O-H O 1.80 2.662(2) 174.0 36 N-H O 1.74 2.647(2) 172.4

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156Table 4.7 Crystallographic data and structure re finement parameters for compounds 21-36 21 22 23 24 25 26 27 28 formula C9H8NO3 C26H24N2O6 C11H12NO3 C18H15NO3 C9H8NO3 C13H15N2O3 C29H24N2O3 C19H18N2O3 MW 178.16 460.47 206.22 293.31 178.16 247.27 448.50 322.35 crystal system Monoclinic Monoclinic Monoclinic M onoclinic Triclinic Monoclinic Monoclinic Triclinic space group P 21/ n P 21/ c P 21/ c C 2/ c P -1 P 21/ c P 21/ n P -1 a () 5..2006(11) 7..3666(3) 10.379(3) 26.780(4) 5..9424(9) 11.693(4) 9..2032(16) 7..9810(15) b () 14.568(3) 23.716(3) 10.307(3) 7.4445(13) 6..8175(10) 8.694(3) 20.819(4) 8..9312(17) c () 10.994(3) 12.5523(15) 10.134(3) 19.471(3) 10.6376(16) 12.722(4) 11.827(2) 11.209(2) (deg) 90 90 90 90 102.963(3) 90 90 97.585(3) (deg) 100.450(5) 103.033(2) 110.257(6) 131.101(2) 97.383(2) 94.920(7) 93.487(3) 90.745(4) (deg) 90 90 90 90 100.057(3) 90 90 90.665(4) V /3 819.1(3) 2136.5(4) 1017.0(5) 2925.1(8) 407.16(11) 1288.5(7) 2261.9(7) 791.9(3) Dc/g cm-3 1.235 1.432 1.347 1.332 1.453 1.275 1.317 1.352 Z 4 4 4 8 2 4 4 2 2 range 4.7050.04 3.44-52.74 4.18 -45.04 4.04-50.14 4.00-52.74 3.500.14 3.92 52.74 4.60-56.48 Nref./Npara. 1417/118 4356/307 1260/136 2477/199 1635/118 2198/163 4628/307 3126/217 T /K 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0418 0.0472 0.0823 0.0495 0.0456 0.0461 0.0534 0.0810 w R2 0.1007 0.1082 0.1771 0.1222 0.1213 0.1110 0.1085 0.2240 GOF 1.066 1.032 1.063 1.020 1.068 1.037 1.047 1.186 Abs coef. 0.110 0.103 0.099 0.091 0.111 0.092 0.086 0.093

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157Table 4.8 Crystallographic data and structure re finement parameters for compounds 21-36 (cont) 29 30 31 32 33 34 35 36 formula C17H14N2O3 C15H12N2O3 C19H24N3O3 C23H18N2O3 C19H16N2O3 C19H16N2O3 C12H11NO3 C13H11NO5 MW 294.30 268.27 342.41 370.39 320.34 320.34 217.22 261.23 crystal system Triclinic Triclinic Monoclinic Tr iclinic Triclinic Triclinic Monoclinic Monoclinic space group P -1 P -1 P 21/ c P -1 P -1 P -1 P c P 21/ n a () 8.1965(12) 7.2850(9) 9.4609(14) 5.9682(8) 6.1928(19) 7.9011(13) 5.007(15) 10.218(5) b () 8.8828(12) 12.1470(15) 17.807(3) 8.7387(12) 6.957(2) 10.3101(16) 9.93(3) 11.001(6) c () 10.3613(15) 14.4319(18) 11.0809(17) 17.938(3) 18.499(5) 10.8629(17) 10.30(3) 10.412(5) (deg) 72.213(3) 87.837(2) 90 78.473(2) 95.046(6) 114.081(2) 90 90 (deg) 72.213(2) 85.937(2) 92.184(3) 82.090(3) 94.058(7) 103.883(3) 100.07(9) 99.983(9) (deg) 86.773(3) 80.916(2) 90 88.921(3) 103.928(6) 93.041(3) 90 90 V /3 685.25(17) 1257.4(3) 1865.5(5) 907.9(2) 767.1(4) 772.8(2) 504(3) 1152.6(10) Dc/g cm-3 1.426 1.417 1.219 1.355 1.387 1.377 1.430 1.505 Z 2 4 4 2 2 2 2 4 2 range 4.8249.42 2.84-52.74 4.88 -52.74 2.34-56.36 2.22-50.18 4.409.42 5.74 50.16 5.48-52.74 Nref./Npara. 2311/199 5006/361 3804/229 3632/253 2508/217 2591/217 607/145 2340/172 T /K 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0442 0.0498 0.0576 0.0564 0.0682 0.0416 0.0437 0.0566 w R2 0.1109 0.1194 0.1303 0.1282 0.1366 0.1112 0.0802 0.1359 GOF 1.092 1.058 1.033 1.040 0.999 1.088 0.804 1.038 Abs coef. 0.100 0.101 0.084 0.091 0.095 0.095 0.104 0.117

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1564.5. References Cited 1. Allen, F. H. Acta Crystallogr. 2002, B58, 380. 2. Allen, F. H, Taylor, R. Chem. Soc. Rev ., 2004, 33 463. 3. Web Page, http://www.rxlist.com/top200.htm 4. Merck Index version. 13.4 5. Aakery, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124 14425. 6. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3 783. 7. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular Pharmaceutics ACS ASAP. 8. Leiserowitz, L. Acta Crystallogr. 1976, B32 775. 9. Leiserowitz, L.; Nader, F. Acta Crystallogr. 1977, 33 2719. 10. Reddy, L. S.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2004, 4 89. 11. Jetti, R. K. R.; Xue, F.; Mak, T. C. W.; Nangia, A. J. Chem. Soc. Perkin Trans. 2 2000, 6 1223. 12. Melendez, R. E.; Hamilton, A. D. Top. Curr. Chem. 1998, 198 97 13. Steiner, T. Acta Crystallogr. 2001, B57 103. 14. Aakery, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem. Int. Ed. 2001, 40 3240. 15. CSD Refcodes: GEHROB, SOFHIE, HAKVEV, GUTSAP, BEQWAV, IDUBUF, VEFVEI, VEFVIM WEPDIF. 16. Bis, J. A.; Zaworotko, M. J. Crystal Growth Des ., 2005, 5 1169.

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157 17. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110 2135. 18. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D. Acta Crystallogr. 2003, B59 794. 19. Mootz, D.; Wussow, H. G. J. Chem. Phys. 1981, 75 1517. 20. Mootz, D.; Hocken, J. Z. Naturforschung B J. Chem. Sci. 1989, 44 1239. 21. Stahl, P.H.; Wermuth, C. G. ed. Handbook of pharmaceutical salts: properties, selection, and use; Intern ational Union of Pure and Applied Chemistry, VHCA; Wiley-VCH: Weinheim, New York, 2002. 22. Johnson, S. L.; Rumon, K. A. J. Phys. Chem ., 1965, 69, 74. 23. Childs, S. L.; Stahly, G. P.; Park, A. Molecular Pharmaceutics 2007 ASAP Alert. 24. Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V. J Am. Chem. Soc ., 2006, 128 8199 25. CSD Refcode: BIRYIK10: Ohms, U.; Guth, H.; Treutmann, Z. Kristallogr.Kristallgeom.; Kristallphys., Krystallchem ., 1983, 162 299. 26. Lynch, D. E.; Lad, J.; Smith, G.; Parsons, S. Crystal Engineering 1999, 2 65. 27. CSD Refcodes: IDUNEA, IDUNIE, I DUNOK, IDUNUQ, JOJJUN, KUKBOC, LEJROH, OCAKAF, PAHZAA, RACBED, VITXUR, YETLUE. 28. CSD Refcode OCAKAF: Gao, S.; Liu, J-W.; Huo, L-H., Zhao, H.; Ng, S. W. Acta Crystallogr ., 2004, E60 o1854. 29. ISNICA: Takusagawa, F.; Shimada, A. Acta Crystallogr ., 1976, B32 1925. 30. NICOAC: Wright, W. B.; King, G. S. D. Acta Crystallogr ., 1953, 6 305. 31. CSD Refcodes: AWUDEB, HAFZIY, PAZHOO, SATLUV and YERXUP

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158 32. CSD Refcodes: AFECAT, REFFIS, S AQJUP, SATMAC, TAQNUV, XOXCUI, QEQVIS, HEWWAI 33. CSD Refcode SESLIM: Jebas, S. R.; Balasubramanian, T. Acta Crystallogr ., 2006, E62 o5621. 34. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20 2372. 35. Gridunova, G. V.; Furmanova, N. G.; Struchkov, Yu. T.; Ezhkova, Z. I.; Grigor'eva, L. P.; Chayanov, B. A. Kristallografiya 1982, 27(2), 267-72. 36. Kariuki, B. M.; Bauer, C. L.; Harris, K. D. M.; Teat, S. J. Angew. Chem., Int. Ed ., 2000, 39 4485. 37. CSD Refcode JOZZIH : Heath, E.A.; Singh P.; Ebisuzaki, Y. Acta Crystallogr., 1992, C48 1960. 38. Kariuki, B.M.; Bauer, C. L.; Harris, K. D.M.; Teat, S. J. Angew. Chem. Int. Ed., 2000, 39, 4485. 39. Single Crystal X-ray diffraction data for a microcrystal of Form II 4hydroxybenzoic acid was recorded on St aton 9.8 at the Synchotron Radiation Source (Daresbury Laborotory). Crystal size 0.10 x 0.07 x 0.05 mm3; T = 296(2) K; = 0.68850; monoclinic, P21/ n ; a = 18.66(2) b=3.860(4) ; c=18.82(3) ; =93.511(6) ; V=1353(3) A3 ; Z = 8. The microcrystal diffraction station comprises a Siemens SMART CCD detector and goniometer system. (R1=0.131; Rw=0.365) 40. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Zeitschrift fuer Kristallographie 2005, 220(4), 340-350. 41. Gavezzotti, A. J. Chem. Soc., Perkin Transactions 2 1995, 1399-404.

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159 42. SADABS [Area-Detector Absorption Co rrection]. Siemens Industrial Automation, Inc.: Madison, WI, 1996. 43. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997.

