Crystal Engineering of
Molecular and Ionic Cocrystals
by
Tien Teng Ong
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. Ning Shan, Ph.D. Örn Almarsson, Ph.D. Shengqian Ma, Ph.D.
Date of Approval: March 25, 2011
Keywords: Aqueous Solubility, Ellagic Acid, Lithium Salts, Amino Acids, Lithium Diamondoid Metal-Organic Materials
© Copyright 2011, Tien Teng Ong
Dedication
To my dearest parents
and esteemed mentor who is apt to judge and appraise this artefact
Acknowledgements
First and foremost, I will seize this opportunity to express my deepest gratitude to my Ph.D. mentor, Dr. Michael J. Zaworotko, for providing me with the physical and mental space to nucleate and crystallize into who I am today.
I must thank the members of my graduate committee: Dr. Ning Shan, Dr. Örn
Almarsson, Dr. Shengqian Ma, for their scientific inputs, guidance and support throughout my doctoral research, and Dr. R. Douglas Shytle for kindly agreeing to serve as the chairperson of my examination committee.
I thank all past and present members in the research groups of Dr. Zaworotko and
Dr. Eddaoudi for their informative discussions, especially the cocrystal team whose earlier work highlighted the trials that lie ahead of me. I especially like to acknowledge and thank Dr. Kapildev K. Arora, Dr. Łukasz Wojtas and Jason A. Perman for imparting their knowledge in the practice of single crystal X-ray crystallography as an indispensable tool in my doctoral research. I thank Dr. Wenge Qiu for lending his ear and more during a testing period of my candidature. And I thank Alexander Schoedel for his help in many ways during the preparation of this dissertation.
Thank you all.
Table of Contents
List of Tables …………………………………………………………………………....vii
List of Figures ………………………………………………………………………...….ix
Abstract ………………………………………………………………………………….xv
Chapter 1. Molecular crystal forms ...... 1
1.1 Preamble ...... 1
1.2 From molecules to crystals ...... 2
1.3 Allotropism ...... 3
1.4 Polymorphism of molecular crystals ...... 4
1.5 Concomitant polymorphism...... 7
1.6 Enantiotropy and Monotropy ...... 9
1.7 Remarks ...... 11
Chapter 2. The Impact of Cocrystal on Aqueous Solubility ...... 12
2.1 Preamble ...... 12
2.2 Biopharmaceutical Classification System (BCS) ...... 13 i
2.3 Noyes-Whitney Equation ...... 14
2.4 Thermodynamic versus apparent solubility ...... 15
2.5 Solubility and Melting Point ...... 16
2.6 Trends in Aqueous Solubility of Cocrystals ...... 17
2.7 Conclusion ...... 36
Chapter 3. Molecular Cocrystals: Crystal Forms of Ellagic Acid ...... 38
3.1 Preamble ...... 38
3.1.1 CSD Survey of Ellagic Acid ...... 44
3.1.2 Cocrystals of Polyphenols with Group 1 Basic Cocrystal Formers
(Pyridine, Imidazole, Pyrazole) ...... 45
3.1.3 Cocrystals of Polyphenols with Group 2 Zwitterionic Cocrystal ......
Formers ...... 48
3.1.4 Cocrystals of Polyphenols with Group 3 Neutral Cocrystal Formers
(Carbonyl) ...... 49
3.2 Results and Discussion ...... 50
3.2.1 Crystal Forms of Ellagic Acid with Group 1 Basic Cocrystal ......
Formers (Pyridine, Imidazole, Pyrazole) ...... 50
3.2.2 Crystal Forms of Ellagic Acid with Group 2 Zwitterionic Cocrystal
Formers ...... 58
ii
3.2.3 Crystal Forms of Ellagic Acid with Group 3 Neutral Cocrystal ......
Formers (Carbonyl) ...... 60
3.2.4 Solvates of Ellagic Acid ...... 62
3.3 Conclusion ...... 67
3.4 Materials and Methods ...... 70
3.4.1 Synthesis of Crystal Forms of Ellagic Acid ...... 71
3.4.2 Crystal Form Characterization ...... 74
Chapter 4. Ionic Cocrystals: Crystal Forms of Lithium Salts...... 82
4.1 Preamble ...... 82
4.1.1 Amino acids as the ideal cocrystal formers ...... 83
- - - 4.1.2 CSD survey of ionic cocrystals of LiX (X = Cl , Br and NO3 ) and ......