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160 5. Pharmaceutical Co-Crystals of Stavudine 5.1. Introduction N N H O O O OH Stavudine Stavudine [1-(2,3-dideoxy-D-glycero-pent-2-enofur anosyl)thymine] is a synthetic thymidine nucleoside analogue with inhibitory ac tivity against HIV/AIDS. A review of the literature reveals three polymorphic m odifications of stavudine.1-4 This includes a monoclinic (Form I), a triclinic (Form II) and an orthorhombic form (Form III). The crystal structures of all three fo rms are sustained by amide dimers and alcoholalcohol interactions as shown in Figure 5. 1 and therefore exhibits persistent supramolecular synthons. These conformational polymorphs5 differ in the three parameters that are typically used to de scribe the conformation of the nucleoside molecule: the geometry of the glycosylic link, the furanose ring puckering and the orientation of the 5 hydroxyl group.6 Structural analysis of all three polymorphs have been reported, several solvates and a hydrate have also been described in the literature.7-12 However we are unaware of any attempts to ge nerate co-crystals of stavudine. In this chapter we exploit the remarkable diversity afforded by the imide moiety and utilize the robust three point recognition supramolecular heterosynthon IX, the alcohol pyridine

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161 heterosynthon VI and the acid-amide heterosynthon X to generate pharmaceutical cocrystals of stavudine. Figure 5.1 Crystal structure of stavudine (Form I) OH COOH COOH OH N N N NH2 N H2 NH2 N N NH2 N H2 NH2 N NH2 melamine 2, 4, 6-triaminopyrimidine (2,4,6-TAP) 2-aminopyridine 4-hydroxybenzoic acid salicylic acid Schematic of co-crystal formers

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1625.2. Results and Discussion N O H O O H X N O H O N N N H H H H IX O H N VI The imide moiety exhibits remarkable diversity in terms of its supramolecular chemistry, it is self complementary and capab le of forming 3-point, 2-point and 1-point recognition13 supramolecular synthons. Self associ ation typically occurs via two point recognition coupling such as that seen in pure stavudine. Of the many supramolecular heterosynthons that the imide moiety can engage in synthon IX is one of the more robust. In fact a database analysis suggests that heterosynthon IX has the highest probability of occurrence observed in bimolecular hydrogen bonde d ring motifs in organic crystals.14 The three-point recognition heterosynthon IX has some analogy with nucleotide recognition in DNA,15 and has been utilized to gene rate numerous co-crystals in a predictable fashion.16-21 An analysis of the Cambridge Structural Database (CSD)22-25 retrieved 74 structures cont aining both the imide moiety and the 2-aminopyridine functional groups. Of these, 46 (62%) structur es exhibit the three point supramolecular heterosynthon IX. The hydrogen bond distances of supramolecular synthons VI, XI and X are presented in Table 5.1.

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163 Table 5.1 Geometrical Features of Supramolecular Synthons Supramolecular Synthon Supramolecular synthon DA [] Mean () [] IX NHOa NHN 2.50-3.25 2.50-3.25 250 315 2.77(8) 2.78(8 VI OHN 2.50-3.00 2.78(8) The alcohol-aromatic nitrogen supramolecular synthon VI is a robust, reliable heterosynthon in crystal engineering, occurr ing in 682/1453 (47%) entries as compared to 274/1453 (19%) crystal structures that exhibit the alcohol homosynthon V. As shown previously in Chapter 3 heterosynthon VI has been utilized in ge nerating co-crystals in a predictable manner.26-42 5.2.1. Crystal Structure Description Co-crystallization of a 3:1 mole ratio of stavudine and melamine resulted in the formation of (stavudine)3 melamine 37 The asymmetric unit of 37 consists of two melamine and six stavudine molecules. The presence of multiple molecules in the asymmetric unit has often been associated with identifiable pa cking problems or conflict.43-44 Melamine has three 2-aminopyridine recognition sites and stavudine has one complementary functional group. Therefore it is anticipated that each melamine and three stavudine molecules complementarily hydrogen bond via robust three-point supramolecular heterosynthon IX [two R2 2 (8)] in a trigonal fashi on (Figure 5.2a). As is observed such trigonal four component adducts are hydrogen bonded via stavudine O HO interactions to generate hexagonal sheet parall el to (001) plane (Figure 5.2b).

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164 The hexagonal sheets are connected through O HO hydrogen bonds between the layers. The supramolecula r sheets stack along the c axis. All the hydrogen bond lengths and angles are in the normal range (Table 5.1). (a) (b) Figure 5.2 (a) Triangular four component supramolecular adduct in co-crystal 37 (b) Hexagonal packing of 3:1 co-crystal of stavudine and melamine, 37 Co-crystallization of a 2:1 mole ratio of stavudine and 2, 4, 6-triaminopyrimidine (2, 4, 6-TAP) 38 results in the formation of a 1:1:1 crystal structure in which water is incorporated in the crystal lattice. 38 contains one molecule each of stavudine, 2, 4, 6TAP and water present in the asymmetric unit and crystallizes in the orthorhombic P212121 space group. The three point recognition heterosynthon IX is observed, however instead of the anticipated 2:1 stoichio metry, we observe stavudine O-H N hydrogen bond (2.7688(19), 167 ) to the 2,4,6-triaminopyrimidine at the second potential hydrogen bonding site. As a result right-handed helic es are formed through 3-point recognition heterosynthon IX (N-H O 2.947(2) 166.8 ; N-H N: 2.945(2), 174.2 N-H O

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165 2.896, 167.4 ) and O-H N heterosynthon VI. Subsequently there are two amino groups NH2 that are not involved in strong H-bond inte ractions. The hydroxyl groups of adjacent primary helix are involved in cooperative hyd rogen bonding to generate channels parallel to the a axis as shown in Fig 5.3. The O-H O hydrogen bond distance within the primary helix is 2.894(2) whereas the O-H O hydrogen bond that bridge adjacent helix is 3.095(3) a) b) Figure 5.3 Crystal Packing of 38 showing right handed helices formed through supramolecular heterosynthons VI and IX. Stavudine also forms a co-crystal with 2 -aminopyridine, 39 The co-crystal contains one molecule of stavudine and a 2-aminopyridine molecule in the asymmetric unit. The presence of the hydroxyl group on th e conformationally fl exible stavudine molecule precludes the formation of the two point 2-aminopyridine-amide synthon. The crystal structure reveals th at the alcohol group bridges the aminopyridine-amide synthon as shown in Fig 5.4. Consequently stavudine molecules interact with 2-aminopyridine molecules through terminal O HN hydrogen bonds. (2.6715(16) 172.6 ) as

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166 illustrated in Figure 5.5. Stavudine molecu les interact with each other via N HO (2.7549(16) 165.4) hydrogen bonds to generate infinite chain along the b -axis. The structure is further stabilized by the bifurca tion of the amino groups by adjacent carbonyl moieties on two different stavudine mo lecules: one within the chain (N-H O 3.274(17) and the other in the adjacent chain (N-H O 3.2056(18) ) as a consequence a two dimensional corrugated supramolecular sheet is generated. Figure 5.4 Illustrates the supramolecular synthons present in co-crystal 39 the insertion of the hydroxyl group precludes the fo rmation of the two-point reco gnition amide-2-aminopyridine supramolecular heterosynthon. Please note that port ions of the stavudine molecule have been deleted for clarity. Figure 5.5 Hydrogen bonded infinite chains of stavudine molecules form terminal OHN hydrogen bonds with pyridyl moiety of 2-aminopyridine in co-crystal 39. A recent study involving the association of nucleobases with carboxylic acids led to the complexation of adenine and cytosi ne with mono and di-carboxylic acids. The

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167 authors observed no complexation with guanine, thymine or uracil.45 Herein we report the co-crystallization of stavudine, a thymine derivative with monocarboxylic acids. A review of the CSD reveals no examples of two point recognition between an imide and a carboxylic acid. However based upon our experience exploiting the acid-amide supramolecular heterosynthon46-47 to generate pharmaceutical co-crystals, stavudine was co-crystallized with a series of monocarboxylic acids. As anticipated stavudine forms a 1:1 co-crystal with 4-hydroxybenzoic acid 40 The asymmetric unit of 40 contains one molecule of stavudine and one molecule of 4-hydroxybenzoic acid. Co-crystal 40 is sustained by the 2-point r ecognition carboxylic acid-amide supramolecular heterosynthon X (N-H O 2.814(2) 171.1 and O-H O 2.649(2); 173 ). The alcohols of stavudine and 4-hydroxybenzoic acid forms right ha nded cooperative helices through O-H O hydrogen bonds48 of 2.831(2) and 2.676( 2) (see Fig 5.6). Figure 5.6 Carboxylic acid-amide supr amolecular heterosynthon in stavudine4-hydroxybenzoic acid 40

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168 Figure 5.7 Crystal packing of stavudine4-hydroxybenzoic acid, 40 Stavudine also forms a 1:1 co-crystal with salicylic acid 41, however the expected carboxylic acid-amide heterosynthon X is not observed. Inst ead stavudine molecules form one point recognition O-H O hydrogen bonds with salicylic acid molecules. A further analysis of the crystal structure rev eals that stavudine molecules are connected to each other in a linear fashion through N-H O hydrogen bonds (2.917(2) 164.5 ) as shown in Fig 5.8. Adjacent chains of stavudine molecules are linked together by salicylic acid molecules through O-H O hydrogen bonds. Figure 5.8 Illustrates supramolecula r synthons present in stavudine salicylic acid 41

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169 37 39 40 and 41 were also investigated in the c ontext of their susceptibility to solid state preparation i.e grinding and solvent drop grinding. With regards to stoichiometry and crystal form, 39 40 and 41 were reproducibly obtained using the aforementioned methods. Grinding and solvent drop grinding however yielded a mixture of starting materials in the case of 37 The syntheses of 38 39 40 and 41 were also accomplished via slurry conversion of stoichio metric amounts of the starting materials in water. However as was the case with the gri nding and solvent drop gr inding, a mixture of starting materials result in the case of 37 It has been demonstrated that solv ent drop grinding can invoke polymorphic transformations. A search for crystal forms of 37 39 40 and 41 via solvent drop grinding of co-crystal formers involving seven solven ts of different polar ity: cyclohexane, chloroform, dimethyl sulfoxide, ethyl acetate, methanol, toluene and water, was also conducted. As determined by FT-IR spectrosc opy and X-ray powder diffraction only one form that same as was obtained from solution was isolated for co-crystals 37 38 40 and 41 5.3. Conclusions Five novel forms of stavudine were presen ted, four co-crystals and a co-crystal hydrate.These results further illustrate th e diversity that may be obtained using a supramolecular approach with respect to API forms. 37-41 exhibit a range of supramolecular synthons including: the one poi nt recognition alcoholaromatic nitrogen heterosynthon VI, two point recognition acid-amide X as well as three-point recognition synthon IX. The syntheses of 39 40 and 41 were also accomplished via solvent-drop

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170 grinding49 of the starting material and 38 39 40 and 41 was also obtained via slurry conversion. These results sugge sts that solid state methodol ogies such as grinding and solvent drop grinding; and slurry conver sions are viable means for synthesis of pharmaceutical co-crystals. 5.4. Experimental Section 5.4.1 Synthesis Stavudine was obtained from Transform Pharmaceutical Inc and used as received. Reagents used to synthesize co-crystals 37 41 were obtained from commercial sources with purity ca. 98% and used as received. Crystals suitable for single crystal X-ray diffractometry were obtained by slow evaporation of the solvent under ambient conditions. (Stavudine)3 melamine, 37: Stavudine (0.132g, 0.58 mmol) and melamine (0.034g, 0.27 mmol) were dissolved in 2 mL of et hanol/water mixture upon warming. Slow evaporation of the solvent at room temp erature yielded colorless crystals of 37 within 4 days, m. pt: 186-190. Stavudine2,4,6-triaminopyri midine hydrate, 38: Stavudine (0.078g, 0.35 mmol) and 2,4,6-triaminopyrimidine (0.022 g, 0.17 mmol) was dissolved in 2ml of 1:1 ethanol / water solvent mixture. Slow evaporation of the solvent yi elded colorless crystals of 38 Stavudine 2-aminopyridine, 39: Stavudine (0.040g, 0.18mmo l) and 2-aminopyridine (0.017g, 0.18mmol) were dissolved in 2 mL of 1:1 ethanol/water solvent mixture upon warming. Slow evaporation of the solv ent afforded colorless crystals of 39, m. pt = 120122C.

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171Stavudine 4-hydroxybenzoic acid, 40: Stavudine (0.035 g, 0.16 mmol) and 4hydroxybenzoic acid (0.22 g, 0.16 mmol) was dissol ved in ethanol (2 mL). The solution was allowed to evaporate slowly under ambien t conditions to yield co lorless crystals of 40 Stavudine salicylic acid, 41: Stavudine (0.035g, 0.16mmol) a nd salicylic acid (0.022 g, 0.16 mmol) was dissolved in ethanol (2 mL). Th e solution was left to evaporate slowly at room temperature to yield colorless crystals of 41 For grinding experiments: stoichiometr ic amounts of starting materials were processed for 4 minutes in a mortar and pest le. The resulting powders were analyzed by IR spectroscopy and X-ray powder diffrac tion. Solvent-drop grinding and slurry conversion afforded the same phase as that obtained from soluti on in all cases except 37 X-ray powder diffraction (XRPD) analyses were conducted on a Rigaku Miniflex diffractometer using Cu K radiation ( =1.540562, 30 kV and 15Ma). The powder data was collected over an angular range of 3 to 40 2 in a continuous mode using a step size of 0.02 2 and a scan speed of 2 /min. Differential Scanning Calorimetry (DSC) analyses were performed on a TA instrume nts 2920 differential scanning calorimeter. The sample cell was equilibrated at 25 and heated under a nitrogen purge at a rate of 10 C/min. Indium metal was used as the calib ration standard. Infrar ed Spectroscopy was conducted using a Nicolet Avatar 320 FTIR. 5.4.2. Single-crystal X-ray diffraction The single crystal x-ray diffraction data were collected on a BrukerAXS SMART APEX CCD diffractometer with monochromatized Mo K radiation ( = 0.71073 ) connected to a KRYO-FLEX low temper ature device.

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172 Data for 37 41 were collected at 100 K. Lattice parameters were determined from least square analysis, and reflection data were in tegrated using the program SAINT. Lorentz and polarization corrections we re applied for diffracted refl ections. In addition, the data was corrected for absorption using SADABS.50 Structures were solved by direct methods and refined by full matrix least squares based on F2 using SHELXTL.51 Non-hydrogen atoms were refined with anisotropic disp lacement parameters. All H-atoms bonded to carbon atoms, except methyl groups, were plac ed geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. N or O bonded protons, as well as Hatoms of methyl groups, were located from Fourier difference map and refined isotropi cally based upon the corresponding N, O or C atom (U(H)=1.2Uq(N, O)). Selected hydrogen bond distan ces are listed in Table 5.2 and 5.3 and crystallographic data for 37-41 are presented in Table 5.4.

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173Table 5.2 Geometric Parameters of Interm olecular Interactions for (stavudine)3 melamine, 37 Interaction d (H...A)/ D(D...A) / / O-HOa 2.05 2.900(5) 137.3 N-HNa 1.95 2.905(5) 153.8 O-HOb 2.02 2.820(4) 165.8 N-HNb 2.03 2.904(5) 166.5 O-HOc 2.00 2.830(5) 157.0 N-HNc 1.91 2.893(5) 150.5 O-HOd 2.09 2.838(4) 134.6 N-HNd 1.99 2.893(5) 168.7 O-HOe 1.95 2.734(4) 149.1 NHNe 1.91 2.912(5) 166.2 OHOf 2.11 2.807(5) 132.3 NHNf 2.02 2.884(5) 155.2 N-HOa 1.97 2.913(5) 169.4 N-HOb 2.24 2.875(5) 131.6 N-HOc 2.12 2.923(4) 174.5 N-HOd 2.06 2.937(5) 163.9 N-HOe 2.10 2.933(4) 161.7 N-HOf 2.06 2.972(5) 153.3 N-HOg 2.07 2.915(4) 173.1 N-HOh 2.03 2.936(5) 143.5 N-HOi 2.06 2.917(5) 176.2 N-HOj 1.93 2.898(5) 168.1 N-HOk 2.11 2.889(5) 168.3 N-HOl 1.98 2.960(5) 171.7

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174 Table 5.3 Geometric Parameters of In termolecular Interactions for 38-41 Interaction d() D () (deg) O-H N 1.91 2.7688(19) 167.0 N-HN 2.10 2.945(2) 174.2 O-H Oa 1.96 2.894(2) 165.6 O-H Ob 2.25 3.095(3) 135.8 N-HOa 2.09 2.896(2) 167.4 N-HOb 2.55 3.194(2) 130.8 N-HOc 2.52 3.356(3) 162.1 N-HOd 2.07 2.947(2) 166.8 38 N-HOe 2.29 3.130(2) 156.3 O-H N 1.85 2.6715(16) 172.6 N-HOa 1.89 2.7549(16) 165.4 N-HOb 2.39 3.2056(18) 151.2 39 N-HOc 2.49 3.2745(17) 153.2 O-H Oa 1.65 2.676(2) 159.6 O-H Ob 1.59 2.649(2) 173.0 N-H O 1.92 2.814(2) 171.1 40 O-HOc 1.96 2.831(2) 174.4 O-H Oa 2.08 2.859(2) 157.3 N-HO 1.92 2.917(2) 164.5 O-H Ob 1.78 2.590(2) 163.3 41 O-H Oc 1.76 2.582(3) 146.2

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175 Table 5.4 Crystallographic Data and structure refinement pa rameters for compounds 37-41 37 38 39 40 41 Chemical formula (C10H12N2O4)3 C3H6N6 C10H12N2 O4 C4H7N5 H2 O C10H12N2O4 C5H6N2 C10H12N2O4 C7H6O3 C10H12N2O4 C7H6O3 stoichiometry 3:1 1:1:1 1:1 1:1 1:1 Formula .wt. 798.79 367.38 318.33 362.33 362.33 crystal system monoclinic orthorhombic orthorhombicMonoclinic orthorhombic space group C2 P212121 P212121 P21 P212121 a () 28.720(4) 7.2074(10) 7.1242(6) 10.3369(18) 7.114(5) b () 16.622(3) 11.9659(17) 13.7996(12)7.3130(13) 14.460(9) c () 15.900(2) 19.940(3) 15. 0163(14)11.065(2) 16.414(10) ( ) 90 90 90 90 90 ( ) 102.909(3) 90 90 94.918(3) 90 () 90 90 90 90 90 volume (3) 7398.3(19) 1719.7(4) 1476.3(2) 833.3(3) 1688.6(18) Dcalc ( g cm-3) 1.434 1.419 1.432 1.444 1.425 Z 8 4 4 2 4 range 1.31-26.37 1.98-26.37 2.71-26.37 1.98-26.37 1.88-26.37 Nref./Npara. 12303/1063 3502/244 3021/214 3192/242 3440/242 T (K) 100 298 100 298 298 R1 0.0643 0.0379 0.0343 0.0389 0.0390 wR2 0.1384 0.0983 0.0851 0.0931 0.0826 GOF 1.038 1.056 1.110 0.999 0.918 abs coef. 0.111 0.110 0.106 0.114 0.112

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1765.5. References Cited 1. Gurskaya, G. V.; Bochkarev, A. V.; Zhdanov, A. S.; Dyatkina, N. B.; Kraevskii, A. A. Molekulyarnaya Biologiya 1991, 25 483. 2. Harte, W. E.; Starrett, J. E.; Ma rtin, J. C.; Mansuri, M. M. Biochem. Biophys. Res. Commun. 1991, 175 298. 3. Mirmehrabi, M.; Rohani, S.; Jennings, M. C. Acta Crystallogr ., 2005, C61 o695. 4. Mirmehrabi, M.; Rohani, S.; Murthy, K. S. K.; Radatus, B Crystal Growth Des 2006, 6, 141. 5. Bernstein, J. Polymorphism in Molecular Crystals. ; Clarendon Press: Oxford, United Kingdom, 2002. 6. Saenger, W. Principles of Nucleic Acid Structure ; Springer-Verlag; New York 1984. 7. Mirmehrabi, M.; Rohani, S.; Jennings, M. C. Acta Crystallogr., 2005, C61 695. 8. Van Roey, P.; Taylor, E. W.; Chu, C. K.; Schinazi, R. F J. Am. Chem. Soc 1993, 115 5365. 9. Gandhi, R. B.; Bogardus, J. B.; Bugay, D. E.; Perrone, R. K.; Kaplan, M. A. Int. J. Pharm ., 2000, 201 221. 10. Skonezny, P. M.; Eisenreich, E.; Stark, D. R.; Boyhan, B. T.; Baker, Stephen R. Eur. Pat. Appl. EP 653435 A1, 1995. 11. Radatus, B. K.; Murthy, K. S. K. US 6635753 B1, 2003.

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177 12. Viterbo, D.; Milanesio, M.; Hernandez, R. P.; Tanty, C. R.; Gonzalez, I. C.; Carrazana, M. S.; Rodriguez, J. D. Acta Crystallogr., 2000, C56 580. 13. Vishweshwar, P.; Thaimattam, R.; Jaskolski, M.; Desiraju, G. R. Chem. Commun 2002, 1830. 14. Allen, F. H.; Motherwell, W. D. S.; Ra ithby, P. R.; Shields, G. P.; Taylor, R. New J. Chem. 1999, 23 25. 15. Jeffrey.G. A. ; Saeger W. ; Springer-Verlag; Berlin 1991. 16. Zerkowski, J. A.; MacDonald, J. C.; Set o, C. T.; Wierda, D. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116 2382. 17. Zerkowski, J. A.; MacDonald, J. C.; Whitesides, G. M. Chem. Mater. 1997, 9 1933. 18. Zerkowski, J. A.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116 4305. 19. Zerkowski, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116 4298. 20. Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992, 114 5473. 21. Lehn, J. M.; Mascal, M.; DeCian, A.; Fischer, J. J. Chem. Soc ., 1990, 479. 22. Allen, F. H.; Kennard, O. Chem. Des. Automation News 1993, 8 31. 23. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res ., 1983, 16 146. 24. Allen, F. H. Acta Crystallogr. 2002, B58 380. 25. Allen, F. H, Taylor, R. Chem. Soc. Rev ., 2004, 33 463. 26. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst Growth Des. 2006, 6 150.

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178 27. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr ., 2003, C59 o481. 28. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm 2000, 2 96. 29. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999, C55 2133. 30. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 1890. 31. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 430. 32. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J. ; Liu, C.; Xu, S.; Li, Y.; Bai, C. Cryst. Growth Des ., 2005, 5 1889. 33. Friscic T.; MacGillivray L. R Chem. Commun ., 2003, 1306. 34. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters 2004, 6 4647-50. 35. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr ., 1999, C55 2133. 36. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr ., 1999, C55 430. 37. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr ., 1999, B55 591. 38. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc ., 2006, 128 2806. 39. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry 1999, 10 429. 40. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr ., 2005, B61 46.

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179 41. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth Des ., 2006, 6 1048. 42. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular Pharmaceutics 2007, 4 401. 43. Hao, X.; Chen, J.; Cammers, A.; Parkin, S.; Brock, C. P. Acta Crystallogr 2005, B61 218. 44. Brock C. P.; Dunitz J. D.; Chem Mater ., 1994, 6 1118. 45. Perumalla, S. R.; Suresh, E.; Pedireddi, V. R. Angew. Chem., Int. Ed 2005, 44 7752. 46. Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D. B.; Rodrguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3 909. 47. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220 340. 48. Taylor R; Macrae C. F. Acta Crystallogr 2001, B57 815-27. 49. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20 2372. 50. SADABS [Area-Detector Absorption Correct ion]. Siemens Industrial Automation, Inc.: Madison, WI, 1996. 51. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997.