amino acids ...... 84
- - - 4.1.3 1:2 ionic cocrystals of LiX (X = Cl , Br and NO3 ) and amino acids ......
as structural analogues of zeolites and silica ...... 86
4.2 Results and Discussion ...... 93
4.2.1 1:1 ionic cocrystals of LiX and amino acids: A discrete ......
supermolecule and linear chains ...... 94
4.2.2 1:2 ionic cocrystals of LiX and amino acids: Square grids, ......
Diamondoids and a Zeolitic ABW net ...... 103
4.3 Conclusion ...... 112
iii
4.4 Materials and Methods ...... 114
4.4.1 Synthesis of Crystal Forms of Lithium Salts ...... 114
4.4.2 Crystal Form Characterization ...... 118
Chapter 5. Conclusions and Future Directions ...... 126
5.1 Conclusions ...... 126
5.2 Future Directons ...... 128
5.3 Crystal Engineering and Crystallization ...... 130
References ...... 132
Appendices ...... 159
Appendix 1. Solid state characterization data for ELANAM ...... 160
Appendix 2. Solid state characterization data for ELAINM•1.7H2O ...... 161
Appendix 3. Solid state characterization data for ELAINM•4NMP ...... 162
Appendix 4. Solid state characterization data for ELAINM•4DMA ...... 163
Appendix 5. Solid state characterization data for ELACAF•H2O ...... 164
Appendix 6. Solid state characterization data for ELATPH•0.13H2O ...... 165
Appendix 7. Solid state characterization data for ELATPH•2DMA ...... 166
iv
Appendix 8. Solid state characterization data for ELADMP ...... 167
Appendix 9. Solid state characterization data for ELASAR ...... 168
Appendix 10. Solid state characterization data for ELADMG ...... 169
Appendix 11. Solid state characterization data for ELACAP ...... 170
Appendix 12. Solid state characterization data for ELAURE•2NMP ...... 171
Appendix 13. Solid state characterization data for ELADMA4 ...... 172
Appendix 14. Solid state characterization data for ELADMA2 ...... 173
Appendix 15. Solid state characterization data for ELADMSO2 ...... 174
Appendix 16. Solid state characterization data for ELANMP2 ...... 175
Appendix 17. Solid state characterization data for ELAPG2 ...... 176
Appendix 18. Solid state characterization data for LICSAR ...... 177
Appendix 19. Solid state characterization data for LINSAR ...... 178
Appendix 20. Solid state characterization data for LICDMG ...... 179
Appendix 21. Solid state characterization data for LINDMG ...... 180
Appendix 22. Solid state characterization data for LICBAL-anhydrate ...... 181
Appendix 23. Solid state characterization data for LICBAL ...... 182
v
Appendix 24. Solid state characterization data for LICABA ...... 183
Appendix 25. Solid state characterization data for LICPRO ...... 184
Appendix 26. Solid state characterization data for LIBPRO ...... 185
Appendix 27. Solid state characterization data for LINPRO ...... 186
Appendix 28. Solid state characterization data for LICSAR2 ...... 187
Appendix 29. Solid state characterization data for LINBTN2 ...... 188
Appendix 30. Solid state characterization data for LICDMG2 ...... 189
Appendix 31. Solid state characterization data for LIBDMG2 ...... 190
Appendix 32. Solid state characterization data for LICPRO2 ...... 191
Appendix 33. Solid state characterization data for LIBPRO2 ...... 192
Appendix 34. Solid state characterization data for LINPRO2 (dia) ...... 193
vi
List of Tables
Table 1-1. Solubility of ritonavir polymorphs at 5°C...... 7
Table 1-2. Melting points and torsion angles of ROY polymorphs...... 8
Table 2-1. Solubility data for itraconazole cocrystals.b ...... 18
Table 2-2. Solubility data for fluoxetine hydrochloride cocrystals...... 19
Table 2-3. Solubility data for Pfizer 1 succinic acid cocrystal.b ...... 20
Table 2-4. Solubility data for norfloxacin isonicotinamide cocrystal solvate.a ...... 20
Table 2-5. Solubility data for AMG517 cocrystals...... 21
Table 2-6. Solubility data for ethenzamide gentisic acid cocrystal.b ...... 22
Table 2-7. Solubility data for cocrystals of hexamethylenebisacetamide
derivative (A).a ...... 23
Table 2-8. Solubility data for lamotrigine cocrystals...... 24
Table 2-9. Solubility data for cytosine cocrystals.b ...... 24
Table 2-10. Solubility data for pterostilbene cocrystals...... 25
Table 2-11. Molecular structures of phenolic acids used in this study and their
three letter code...... 26
Table 2-12. Polyphenols used in this study and their three letter code...... 27
Table 2-13. Pyridines, Purines and their three letter code...... 27
Table 2-14. Zwitterions and their three letter code...... 28
Table 2-15. Molecules with carbonyl groups and their three letter code...... 28
Table 2-16. Aqueous solubility and melting point for target molecules...... 28
vii
Table 2-17. Solubility data for in-house cocrystals...... 29
Table 3-1. Molecular Structures of Ellagic Acid and Group 1 Basic Cocrystal
Formers with their three letter code...... 42
Table 3-2. Group 2 Zwitterionic Cocrystal Formers with their three letter
code...... 42
Table 3-3. Group 3 Neutral Cocrystal Formers with their three letter code...... 42
Table 3-4. Solvates of Ellagic Acid...... 43
Table 3-5. Selected hydrogen bond parameters for ellagic acid cocrystals...... 76
Table 3-6. Selected hydrogen bond parameters for ellagic acid cocrystal
solvates/hydrates...... 77
Table 3-7. Selected hydrogen bond parameters for ellagic acid solvates...... 78
Table 3-8. Crystallographic data for ellagic acid cocrystals...... 79
Table 3-9. Crystallographic data for ellagic acid cocrystal solvates/hydrates...... 80
Table 3-10. Crystallographic data for ellagic acid solvates...... 81
Table 4-1. Ionic cocrystals of lithium salts from the CSD...... 85
Table 4-2. Table of zwitterionic cocrystal formers...... 93
Table 4-3. Analysis of Li-C-Li angles forming 4-, 6- and 8-membered ring
motifs...... 112
Table 4-4. Selected hydrogen bond parameters for 1:1 ionic cocrystals...... 120
Table 4-5. Selected hydrogen bond parameters for 1:2 ionic cocrystals...... 122
Table 4-6. Crystallographic data for 1:1 ionic cocrystals...... 123
Table 4-7. Crystallographic data for 1:1 ionic cocrystals (continued)...... 124
Table 4-8. Crystallographic data of 1:2 ionic cocrystals...... 125
viii
List of Figures
Figure 1-1. Crystal Packing of Benzamide (Form I, top left, Form II, bottom
left, Form III, bottom right) and the amide dimer supramolecular
homosynthon present in all three polymorphs (top right)...... 5
Figure 1-2. The conformations of ritonavir Form I (top) and Form II (bottom)...... 6
Figure 1-3. Molecular structure of ROY...... 8
Figure 2-1. Significance of quadrants Q1, Q2, Q3 and Q4 in log plot of
solubility ratios. CCF1 denotes API. CCF2 denotes cocrystal
former...... 30
Figure 2-2. Solubility plot of in-house cocrystals...... 31
Figure 2-3. Solubility plot of literature cocrystals...... 32
Figure 2-4. Relationship between cocrystal solubility and cocrystal former
solubility with respect to the API...... 33
Figure 2-5. The relationship between change in melting point (CC mp - CCF1
mp) and the log of solubility ratio of cocrystal and API. CCF1
denote API...... 35
Figure 3-1. The phenol-carbonyl supramolecular heterosynthon is featured in
the cocrystals of (caffeine)•(pterostilbene) (left) and
(carbamazepine)•(pterostilbene) (right)...... 40
Figure 3-2. Crystal forms of ellagic acid: anhydrate (top left), dihydrate (top
right) and tetrakis(pyridine) solvate (bottom)...... 44
ix
Figure 3-3. The phenol-pyridine supramolecular heterosynthon aligns two
olefins into a discrete photoreactive supermolecule105 (top). A
projection of the discrete photoproduct on the ac plane (bottom)...... 46
Figure 3-4. A chain of alternating caffeine molecules and methyl gallate
molecules in (caffeine)·(methyl gallate) cocrystal (top), alternating
pairs of methyl gallate and theophylline dimer forms a flat sheet in
the (theophylline)·(methyl gallate) cocrystal (bottom)...... 47
Figure 3-5. A 1:1 cocrystal of L-ascorbic acid and sarcosine sustained by
carboxylate-hydroxyl supramolecular heterosynthon...... 49
Figure 3-6. ε-caprolactam molecules exist as dimers and bridge resorcinol
molecules...... 49