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180 6. Summary and Future Directions 6.1. Summary When two or more molecules are co-cryst allized the following possibilities exist: a physical mixture of the initial components, the formation of pol ymorphs of either component, solvate or hydrate of either compon ent, a co-crystal, a sa lt (given appropriate pKa difference between the components) or a combination of one or more of the aforementioned. The exterior functional groups present on the target molecule, their ability to form robust supramolecular synt hons, the appropriate co-crystal former, conformational flexibility of the molecule mismatched solubility, crystallization conditions and methods of preparation are some factors that will ultimately dictate which of these possibilities occur. The research presented herein focus upon the identification of reliable robust supramolecular synthons which has become a pr e-requisite in the design process of any crystal engineering experiment. This is of im portance since it affords a certain level of predictability with respect to anticipated pa ttern formation in the crystal structure and facilitates the appropriate selection of co-c rystal formers. Specifically, the research presented focus on the iden tification of reliable hydr ogen bonded supramolecular heterosythons in the generation of co-crystal s and ultimately pharmaceutical co-crystals. Systematic studies combining CSD analysis and model co-crystal experiments have

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181 afforded a better understanding of supramolec ular synthons in the solid state. In particular, the knowledge acquired has led to the delineation of the reliability of two supramolecular heterosynthons namely the carboxylic acidaromatic nitrogen (III) and alcohol aromatic nitrogen (VI) heterosynthons. Specifically structural analysis of twelve compounds indicate that the carboxylic acidaromatic nitrogen supramolecular heterosynthon (III) forms reliably as compared to the carboxylic acid homosynthon I or II. Compounds 1 12 formed in predictable stoichiometries in all cases but one, cocrystal 3 to generate hydrogen bonded discrete, 2D and 3D struct ures. The co-crystal of (trimesic acid)2 (1,2-bis(4-pyridyl)ethane)3 12 exhibits concomitant polymorphism. Form II of which displays anti cipated (6, 3) networks. Form I however display (10, 3)-a networks and exhibits the highest level of in terpenetration yet observe d in an organic or metal-organic network. The existence of a ( 10, 3)-a network with such large dimensions and the inherent modularity of co-crystals il lustrates how co-crystals of TMA might be worthy of further investiga tion in the context of open framework networks. Co-crystallization of alcohols with ar omatic nitrogen containing molecules yielded single crystal data for seven co-cryst als all of which are su stained by the alcoholaromatic nitrogen supramolecular heterosynthon VI. Based on the statistical analysis and experimental results the formation of th e alcohol-aromatic nitrogen supramolecular heterosynthon appears more dominant to that of the alcohol homosynthon V. The strategy for the experiments to evaluate the competition existing between carboxylic acids and alcohols for aromatic n itrogen involved two co-crystal formers containing different permutation of the functio nal groups of interest In an individual

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182 experiment two co-crystal formers were co mbined, one co-crystal former possessed two of the three moieties (e.g. COOH/Narom) and the second co-crystal former possessed the remaining moiety (e.g. OH). According to this strategy, the individual pairs of co-crystal formers are combined as follows: COOH/Narom with OH, COOH/OH with Narom, and OH/Narom with COOH. Such an approach to de lineate the hierarch ies existing between two supramolecular heterosynthons is premised on idea that a co-crystal can result only if the favored supramolecular heterosynthon is formed between the co-crystal formers. Conversely, a co-crystal is not expected to be formed if a dominant supramolecular heterosynthon already exists in one of the pure components. Of the 16 compounds for which single crystal data was obtained, 14 structures were based upon strategy 2 involving COOH/OH with Narom. Of the obtained structures, co-crystals 21 23 were sustained by carboxylic acid-a romatic nitrogen supramolecular heterosynthon III as well as alcoholcarbonyl(acid) synthon VII, 24 26 exhibited alcohol-pyridine supramolecular heterosynthon VI and carboxylic acid dimer I. 27 34 exhibit both acid-pyridine III and alcohol-aromatic nitrogen VI supramolecular heterosynthons. Solution and solvent drop grinding attempts to obtain co-crystals of nicotinic acid and isonicotinic acid with carboxylic acids were unsuccessful; the IR spectroscopy and PXRD spectra of the solid obtained revealed a mixture of starting materials. Solvent drop grinding and me lt experiments involving 3-hydroxypyridine and 5-hydroxyisoquinoline with carboxylic acids yielded new phases as characterized by XRPD and DSC. Single crystals of 3-hydroxypyridinium benzoate, 35 and 3hydroxypyridinium isophthalate, 36 obtained within this series exhibited proton transfer between the carboxylic acid and th e aromatic nitrogen and was sustained by

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183 charge assisted interaction, IV. The ionic version of III results perhaps as a consequence of the pKa difference existing between the components. The negative results obtained within the series of compounds involving is onicotinic acid and ni cotinic acid with alcohols, coupled with the positive results obtained within the series involving OH/Narom with COOH suggests that the formation of the carboxylic acid-aromatic nitrogen supramolecular heterosynthon III appears to dominate over th at of the alcohol-aromatic nitrogen supramolecular heterosynthon VI. The supramolecular organization in crystal st ructures of four co-crystals and a cocrystal hydrate of stavudine formed by co-c rystallization with 2aminopyridines and carboxylic acids was presented. Stavudine exhibi ts a range of 1-point, 2-point and 3-point recognition heterosynthons via O-H N, O-H O and N-H O interactions to generate pharmaceutical co-crystals. The co-crystals of stavudine further illustrate the diversity that may be obtained using a supramolecula r approach with respect to API forms. The susceptibility of co-crystals toward method of preparation alternative to solution was also evaluated. Me thods of preparation included growth from melt, grinding and solvent-drop grinding. The results sugge st that solid state methodology are viable means of synthesizing co-crystals, in most instances the same phase was obtained as that from solution. Grinding and solvent drop gr inding approaches to supramolecular synthesis is highly relevant in the context of green chemistr y. In general the solvent drop grinding technique has proven to be a reliable technique for the reproducible formation of multi-component phases requiring less time at achieving conversion than grinding and consequently may form the basis of an initia l co-crystal screening regiment. With respect to growth from melts sublimation or decom position of the components need to be taken

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184 into consideration when large difference in melting point exists between the initial components. The ultimate goal of crystal engineering is the understanding of intermolecular interactions in an effort to design novel crystalline solids for functional applications. The presented research has contributed to the overall progress of the field of crystal engineering by facilitating a better un derstanding of hydrogen bonded supramolecular synthons. By combining statistical analysis obtained from the CSD analysis and model co-crystals studies crystal engineer ing of pharmaceuticals is feasible. Physical and chemical properties are intrinsically dependent on molecular arrangement within the crystal structure. Cons equently the applicati on of principles of crystal engineering towards APIs is inhere ntly related to the modification of their physicochemical properties. That pharmaceutic al co-crystal represents a significant opportunity in the context of drug developmen t and intellectual prope rty consideration is without question however the role of pharmaceu tical co-crystal within the pharmaceutical industry still remains to be explored. Several foreseeable challenges exists including scale up, property evaluation of the co -crystalline material, issu es related to regulatory procedures, etc. 6.2. Future Directions Attempts to identify reliable supramolecu lar synthons have for the most part been confined to commonly occurri ng functional groups such as acids, amides, aromatic nitrogen, alcohol etc. However further inves tigation of the reliability of supramolecular synthons and hierarchies in a competitive en vironment may be applied to a wider range

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185 of hydrogen bonding and halogen bonding moieties. The focus of the presented research has concentrated on the competition between two supramolecular synthons, perhaps investigation of the competition of various hydrogen bonds in the presence of three, four, or even more functional groups should be addressed as well. Great stride s have been made with respec t to the generation of binary co-crystals especially those involving co mmon functional groups, however there is a wide landscape for the formation of ternary or quaternary co-crystals, that remains largely unexplored. In the context of pharmaceutical co-cry stals, the choice of co-crystal formers should be expanded to utilize pharmaceutically acceptable molecules including excipients already utilized in the formulation process. T hus far, there have been limited reports on the physicochemical performance of pharmaceu tical co-crystals as compared to the parent API. Consequently the evaluation of physicochemical properties of pharmaceutical co-crystal is an important area for additional research. Milling or grinding has long been utilized in the pharmaceutical industry as an effective method of particle size reducti on. Many bulk properties such as, flowability bulk density, mixing ability, segr egation of mixed materials, bu lk density etc. are related to particle size. The determination of bulk properties as a consequence of the method of preparation specifically grinding and/or solvent drop grinding also needs to be addressed. Additionally, there exists a vi able opportunity to apply th e solvent-grind and grinding technique towards initial screening and ultimate large scale preparation of pharmaceutical co-crystals. A temperature regulated High Throughput (HT) grinding or solvent grind screen can potentially lead to the isolation of new phases-polymorphs, co-crystals, salts-

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186 that may not be viable in a trad ition HT crystallization screen. The phenomenon of polymorphism has long a ttracted attention, in the case of pharmaceuticals the effect range from issues related to bioavailabi lity to intellectual property. Exhaustive screen involving an HT approach during the preformulation stages could provide more insight toward bette r understanding the phe nomenon and evaluating its frequency. In the context of pharmaceuti cal co-crystals addressing whether or not pharmaceutical co-crystals are more or less prone to polymorphism may lead to important scientific and intellectual property implications. Additionally, the origins of the polymorphism in pharmaceutical co-crystals a nd co-crystals in gene ral perhaps require further investigation. The multi-disciplinary nature of crystal engineering may be expanded to address other molecular targets, such as nucleoba ses, proteins and molecules that mimic biologically active compounds etc. Reco mbinant DNA technology produces a large number of proteins and prot ein products however these so lids are typically produced by precipitation or lyophillizati on and tend in most cases to be amorphous or partially amorphous. Consequently the stability of prot ein pharmaceutics presents a problem that may be addressed by applying crystal engi neering. The approach towards such biomolecular co-crystals may be multi-fold ad dressing issues of stability as well as providing models for drug design, and their bindi ng interactions in th e solid state. Other molecular targets that would also prove attractive and amenable for study include: molecules with high polarizability to generate new classes of non-linear-optical materials; explosives or propellants with the potential to reformulate and enhance thermal stability etc; agrichemicals and volatile organics. Th e exploration and crystal engineering of

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187 hydrogen bonded 2D and 3D polymers and c onsequently the use of the hydrogen bonded synthons as precursors to a range of solid stat e synthetic reaction are other areas that still remain to be chartered.

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188 Appendices

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189Appendix 1. Experimental Data for (benzoic acid)2 1,2-bis(4-pyridyl)ethane 1 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of (benzoic acid)2 1,2-bis(4-pyridyl)ethane 1 ts501d bipethane_benzoic acid 87 88 89 90 91 92 93 94 95 96 97 98 99 100 %T 1000 2000 3000 Wavenumbers (cm-1)

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1900510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 Relative Intensity2-theta/degSimulated benzoic acid_bipethane benzoic acid bipethane

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191 0510152025303540 0 50 100 150 200 250 300 350 400 Relative Intensity2-theta/deg grind solvent grind melt Polymorphism screen data for (benzoic acid)2 1,2-bis(4-pyridyl)ethane, 1. X-ray powder diffraction (XRPD) patterns of powders obtai ned based upon solvent-drop grinding with: cyclohexane, toluene, chloro form, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 400 500 600 Relative Intensity2-theta/deg trace peaks from benzoic acid. Incomplete conversion as evidenced by XRPD, resultin g in a mixture of co-cry stal and trace amounts of starting materials-only one form obtained.