Figure 3-7. The undulating ELANAM tapes are crosslinked by sandwiching
the amide dimer with a pair of ellagic acid molecules...... 51
Figure 3-8. Crystal packing of ELAINM·1.7H2O reveals isonicotinamide
dimers with lateral hydrogen bonding to phenolic and carbonyl
moieties of ellagic acid. Water molecules (shown as large vdw
spheres) occupy channels parallel to the crystallographic a axis...... 52
Figure 3-9. The supramolecular tape in ELAINM has excess hydrogen bond
donors from phenolic moieties of ellagic acid and amide dimer of
isonicotinamide, attracting the NMP solvent molecules (top) and
DMA solvent molecules (bottom)...... 53
Figure 3-10. Crystal Packing in ELACAF·H2O reveals hydrogen bonding
between ELA and CAF molecules (top). Water molecules
x
reinforce the hydrogen bonding interaction between adjacent
sheets (bottom)...... 55
Figure 3-11. A projection of ELATPH·0.13H2O on the ac plane (top), a chain is
constructed in ELATPH·2DMA (bottom)...... 56
Figure 3-12. A discrete assembly is established in ELADMP...... 57
Figure 3-13. The phenol-carboxylate supramolecular heterosynthon (top), π-
stacking interactions in the crystal packing of ELASAR (bottom) ...... 59
Figure 3-14. The phenol-carboxylate supramolecular heterosynthon (left), π-
stacking interactions reinforce the crystal packing forces in
ELADMG (right) ...... 60
Figure 3-15. A supramolecular heterocatemer is assembled in ELACAP...... 61
Figure 3-16. A chain of hydrogen bonded urea molecules occupy channels
down the crystallographic a axis in the crystal packing of
ELAURE·2NMP...... 62
Figure 3-17. The similarity in crystal packing between the ELADMA4 solvate
and the tetrakis(pyridine) solvate (inset)...... 63
Figure 3-18. The similarity in crystal packing between the ELADMA2 solvate
and the dihydrate (inset)...... 64
Figure 3-19. DMSO molecules tether ELA molecules into a straight chain...... 65
Figure 3-20. A projection of ELANMP2 on the ac plane...... 66
Figure 3-21. (±)PG molecules align the ellagic acid molecules...... 67
Figure 4-1. A chain of fused six-atom rings in HEFWUK (top) and alternating
eight-atom and four-atom rings in ALUNEA (bottom)...... 85
xi
Figure 4-2. Secondary building units (SBUs) in zeolites...... 87
Figure 4-3. Synthetic zeolite based on imidazolates, LTA (top left), RHO, (top
right), RHO (BIF-9-Li, bottom left), SOD (bottom right). Yellow
spheres highlight the empty polyhedral cages...... 89
Figure 4-4. Polymorphs of silica, β-cristobalite (top left), β-tridymite (top
right), β-quartz, (bottom left), faujasite (bottom right)...... 90
Figure 4-5. Distribution of the Li-C-Li angle in crystal structures that contain
lithium cations bridged by carboxylate moieties (data obtained
using CSD version 5.31)...... 93
Figure 4-6. A chain of fused six-atom rings is observed in LICSAR...... 94
Figure 4-7. The nitrate anions coordinate to the lithium cations in LINSAR...... 95
Figure 4-8. Li2(DMG)2 clusters are hydrogen bonded into a 1-periodic
structure...... 96
Figure 4-9. The nitrate anions are coordinated to the lithium cations in
LINDMG...... 97
Figure 4-10. An undulating chain is constructed by bridging discrete
(LiCl)2·(H2O)2 clusters with betaine zwitterions...... 97
Figure 4-11. A chain of fused alternating eight-atom rings and four-atom rings
in LICBAL-anhydrate...... 98
Figure 4-12. Water molecules coordinate to the lithium cations in LICBAL...... 99
Figure 4-13. The chloride anions are coordinated to the lithium cations in
LICABA...... 100
xii
Figure 4-14. A chain of fused six-atom rings in LICPRO (top) and LIBPRO
(bottom)...... 101
Figure 4-15. An adamantane cage (left) is constructed with L-proline zwitterions
and nitrate anions as bridging ligands, hexagonal channels in the
dia net (right) are occupied by the pyrrolidinium ring of the
zwitterions to mitigate interpenetration...... 102
Figure 4-16. Structural diversity in the networks formed by 1:2 cocrystals of
lithium salts with amino acids: (a) square grids; (b) diamondoid
LiDMOM nets; (c) zeolitic ABW topology in the first LiZMOM.
Hydrogen atoms and counteranions are omitted for clarity...... 104
Figure 4-17. Undulating square grid (left) and bilayered packing arrangement
(right) in LICSAR2...... 104
Figure 4-18. Undulating square grid (left) and bilayered packing arrangement
(right) in LINBTN2...... 105
Figure 4-19. Hexagonal channels in dia nets of LICDMG2 (left) and LIBDMG2
(right)...... 106
Figure 4-20. Hexagonal channels in dia nets of LICPRO2 (left) and LIBPRO2
(right)...... 108
Figure 4-21. Hexagonal channels in LINPRO2 (dia, top) and octagonal channels
in LINPRO2 (ABW, bottom)...... 109
Figure 4-22. Significant expansion of dimensions occurs because of the ditopic
carboxylate linker in the ABW-type LiZMOM LINPRO2 when
compared to prototypal ABW zeolite...... 111
xiii
Figure 5-1. Triclinic modification of quinhydrone...... 128
Figure 5-2. Carbonyl as the hydrogen bond acceptor in the cocrystal of
diphenylamine and benzophenone...... 129
xiv
Abstract
Solubility enhancement of poorly-soluble active pharmaceutical ingredients
(APIs) remains a scientific challenge and poses a practical issue in the pharmaceutical
industry. The emergence of pharmaceutical cocrystals has contributed another dimension
to the diversity of crystal forms available at the disposal of the pharmaceutical scientist.
That pharmaceutical cocrystals are amenable to the design principles of crystal engineering means that the number of crystal forms offered by pharmaceutical cocrystals is potentially greater than the combined numbers of polymorphs, salts, solvates and hydrates for an API. The current spotlight and early-onset dissolution profile (“spring- and-parachute” effect) exhibited by certain pharmaceutical cocrystals draw attention to an immediate question: How big is the impact of cocrystals on aqueous solubility? The scientific literature and in-house data on pharmaceutical cocrystals that are
thermodynamically stable in water are reviewed and analyzed for trends in aqueous
solubility and melting point between the cocrystal and the cocrystal formers. There is
poor correlation between the aqueous solubility of cocrystal and cocrystal former with
respect to the API. The log of the aqueous solubility ratio between cocrystal and API has
a poor correlation with the melting point difference between cocrystal and API.
Structure-property relationships between the cocrystal and the cocrystal formers remain
elusive and the actual experiments are still necessary to investigate the desired
physicochemical properties.