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192Appendix 2. Experimental Data for (benzoic acid)2 trans-1,2-bis(4pyridyl)ethylene 2 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of (benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene 2 660.04 668.67 686.58 709.82 796.79 822.58 836.85 955.73 976.84 1014.35 1068.32 1120.71 1168.44 1204.88 1272.00 1308.94 1416.56 1448.41 1559.46 1583.24 1600.62 1653.17 1670.45ts501e bipethylene_benzoic acid 82 84 86 88 90 92 94 96 98 100 %T 1000 2000 3000 Wavenumbers (cm-1)

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193 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 1600 1800 Relative Intensity2-theta/degbenzoic acid bipethylene simulated benzoic acid _bipethylene

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1940510152025303540 0 100 200 300 400 500 Relative Intensity2-theta/deg grind solvent grind melt Polymorphism screen data for (benzoic acid)2 trans-1,2-bis(4-pyridyl)ethylene, 2. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 200 400 600 800 Relative Intensity2-theta/deg Incomplete conversion as evidenced by XRPD, resulting in a mixture of co-cryst al and starting materialsonly one form obtained.

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195Appendix 3. Experimental Data for benzoic acid 4,4-bipyridine, 3 Infrared Spectrum, DSC thermogram and X -ray powder diffraction pattern of benzoic acid 4,4-bipyridine 3. 61570 626.33 689.29 715.53 806.53 1005.79 1026.05 1061.56 1116.88 1172.30 1211.60 1269.03 1313.66 1405.94 1449.08 1581.91 1597.89 1698.55 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100%Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1)

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1960510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 1600 1800 Relative Intensity2-theta/deg4,4-bipy benzoic acid simulated bezoic acid _4,4'-bipy

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1970510152025303540 0 100 200 300 400 500 600 700 800 900 Relative Intensity2-theta/degmelt grind solvent grind simulated benzoic acid _4,4'-bipy Polymorphism screen data for benzoic acid 4,4-bipyridine, 3 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 400 500 Relative Intensity2-theta/degwater DMSO methanol ethyl acetate chloroform toluene cyclohexane

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198Polymorphism screen data for 2:1 (benzoic acid)2 4,4-bipyridine 0510152025303540 0 100 200 300 400 500 Relative Intensity2-theta/deg Solvent drop grind screen of a 2:1 mole ratio of benzoic acid and 4,4-bipyridine reveals a new phase that is different from the 1:1 co-crystal 3

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199Appendix 4. Experimental Data for sorbic acid1,2-bis(4-pyridini um)ethane sorbate 4 Infrared Spectrum, DSC thermogram and X -ray powder diffraction pattern of sorbic acid1,2-bis(4-pyridium)ethane sorbate 4 835.55 1002.44 1068.64 1146.25 1191.82 1250.32 1327.72 1604.69 1643.52 1686.04 82 84 86 88 90 92 94 96 98 100 102 %T 1000 2000 3000 Wavenumbers (cm-1)

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2000510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 3000 3500 4000 Relative Intensity2-theta/degsorbic acid bipethane simulated sorbic acid _bipethane xtal

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2010510152025303540 0 50 100 150 Relative Intensity2-theta/deggrind sorbic acid_bipethane melt sorbic acid_bipethane solvent grind sorbic acid_bipethane Polymorphism screen data for sorbic acid 1,2-bis(4-pyridinium)e thane sorbate, 4. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 100 200 300 400 500 Relative Intensity2-theta/degcyclohexane toluene chloroform ethyl acetate methanol DMSO water

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202Appendix 5. Experimental Data for (naproxen)2 trans-1,2-bis(4pyridyl)ethylene 5 Infrared Spectrum and X-ray powder diffraction pattern of (naproxen)2 trans-1,2-bis(4pyridyl)ethylene 5 82 84 86 88 90 92 94 96 98 100 102%Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1) 0510152025303540 0 2000 4000 6000 8000 10000 Intensiity2-theta/deg

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203 0510152025303540 0 400 800 1200 1600 2000 2400 Intensity2-theta/degnaproxen trans-1,2-bis(4-pyridyl) ethylene co-xxtals 0510152025303540 0 50 100 150 200 250 Relative Intensity2-theta/deggrind melt solvent grind xtals

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204 Polymorphism screen data for (naproxen)2 trans-1,2-bis(4-py ridyl)ethylene, 5. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 Relative Intensity2-theta/deg

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205Appendix 6. Experimental Data for glutaric acid 1,2-bis(4-pyridyl)ethane, 6 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of glutaric acid 1,2-bis(4-pyridyl)ethane, 6. 759.36 812.17 827.74 876.01 1014.09 1065.38 1176.33 1212.96 1270.66 1375.56 1414.18 1562.80 1607.42 1705.96ts502c glutaric acid_bipethane 88 89 90 91 92 93 94 95 96 97 98 99 100 101%T 1000 2000 3000 Wavenumbers (cm-1)

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2060510152025303540 0 2000 4000 6000 8000 10000 intensity2-theta/deg 0510152025303540 0 100 200 300 400 500 Relative Intensity2-theta/degMelt Solvent grind Grind Simulated glutaric acid _bipethane

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207 Polymorphism screen data for glutaric acid 1,2 (4-pyridyl)ethane, 6 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 100 200 300 400 500 600 Relative Intensity2-theta/degwaterDMSO methanol ethyl acetate chloroform toluene cyclohexane

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208Appendix 7. Experimental Data for glutaric acid trans-1,2-bis(4-py ridyl)ethylene, 7 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of glutaric acid trans-1,2-bis(4pyridyl)ethylene, 7. 56076 639.05 760.63 824.02 878.85 955.80 972.26 1016.14 1063.85 1179.80 1260.64 1285.83 1411.84 1561.21 1601.05 1722.82ts502d bipethylene_glutaric acid 74 76 78 80 82 84 86 88 90 92 94 96 98 100 %T 1000 2000 3000 Wavenumbers (cm-1)

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2090510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 051015202530354045 0 500 1000 1500 2000 2500 Relative Intensity2-theta/deg bipethylene glutaric acid simulated glutaric acid _bipethylene xtal

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210 0510152025303540 0 100 200 300 400 500 600 700 800 900 Relative Intensity2-theta/degsolvent grind grind melt Polymorphism screen data for glutaric acid trans-1,2 (4-pyridyl)ethylene, 7. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 400 500 600 700 Relative Intensity2-theta/degwater DMSO methanol ethyl acetate chloroform toluene cyclohexane Solvent drop grind screen results in only one form as evidenced by XRPD.

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211Appendix 8. Experimental Data for oxalic acidtetramethylpyrazine, 8 Infrared Spectrum, DSC thermogram and X -ray powder diffraction pattern of oxalic acidtetramethylpyrazine, 8 61990 68504 697.84 807.96 989.84 1184.20 1272.56 1363.24 1451.44 1615.59 1716.79 2852.64 2923.63ts436a tetramethylpyrazine_oxalic acid 50 55 60 65 70 75 80 85 90 95 100 105 %Transmittance 1000 2000 3000 Wavenumbers (cm-1)

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2120510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/deg oxalic acid Form I oxalic acid Fom II TMP Simulated oxalic acid _TMP

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213 Polymorphism screen data for oxalic acid tetramethylpyrazine, 8 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 400 500 600 Relative Intensity2-theta/degwater DMSO methanol ethyl acetate chloroform toluene cyclohexane XRPD pattern is a mixture of co-crystal 8 and trace amounts of starting material.

PAGE 235

214Appendix 9. Experimental Data for isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of isophthalic acid 1,2-bis(4-pyridyl)ethane, 9 689.92 738.51 824.74 1018.25 1027.25 1145.21 1217.39 1251.00 1277.77 1417.58 1499.62 1609.42 1696.85ts504c isophthalic acid_bipethane in DMSO 56 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100%T 1000 2000 3000 Wavenumbers (cm-1)

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2150510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 Relative Inensity2-theta/deg bipethaneisophthalic acid simulated isophthalic acid _bipethane

PAGE 237

2160510152025303540 0 200 400 600 Relative Intensity2-theta/deggrind solvent grind melt simulated isophthalic _bipethane xtal Polymorphism screen data for isophthalic acid 1,2-bis(4-pyridyl)ethane, 9. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water. 0510152025303540 0 100 200 300 400 500 600 Relative Intensity2-theta/deg Incomplete conversion as evidenced by XRPD, resulting in a mixture of co-crystal and trace amounts of starting materi als. Only one form obtained.

PAGE 238

217Appendix 10. Experimental Data for (trimesic acid)2 trans-(1,2-bis(4pyridyl)ethylene)3, 11 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of (trimesic acid)2 trans-(1,2-bis(4-pyridyl)ethylene)3, 11 301 688.81 746.24 823.13 841.12 953.19 1017.51 1170.01 1418.71 1604.07 1702.92 3425.18ts503e bipethylene trimesic acid 3:2 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 239

218 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/eg 0510152025303540 0 500 1000 1500 2000 2500 Relative Intensity2-theta/degtrans-1,2-bis(4-pyridyl) ethylene trimesic acid simulated trimesic acid _trans-1,2-bis(4-pyridyl)ethylene

PAGE 240

219Polymorphism screen data for (trimesic acid)2 trans-(1,2-bis(4-pyridyl)ethylene)3, 11 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 100 200 300 400 500 600 Relative Intensity2-theta/degsolvent grind trimesic acid simulated trimesic acid _trans 1,2-(4-pyridyl) ethylene xtal 0510152025303540 0 100 200 300 400 Relative Intensity2-theta/degDMSO chloroform toluene cyclohexane methanol ethyl acetate Solvent drop grinding for 4 minute results in a mixture of trimesic acid 1,2-bis(4-pyridyl)ethylene, 11 and trimesic acid in all cases except that of DMSO solv ent grind in which complete conversion is achieved.

PAGE 241

220Appendix 11. Experimental Data for trimesic acid1,2-bis(4-pyri dyl)ethane, 12 Infrared Spectrum, DSC thermogram and X-ra y powder diffraction pattern of trimesic acid1,2-bis(4-pyridyl)ethane, 12 56897 594.62 664.88 688.84 746.79 823.45 899.03 951.86 1018.50 1090.49 1170.37 1221.89 1418.95 1609.91 1701.63 3410.66ts503c trimesic acid:1,2bis(4-pyridyl)ethane (2:3) 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 242

221 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg Form I 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg Form 2

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222 0510152025303540 0 100 200 Relative Intensity2-theta/deg bipethane TMA acetone 0510152025303540 0 500 1000 1500 2000 Simulated FormIIRelative Intensity2-theta/degbipethane TMA Simulated Form I

PAGE 244

223Polymorphism screen data for (trimesic acid)2 (1,2-bis(4-pyridyl)ethane)3, 12 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 -50 0 50 100 150 200 250 300 350 400 450 500 550 Relative Intensity2-theta/degForm II Form I TMA 1,2-bis(4-pyridyl)ethane amorphous isopropanol chloroform dichloromethane cyclohexane heptane DMA amorphous toluene DMSO ethyl acetate THF acetonitrile isopropyl aetate ethanol methanol acetone Two different XRPD patterns are observed in the above solvent drop grind screen of 2:3 molar ratio of TMA and 1,2-bis(4pyridyl)ethane and are grouped accordingly. Group A: Solvent drop grinds involving isopr opanol, chloroform, dichloromethane, cyclohexane, heptane, ethyl acetate, tetr ahydrofuran, acetonitrile, isopropyl acetate, methanol, heptane, DMA and DMSO. Group B : Solvent drop grinds involving toluene, acetone and ethanol. The solvent drop grinds were compared to th e starting materials as well as co-crystal 12a (form I) and 12b (form II). Based upon this compar ison the solvent drop grinds of group A were found to be a mixture of starting ma terials whereas group B appears to be a new form.

PAGE 245

2240510152025303540 0 40 80 120 160 200 240 280 320 Relative Intensity2-theta/deg TMA 1,2-bis(4-pyridyl)ethane Form I Form II cyclohexane 0510152025303540 0 40 80 120 160 200 240 280 Relative Intensity2-theta/degTMA 1,2-bis(4-pyridyl)ethane Form I Form II toluene

PAGE 246

225Appendix 12. Experimental Data for (1-naphthol)2 1,2-bis(4-pyridyl)ethane, 13 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (1naphthol)2 1,2-bis(4-pyridyl)ethane, 13. 770.23 793.63 825.50 1008.37 1283.50 1389.64 1573.96 1603.68 55 60 65 70 75 80 85 90 95 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 247

226 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 3000 3500 Relative Intensity2-theta/deg 1-naphthol 1,2-bis(4-pyridyl)ethane calc. from single crystal grind solvent grind melt

PAGE 248

227Appendix 13. Experimental Data for (1-naphthol)2 trans-1,2-bis(4-pyridyl)ethylene, 14. Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (1naphthol)2 trans-1,2-bis(4-pyridyl)ethylene, 14. 770.37 793.31 829.03 1007.50 1390.28 1573.92 1598.40 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 249

228 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 Relative Intensity2-theta/deg1-naphthol trans-1,2(4-pyridyl) ethylene calc from xtals grind solvent drop grind melt

PAGE 250

229Appendix 14. Experimental Data for 4,4-biphenol 1,2-bis(4-pyridyl)ethane, 15 DSC and X-ray powder diffracti on pattern of 4,4-biphenol 1,2-bis(4-pyridyl)ethane, 15 0510152025303540 0 2000 4000 6000 8000 10000 iIntensity2-theta/deg

PAGE 251

230 0510152025303540 0 500 1000 1500 2000 2500 1,2-bis(4-pyridyl)ethaneRelative Intensity2-theta/degsimulated 4,4'-biphenol _1,2-bis(4-pyridyl)ethane 4,4'-biphenol 051015202530354045 0 500 1000 1500 2000 2500 3000 Relative Intensity2-theta/deg4,4-biphenol 1,2-bis(4-pyridyl)ethane calculated fr. xtal grind solvent grind melt

PAGE 252

231Appendix 15. Experimental Data for 4,4-biphenol trans-1,2-bis(4pyridyl)ethylene, 16. Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4,4biphenol trans-1,2-bis(4-pyridyl)ethylene, 16. 740.06 815.07 980.80 1005.96 1166.65 1239.38 1267.04 1497.33 1600.46 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 253

2320510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 3000 3500 Relative Intensity2-theta/deg4,4-biphenol trans-1,2(4-pyridyl) ethylene grind calc. from xtals grind solvent drop grind

PAGE 254

233Appendix 16. Experimental Data for hydroquinone trans-1,2-bis(4pyridyl)ethylene, 17 Infrared Spectrum, DSC thermogram a nd X-ray powder diffraction pattern of hydroquinone trans-1,2-bis(4-pyridyl)ethylene, 17. 736.63 757.03 806.07 829.74 976.74 1006.44 1253.47 1473.83 1601.62 2923.35 82 84 86 88 90 92 94 96 98 100 102%T 1000 2000 3000 4000 Wavenumbers (cm-1)

PAGE 255

234 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 -100 0 100 200 300 400 500 600 700 Relative Intensity2-theta/deggrind melt solvent grind calc. from xtal hydroquinone trans1,2(4-pyrdyl))ethylene

PAGE 256

235Appendix 17. Experimental Data for hydroquinone tetramethylpyrazine, 18 Infrared Spectrum, DSC thermogram a nd X-ray powder diffraction pattern of hydroquinone tetramethylpyrazine, 18 761.61 820.62 1214.43 1235.42 1253.28 1420.33 1443.88 1470.35 1519.07 82 84 86 88 90 92 94 96 98 100 102 %T 1000 2000 3000 4000 Wavenumbers (cm-1)

PAGE 257

236 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Relative Intensity2-theta/degsolvent grind grind melt calc from xtal hydroquinone TMP

PAGE 258

237Appendix 18. Experimental Data for (resorcinol)2 (TMP)3, 19 Infrared Spectrum, DSC thermogram a nd X-ray powder diffraction pattern of (resorcinol)2 (TMP)3, 19. 802.15 837.01 969.78 1152.66 1183.72 1220.96 1415.16 1602.63 95.0 95.5 96.0 96.5 97.0 97.5 98.0 98.5 99.0 99.5 100.0 100.5 101.0 101.5%Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1)

PAGE 259

238 510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 100 200 300 400 500 600 Relative Intensity2-theta/deggrind melt solvent grind xtals from soln resorcinol TMP

PAGE 260

239Appendix 19. Experimental Data for 2,7-dihydroxynaphthalene (TMP)2, 20 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 2,7dihydroxynaphthalene (TMP)2, 20 82 84 86 88 90 92 94 96 98 100 102 104 106%Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1)

PAGE 261

2400510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/deg 2,7-DHN TMP calc from xtal grind solvent grind

PAGE 262

241Appendix 20. Experimental Data for (3-hydroxybenzoic acid)2 pyrazine, 21 Infrared Spectrum and X-ray powder diffr action pattern of (3-hydroxybenzoic acid)2 1,2bis(4-pyridyl)ethane, 21. 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 %T 1000 2000 3000 Wavenumbers (cm-1) 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

PAGE 263

242 051015202530354045 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deg 3-HB Form I 3HB Form II pyrazine alc. 3HB2 pyrazine melt New Phase obtained upon melt that does not correspond to calc. co-cry stal XRPD pattern, has peaks that are shifted relative to starting materials and co-crystal. 051015202530354045 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deg Form I Form II calc. 3HB2 pyrazine pyrazine grind Dry grinding for 6 minutes yields phase that does not correspond to co-crystal, possibly a mixture of Form I and Form II 3-hydroxybenzoic acid

PAGE 264

243051015202530354045 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deg Form I 3HB Form II 3HB pyrazine calc 3HB2 pyrazine solvent-drop grind New Phase obtained that does not correspond to calc. co-crystal XRPD pattern, has peaks that are shifted relative to starting materials and co-crystal. Polymorphism screen data for 3-hydroxybenzoic acid)2 pyrazine 21 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 50 100 150 200 250 300 350 Relative Intensity2-theta/deg cyclohexane DMSO ethyl acetate water toluene methanol calc 3HB2 pyrazine xtal (3-hydroxybenzoic acid)2 pyrazine co-crystal reproduced from MeOH grind. Solvent drop grinding involving DMSO, ethyl acetate, water and cyclohexane produced a new phase that does not correspond to calc. co-crystal XRPD patte rn and has peaks that are shifted relativ e to starting materials and co-crystal. Toluene grind appears to give a mixture of 3-hydroxybenzoic acid Form I and Form II exhibiting a similar pattern as seen in the dry grind.

PAGE 265

244Appendix 21. Experimental Data for 4-hydroxybenzoic acid 1,2-bis(4pyridinium)ethane 4hydroxybenzoate, 22 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4hydroxybenzoic acid 1,2-bis(4-pyridinium)ethane 4hydroxybenzoate, 22 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 %T 1000 2000 3000 4000 Wavenumbers (cm-1)

PAGE 266

2450510152025303540 0 2000 4000 6000 8000 10000 Relative Intensity2-theta/deg 051015202530354045 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deg 4HB 1,2-bis(4-pyridyl)ethane calc. XRPD xtal dry grind solvent drop grind melt Co-crystal obtained from melt, grind and solvent drop grind resulted in mixture of starting materials

PAGE 267

246 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water 0510152025303540 0 500 1000 1500 2000 2500 Relative Intensity2-theta/deg 4HB 1,2-bis(4-pyridyl)ethane calc. XRPD xtal cyclohexane dmso ethyl acetate methanol toluene A search for crystal forms using solvent drop grinding yield new crystalline phase that contain peaks that do not correspond to isolated single crystal or starting materials

PAGE 268

247Appendix 22. Experimental Data for (4-hydroxybenzoic acid)2 tetramethylpyrazine, 23 Infrared Spectrum and X-ray powder diffr action pattern of (4-hydroxybenzoic acid)2 tetramethylpyrazine, 23 ts434d TMpyrazine/4-hydroxybenzoic acid 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 106 108 %T 1000 2000 3000 Wavenumbers (cm-1) 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

PAGE 269

2480510152025303540 0 300 600 900 1200 1500 1800 Relative Intensity2-theta/deg 4HBTMP calc from xtal grind solvent drop grind melt Melt, solvent drop grind and dry grind yield th e co-crystal as well as starting materials. X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene ethyl acetate, methanol, water and DMSO 510152025303540 0 1000 Relative Intensity2-theta/deg4HB TMP calc from xtal cyclohexaneDMSOethyl acetate methanol water toluene Water, methanol and ethyl acetate grin d contain additional peaks that are not present in either co-crystal or starting materials. Complete conversion to co-crystal from DMSO grind whereas peaks corresponding to 4hydroxybenzoic acid are present in cyclohexane and toluene grinds.

PAGE 270

249Appendix 23. Experimental Data for 4-hydroxybenzoic acid 4-phenylpyridine, 24 Infrared Spectrum and X-ray powder diffr action pattern of 4hydroxybenzoic acid 4phenylpyridine, 24. ts458d 4-phenylpyridine_4-hydroxybenzoic acid 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 106 108 %T 1000 2000 3000 Wavenumbers (cm-1) 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

PAGE 271

250 051015202530354045 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/deg 4HB 4phenylpyridine calc from xtal grind solvent drop grind melt Peak shifts as compared to co-crystal and starting material evident in melt and solvent drop grind. Dry grind appears to be a mixture of starting materials X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 051015202530354045 0 500 1000 1500 2000 Relative Intensity2-theta/deg dmso ethyl acetate methanol tol cyclohexane 4HB 4-phenylpyridine calc. from xtal MeOH and EtoAc grinds results in mixture of starting materials, DMSO grinds have peaks corresponding to co-crystals howeve r peaks at higher 2 values are shifted relative to the co-crystal

PAGE 272

251Appendix 24. Experimental Data for (4-hydroxybenzoic acid)2 pyrazine, 25 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (4hydroxybenzoic acid)2 pyrazine, 25 ts441b pyrazine/4-hydroxybenzoic acid 1:2 in acetonitrile 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102%T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 273

252 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 300 600 900 1200 1500 1800 Relative Intensity2-theta/deg4HB pyrazine calc. fr. xtal grind solvent-drop grind melt

PAGE 274

2530510152025303540 0 300 600 900 1200 1500 Relative Intensity2-theta/deg 4HB pyrazine calc fr. xtal cyclohexane dmso ethyl acetate methanol toluene water New crystalline phase obtained that contain peaks that are not present or are shif ted relative to co-crystal and starting materials.

PAGE 275

254Appendix 25. Experimental Data for 4-hydroxybenzoic acid)2 tetramethylpyrazine acetonitrile solvate, 26 Infrared Spectrum, DSC thermogram and X -ray powder diffraction pattern of (4hydroxybenzoic acid)2 tetramethylpyrazine acetonitrile solvate, 26 ts788c 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101%Transmittance 1000 2000 3000 Wavenumbers (cm-1)

PAGE 276

2550510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 Relative Intensity2-theta/deg 4HB TMP calc. 4HB2TMP acetonitrile sovate acetonitile Acetonitrile grind does not yield the (4-hydroxybenzoic acid)2 tmp acetonitrile solvate

PAGE 277

256Appendix 26. Experimental Data for 3-hydroxybenzoic acid (4-phenylpyridine)2, 27 Experimental Data for Infrared Spectru m, DSC thermogram and X-ray powder diffraction pattern of 3-hydroxybenzoic acid (4-phenylpyridine)2, 27 ts480b 4-phenylpyridine_3-hydroxybenzoic acid 90 91 92 93 94 95 96 97 98 99 100 101 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 278

2570510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 400 800 1200 1600 2000 2400 Relative Intensity2-theta/degmelt solvent grind grind 4-phenylpyridine Form II 3HB Form I 3HB calc. fr. 3HB_4pp2 The co-crystal is reproduced from the melt. A mixture of the co-crystal and star ting material was obtained from dry grind and aceton e solvent drop grind.

PAGE 279

258 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 0510152025303540 0 300 600 900 1200 1500 1800 2100 2400 Relative Intensity2-theta/degForm I 3HB Form II 3HB 4-phenylpyridine calc. fr. xtal cyclohexane dmso ethyl acetate methanol toluene water Solvent drop grinding for 4minutes yield a mixture of co-crystal and starting materials, peak shift ca. 27

PAGE 280

259Appendix 27. Experimental Data for 3-hydroxybenzoic acid 1,2-bis(4pyridyl)ethane, 28 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxybenzoic acid 1,2-bis(4-pyridyl)ethane, 28 ts480e bipethane_3-hydroxybenzoic acid in MeOH/EtOH 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100%T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 281

2600510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 400 800 1200 1600 2000 2400 Relative Intensity2-theta/deg Form I 3HB Form II 3HB 1,2bis(4-pyridyl)ethane calc fr. xtal melt Co-crystal produced from the melt.

PAGE 282

261 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water 0510152025303540 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deggrind water DMSO methanol ethyl acetate chloroform toluene cyclohexane Dry grind and solvent drop grinds give a mixture of co-crystal and starting materials

PAGE 283

262Appendix 28. Experimental Data for 3-hydroxybenzoic acid 4,4-bipyridine, 29 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxybenzoic acid 4,4-bipyridine, 29. ts480d bipy/3-hydroxybenzoic acid in EtOH/MeOH 80 82 84 86 88 90 92 94 96 98 100 102 104 106 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 284

263 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 1600 1800 Relative Intensity2-theta/deg3HB Form I 3HB Form II 4,4'-bipyridine calc. fr. xtal grind melt Dry grind for 4 minutes gives a mixture of st arting materials as well as a peak ca. 27 2 that is present in co-crystal. Co-crystal is produced from the melt.

PAGE 285

264 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water 5101520253035 0 100 200 300 400 500 600 700 800 900 Relative Intensity2-theta/deggrind methanol dmso water cyclohexane chloroform ethyl acetate toluene calc. from xtal Co-crystal is reproduced from solvent drop grindings involving methanol, cyclohexane, water and dmso, all other solvent and dry grind produce the co-crystal as well as starting materials.

PAGE 286

265Appendix 29. Experimental Data for 3-hydroxybenzoic acid quinoxaline, 30 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxybenzoic acid quinoxaline, 30. ts447 quinoxaline_3-hydroxybenzoic acid 89 90 91 92 93 94 95 96 97 98 99 100 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 287

2660510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/degForm 3HB Form II 3HB quinoxaline calc. from xtal dry grind Dry grind gives mixture of co-crystal and starting materials.

PAGE 288

267 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 0510152025303540 0 400 800 1200 1600 2000 2400 Relative Intensity2-theta/deg Form I 3HB FormII 3HB quinoxaline calc fr. xtal dmso cyclohexane ethyl acetate methanol toluene water Solvent drop grind results in mixture of co-crystal and starting materials

PAGE 289

268Appendix 30. Experimental Data for (3-hydroxybenzoic acid)2 (tetramethylpyrazine)3, 31 DSC thermogram and X-ray powder diffrac tion pattern of (3-hydroxybenzoic acid)2 (tetramethylpyrazine)3, 31 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

PAGE 290

2690510152025303540 0 200 400 600 800 1000 1200 1400 1600 1800 Relative Intensity2-theta/deg3HB Form I 3HB Form IITMPcalc. fr. xtal melt grind acn grind Melt produces co-crystal 31, grind gives mixture of starting materials X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 0510152025303540 0 400 800 1200 1600 2000 2400 Relative Intensity2-theta/deg Form I 3HB Form II 3HB TMP cal fr. xtal clohexane dmso methanol toluene water ethyl acetate Ethyl acetate grind gives new crystalline phase, mixture of starting material and co-crystals obtained from other solvent drop grinds.

PAGE 291

270Appendix 31. Experimental Data for 6hydroxy-2-naphthoic acid trans-1,2-bis(4pyridyl)ethylene, 32 Infrared Spectrum, DSC thermogram and X -ray powder diffraction pattern of 6-hydroxy2-naphthoic acid trans-1,2-bis(4-pyridyl)ethylene, 32 ts460d bipethylene_6-hydroxy-2-naphthoic acid in EtOH 80 82 84 86 88 90 92 94 96 98 100 102 104 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 292

271 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

PAGE 293

272Appendix 32. Experimental Data for 4-hydroxybenzoic acid trans-1,2-bis(4pyridyl)ethylene, 33 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4hydroxybenzoic acid trans-1,2-bis(4-pyridyl)ethylene, 33. ts461a bipethylene/4-hydroxybenzoic acid 1:1 in MeOH 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 106 108%T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 294

2730510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 500 1000 1500 2000 2500 3000 Relative Intensty2-theta/degdry grind trans-1,2-bis(4-pyridyl)ethylene 4-hydroxybenzoic acid calc. fr. xtal Grind results in a mixture of starting materials

PAGE 295

274Appendix 33. Experimental Data for 3-hydroxybenzoic acid trans-1,2-bis(4pyridyl)ethylene, 34 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxybenzoic acid trans-1,2-bis(4-pyridyl)ethylene, 34. ts 460b bipethylene/3-hydroxybenzoic acid 1:1 84 86 88 90 92 94 96 98 100 102 %T 1000 2000 3000 Wavenumbers (cm-1)

PAGE 296

2750510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/deg3HB Form I 3HB Form II trans_1,2-bis(4-pyridyl)ethylene calc. from xtal grind Grind results in a mixture of starting materials

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276Appendix 34. Experimental Data for 3-hydroxypyridinium benzoate, 35 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxypyridinium benzoate, 35. 675.93 722.75 802.59 837.10 982.50 1069.68 1168.70 1293.11 1353.75 1390.25 1508.09 1579.71 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 %T 1000 2000 3000 4000 cm-1

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2770510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 300 600 900 1200 1500 1800 Relative Intensity2-theta/deg3-hydroxypyridine benzoic acid 3-hydroxypyridinium benzoate

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278 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 0510152025303540 0 100 200 300 400 500 600 700 Relative Intensity2-theta/degcyclohexane methanol ethyl acetate toluene water DMSO Solvent drop grinding yields organic salt of 3-hydroxypyridinium benzoate

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279Appendix 35. Experimental Data for 3-hydroxypyridinium isophthalate, 36 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3hydroxypyridinium isophthalate, 36. 55 60 65 70 75 80 85 90 95 100 105 %T 1000 2000 3000 4000 Wavenumbers (cm-1)

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280 0510152025303540 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 Relative Intensity2-theta/deg3-hydroxypyridine isophthalic acid 3-hydroxypyridinium isophthalate 0510152025303540 0 50 100 150 200 250 Relative Intensity2-theta/deg calc. fr. xtal grind

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281 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water 0510152025303540 0 50 100 150 200 250 300 350 400 Relative Intensity2-theta/degcyclohexane ethyl acetate toluene methanol DMSO water

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282Appendix 36. X-ray powder diffraction patterns of grinding and solvent drop grinding of isonicotinic acid 1-naphthol, nicotinic acid 1-naphthol, (nicotinic acid)2 4,4-biphenol, (isonicotinic acid)2 4,4-biphenol, (isonicotinic acid)3 phloroglucinol, (nicotinic acid)3 phloroglucinol, (isonicotinic acid)2 resorcinol, (nicotinic acid)2 resorcinol. 51015202530354045 0 500 1000 1500 2000 2500 no solvent MeoH solv grind water solv grind dmso solv grind cyclohexane solv grind toluene solv grind chloroform solv grind EtOAc solv grind isonicotinic acid 1-naphtholRelative Intensity2-theta/deg 51015202530354045 0 500 1000 1500 2000 2500 no solvent meoh grind water grind dmso grind cyclohexane grind toluene grind chloroform grind EtOAc grind nicotinic acid 1-naphtholRelative Intensity2-theta/deg

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283 51015202530354045 0 500 1000 1500 2000 2500 no solvent methanol grind water grind dmso grind cyclohexane grind chloroform grind toluene grind EtOAc grind nicotinic acid 4,4'-biphenolRelative Intensity2-theta/deg051015202530354045 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 no solvent MeOH grind water grind DMSO grind cyclohexane grind toluene grind chloroform grind EtoAc grind nicotinic acid phloroglucinolRelative Intensity2-theta/deg

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28451015202530354045 0 500 1000 1500 2000 2500 no solvent MeOH grind water grind DMSO grind toluene grind cyclohexane grind chloroform grind EtOAc grind isonicotinic acid phloroglucinol dihydrate phloroglucinolRelative Intensity2-theta/deg51015202530354045 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 MeOH grind water grind dmso grind cyclohexane grind toluene grind chloroform grind EtOac grind no solvent resorcinol bulk isonicotinic bulk sim_resorcinol sim_isonicotinicRelative Intensity2-theta/deg

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285051015202530354045 0 500 1000 1500 2000 MeOH grind water grind DMSO grind cyclohexane grind toluene grind choroform grind no solvent EtOAc grind nicotinic acid sim_resorcinol resorcinolRelative Intensity2-theta/deg

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286Appendix 37. DSC thermograms for the attemp ted co-crystallizations of 5hydroxyisoquinolinebenzoic acid, 5-hydroxyisoquinoline sorbic acid, (5hydroxyisoquinoline)2 isophthalic acid, (5-hydroxyisoquinoline)2 glutaric acid, (5-hydroxyisoquinoline)3 trimesic acid, 3-hydroxypyridine sorbic acid, (3hydroxypyridine)2 glutaric acid, (3-hydroxypyridine)3 trimesic acid. DSC thermogram for the solvent drop grinding of 1:1 mole ratio of 5hydroxyisoquinoline and benzoic acid DSC thermogram comparing the solven t drop grind of 5-hydroxyisoquinoline and benzoic acid versus starting materials

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287 DSC thermogram for the solvent drop grinding of 1:1 mole ratio of 5hydroxyisoquinoline and sorbic acid DSC thermogram comparing solvent drop gr ind 5-hydroxyisoquinoline and sorbic acid versus starting materials

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288 DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 5hydroxyisoquinoline and glutaric acid DSC thermogram comparing solvent drop gr ind 5-hydroxyisoquinoline and glutaric acid versus starting materials

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289 DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 5hydroxyisoquinoline and isophthalic acid DSC thermogram comparing solvent drop grind 5-hydroxyisoquino line and isophthalic acid versus starting materials

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290 DSC thermogram for the solvent drop grinding of 3:1 mole ratio of 5hydroxyisoquinoline and trimesic acid DSC thermogram comparing solvent drop gr ind 5-hydroxyisoquinoline and trimesic acid versus starting materials

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291 DSC thermogram showing comparison of solvent drop grind of 3-hydroxpyridine and benzoic acid versus single crysta ls of 3-hydroxypyridinium benzoate

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292 DSC thermogram for the solvent drop grindi ng of 2:1 mole ratio of 3-hydroxypyridine and isophthalic acid DSC thermogram comparing solvent drop gr ind 3-hydroxypyridine and isophthalic acid versus starting materials

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293 DSC thermogram for the solvent drop grindi ng of 1:1 mole ratio of 3-hydroxypyridine and sorbic acid DSC thermograms comparing solvent drop grind 3-hydroxypyridine and sorbic acid versus starting materials

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294 DSC thermogram for the solvent drop grindi ng of 2:1 mole ratio of 3-hydroxypyridine and glutaric acid DSC thermograms comparing solvent drop gr ind 3-hydroxypyridine a nd glutaric acid versus starting materials

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295 X-ray powder Diffraction of attempted co-cry stallization of 3-hydr oxypyridine and sorbic acid 0510152025303540 0 100 200 300 400 500 600 700 Intensity2-theta/deg Histogram showing contact distance fo r alcohol-carbonyl (acid) interactions 0 5 10 15 20 25 30 35 40 45 2.52.62.72.82.933.13.23.33.43.5alcohol-carbonyl(acid) O-H...O Hydrogen bondFrequenc y There are 1495 entries that contain both a carbox ylic acid and an alcohol. Of this number 566/1495 (37%) exhibit the alc ohol-carbonyl heterosynthon. The interaction was found to occur within th e range 2.6-3.0, Mean: 2.80(8) Search Filters: CSD 5.28, Jan 2007 update: Organi cs only, 3D coordinates determined, R>7.5%.

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296Tabulated pKa values of existing CSD structures containing 3-hydroxypyridine REFCODE Compound Pka (acid) Pka (base) Pka(baseacid) IDUNEA 3-hydroxypyridinium_ 5nitrofuran-2-carboxylate 2.06 8.51 4.86 6.45 IDUNIE 3-hydroxypyridinium_ 4nitrobenzoate 3.42 8.51 4.86 5.09 IDUNOK 3-hydroxypyridinium_ 2,4dinitrobenzoate 1.43 8.51 4.86 7.08 IDUNUQ 3-hydroxypyridinium_3,5dinitrobenzoate 2.77 8.51 4.86 5.74 JOJJUN 3-hydroxypyridinium_2,4,6trinitrobenzoate 0.42 8.51 4.86 8.09 KOKBOC 3-hydroxypyridinium_(2,4dichlorophenoxy acetate 2.98 8.51 4.86 5.53 LEJROH 3-hydroxypyridinium_ pyrazine2,6-dicarboxylate 2.24 -4.01 8.51 4.86 6.27 OCAKAF 3-hydroxypyridinium_3(carboxymethoxy)phenoxy acetate 2.83 8.51 4.86 5.68 PAHZAA 3-hydroxypyridinium_2hydroxypropanedioate 1.98 8.51 4.86 6.53 RACBED 3-hydroxypyridinium_2,5dihydroxybenzoate 3.01 8.51 4.86 5.50 VITXUR 3-hydroxypyridinium tartrate 3.07 8.51 4.86 5.44 YETLUE 3-hydroxypyridinium_L-malate 3.61 8.51 4.86 4.90

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297Tabulated pKa values for components used in at tempted co-crystallization involving molecules containingOH/Narom with COOH melecules pKa (base) pKa(acid) pKa 3-hydroxypyridine and sorbic acid 8.51 4.86 4.59 3.92 3-hydroxypyridine and glutaric acid 8.51 4.86 4.33 4.18 3-hydroxypyridine and trimesic acid 8.51 4.86 2.98 5.53 5-hydroxyisoquinoline and benzoic acid 8.31 5.31 4.2 4.11 5-hydroxyisoquinoline and sorbic acid 8.31 5.31 4.59 3.72 5-hydroxyisoquinoline and glutaric acid 8.31 5.31 4.33 3.98 5-hydroxyisoquinoline and isophthalic acid 8.31 5.31 3.53 4.78 5-hydroxyisoquinoline and trimesic acid 8.31 5.31 2.98 5.53

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298Appendix 39. Experimental Data for (stavudine)3 melamine, 37 DSC thermogram, FT-IR spectrum and X-ray powder diffraction patterns of bulk sample and calculated from the single cr ystal structure for (stavudine)3 melamine, 37 614.42 649.39 690.05 763.90 799.18 1044.12 1091.10 1113.48 1268.32 1446.35 1541.58 1654.93 1688.16 87 88 89 90 91 92 93 94 95 96 97 98 99 100%T 1000 2000 3000 4000 Wavenumbers (cm-1)

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299 051015202530354045 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

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300Polymorphism screen data: X-ray powder diffraction pa tterns of powders obtained based upon solvent-drop grinding with: cyclohe xane, toluene, ethyl acetate, methanol, DMSO, and water. 0510152025303540 0 20 40 60 80 100 120 140 Relative Intensity2-theta/degcyclohexane dmso ethyl acetate methanol toluene water Comparison of X-ray powder diffraction pattern s of bulk sample obtai ned via slurry in water and calculated from th e single crystal structure 051015202530354045 0 200 400 600 800 1000 1200 1400 Relative Intensity2-theta/deg simulated PXRD stavudine_melamine co-crystal slurry stavudine_melamine stavudine

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301Appendix 40. Experimental Data for stavudine 2,4,6-triaminopyrimidine hydrate, 38. X-ray powder diffraction pattern s calculated from the single crystal structure for stavudine 2,4,6-triaminopyrimidine hydrate, 38. 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 %Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1) 051015202530354045 0 2000 4000 6000 8000 10000 Intensity2-theta/deg

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302 Comparison of X-ray powder diffraction pattern s of bulk sample obtai ned via slurry in water and calculated from th e single crystal structure 510152025303540 0 100 200 300 400 500 600 700 Relative Intensity2-theta/deg Simulated PXRD stavudine_2,4,6-TAP hydrate Slurry Stavudine_2,4,6-TAP

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303Appendix 41. Experimental Data for stavudine2-aminopyridine, 39 DSC termogram, FT-IR spectrum and X-ra y powder diffraction patterns of stavudine2aminopyridine, 39 575.92 738.49 758.85 774.17 801.22 816.94 850.31 973.76 1075.11 1089.19 1106.59 1220.71 1433.42 1628.96 1666.28 1698.04 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 %T 1000 2000 3000 4000 Wavenumbers (cm-1)

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304 051015202530354045 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 200 400 600 800 1000 1200 1400 1600 Relative Intensity2-theta/deg2-aminopyridine stavudine simulated stavudine _2-aminopyridine xtals

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3050510152025303540 0 50 100 150 200 250 300 350 400 450 Relative Intensity2-theta/deg simulated stavudine _2-aminopyridine grind solvent grind melt Polymorphism screen: X-ray powder diffract ion patterns of powders obtained based upon solvent-drop grinding with: cyclohexane toluene, chloroform, ethyl acetate, methanol, DMSO, and water. 0510152025303540 0 200 400 600 Relative Intensity2-theta/deg

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306 Comparison of X-ray powder diffraction pattern s of bulk sample obtai ned via slurry in water and calculated from th e single crystal structure 051015202530354045 0 200 400 600 800 1000 1200 Intensity2-theta Simulated PXRD ts369e Slurry stavudine_2-aminopyridine

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307Appendix 42. Experiment al Data for stavudine4-hydroxybenzoic acid, 40 DSC termogram, FT-IR spectrum and X-ra y powder diffraction patterns of stavudine4hydroxybenzoic acid, 40. 616.84 798.93 817.18 850.71 1073.55 1241.29 1280.99 1596.88 1689.08 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102%T 1000 2000 3000 4000 Wavenumbers (cm-1)

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308051015202530354045 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 -100 0 100 200 300 400 500 600 700 800 Relative Intensity2-theta/deg4-hydroxybenzoic acid stavudine simulated XRPD stavudine _4-hydroxybenzoic acid xtal

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3090510152025303540 0 100 200 300 400 500 600 700 Relative Intensity2-theta/deggrind solvent grind melt simulated stavudine _4-hydroxybenzoic acid xtal Polymorphism screen data for stavudine4-hydroxybenzoic acid, 40 X-ray powder diffraction patte rns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water. 0510152025303540 0 200 400 600 800 1000 Relative Intensity2-theta/deg

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310 Comparison of X-ray powder diffraction pattern s of bulk sample obtai ned via slurry in water and calculated from th e single crystal structure 510152025303540 0 200 400 600 800 1000 Relative Intensity2-Theta/deg Simulated PXRD Stavudine_4-hydroxybenzoic acid co-crystal Slurry Stavudine_ 4-hydroxybenzoic acid

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311Appendix 43. Experiment al Data for stavudine salicylic acid 41 DSC termogram, FT-IR spectrum and X-ray powder diffraction patterns of bulk sample and calculated from the single crystal structure of stavudine salicylic acid, 41 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 %Transmittance 1000 2000 3000 4000 Wavenumbers (cm-1)

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312 051015202530354045 0 2000 4000 6000 8000 10000 Intensity2-theta/deg 0510152025303540 0 100 200 300 400 500 600 700 Relative Intensity2-theta/degsalicylic acid stavudine simulated stavudine _salicylic acid

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3130510152025303540 -50 0 50 100 150 200 250 300 350 400 450 500 Relative intensity2-theta/deg simulated stavudine _salicylic acid solvent grind grind melt Polymorphism Screen for stavudine salicylic acid, 41 : X-ray powder diffraction patterns of powders obtained based upon solvent-dr op grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water 051015202530354045 0 200 400 600 800 Relative Intensity2-theta/deg

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314 Comparison of X-ray powder diffraction pattern s of bulk sample obtai ned via slurry in water and calculated from th e single crystal structure 510152025303540 0 200 400 600 800 1000 1200 Relative Intensity2-Theta/deg Simulated PXRD Stavudine-salicylic acid co-crystal Slurry Stavudine_Salicylic acid

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315 About the Author Tanise Shattock received her Bachelors degree in Chemistry from the University of West Indies, Kingston, Jamaica in 1998. In 2002, Tanise entered the Ph. D program at the University of South Florida and joined Dr. Michael J. Zaworotkos research group. While in the Ph.D. program she obtained a Research Assistantship from TransForm Pharmaceuticals Inc. and was awarded th e 2006-2007 Merck Research Laboratories Graduate Fellowship in Chemistry, Pharmaceu tical Science, Material Science, and Engineering as well as the Florida Caribbe an Scholarship 2003-2006. Tanise is a coinventor on two patent applica tions and has co-authored seve ral scientific publications. She has presented her research at regional and national scientific meetings of the American Chemical Society, American Crys tallographic Association and International Quality & Productivity Center.


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Crystal engineering of co-crystals and their relevance to pharmaceutical forms
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by Tanise R. Shattock.
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[Tampa, Fla.] :
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2007.
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ABSTRACT: The research presented herein focus upon crystal engineering of co-crystals with an emphasis upon the exploration of co-crystals in the context of delineation of the reliability of hydrogen bonded supramolecular synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthesis of co-crystals and the effect on polymorphism is also addressed. The application of the acquired knowledge is towards the crystal engineering of pharmaceutical co-crystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by the selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.
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Dissertation (Ph.D.)--University of South Florida, 2007.
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Supramolecular chemistry.
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