Crystal form (cocrystals, polymorphs, salts, hydrates and solvates) diversity is and
will continue to be a contentious issue for the pharmaceutical industry. That the crystal
xv
form of an API dramatically impacts its aqueous solubility (a fixed thermodynamic
property) is illustrated by the histamine H2-receptor antagonist ranitidine hydrochloride
and HIV protease inhibitor ritonavir. For more than a century, the dissolution rate of a
solid has been shown to be directly dependent on its solubility, cēterīs paribus. A century later, it remains impossible to predict the properties of a solid, given its molecular structure. If delivery or absorption of an API are limited by its aqueous solubility, aqueous solubility then becomes a critical parameter linking bioavailability and pharmacokinetics of an API. Since the majority of APIs are Biopharmaceutical
Classification System (BCS) Class II (low solubility and high permeability) compounds, crystal form screening, optimization and selection have thus received more efforts, attention and investment. Given that the dissolution rate, aqueous solubility and crystal form of an API are intricately linked, it remains a scientific challenge to understand the nature of crystal packing forces and their impact upon physicochemical properties of different crystal forms. Indeed, the selection of an optimal crystal form of an API is an indispensable part of the drug development program. The impact of cocrystals on crystal form diversity is addressed with molecular and ionic targets in ellagic acid and lithium salts. A supramolecular heterosynthon approach was adopted for crystal form screening.
Crystal form screening of ellagic acid yields molecular cocrystals, cocrystal solvates/hydrates and solvates. Crystal form screening of lithium salts (chloride, bromide and nitrate salts) afforded ionic cocrystals and cocrystal hydrates.
xvi
Chapter 1. Molecular crystal forms
“…, crystals should not be regarded as chemical graveyards.”1
Michael J. Zaworotko
1.1 Preamble
Scientists have a natural inclination to correlate structure with properties. It is
owing to the curiosity (and I must add persistence) of the individual to make new
discoveries and relate them to what is known. I was trying to recall my first chemistry
lesson ever but strangely enough, I could not. It must have been a lesson on the periodic
table. Afterall, the periodic table provides a systematic classification of all known
elements into different horizontal rows (periods) and vertical columns (groups) to help
chemists to rationalize the properties of these elements as atoms. In short, the periodic
table is useful in correlating the electronic configuration (electronic structure) of atoms
with their properties. Dmitri Ivanovich Mendeleev is credited for creating the first version of the periodic table.2 With the table, he was successful in predicting the
properties of elements that have yet to be discovered and was honoured with the radioactive “mendelevium”, named after him. Early scientists have demonstrated success
in establishing structure-property relationships in atoms.
Linking atoms together, we can have ions or molecules. According to the Oxford
English Dictionary,3 a molecule is (1) one of the minute discrete particles of which
material substances were thought to be composed; (2) the smallest unit of a chemical
compound that can take part in the reactions characteristic of that compound; (3) a group 1 of atoms chemically bonded together and acting as a unit. One may think of a molecule as an assembly of atoms held together by an attractive force. Following the introduction to acids, bases and general organic chemistry, the floodgates were opened to a massive amount of information on the states of matter. The kinetic theory of gases assumes negligible interactions between gaseous molecules.4 Liquids and solids enter the picture when the interactions between molecules are significant and cannot be ignored. Moving along a homologous series of alkanes, gases, liquids and solids are encountered, characterized by their boiling points or melting points.5-6 In a way, this collection of data enabled us to associate structural features (of the molecules) with properties. There is an urge to analyze for trends in the physical properties across the same class of compounds and correlate the molecular structure with their properties.
When the intermolecular forces of attraction are sufficiently strong, molecules aggregate into a solid. The controlled aggregation in an organized mode results in a crystalline solid. How much do we know about the solid as a crystalline material?
1.2 From molecules to crystals
“The crystal is … the supermolecule par excellence.”7 A crystal is a material made up of atoms, molecules or ions that are organized in an orderly periodic arrangement that repeats in three spatial directions. “While analyzing crystal structures in terms of intermolecular interactions, one recognizes certain repetitive structural units.
These are typically small in size and are composed of specific molecular functionalities and their resulting interactions arranged in specific ways. The identification of these structural units is somewhat subjective but they are important in that they may be
2
associated with particular crystal packing characteristics.”8 Thus molecules recognize
themselves in the solid state and organize themselves through molecular recognition
events so that one can think of the smallest repeating unit as the unit cell. The
propagation of the unit cell along the three crystallographic axes illustrates a crystal.
However, the same molecules can organize themselves with different molecular recognition events to achieve another crystal. This gives rise to polymorphism. McCrone
describes a polymorph9 as “a solid crystalline phase of a given compound resulting from
the possibility of at least two different arrangements of the molecules of that compound
in the solid state.”
1.3 Allotropism
The phenomenon and consequences of at least two different arrangements of the
constituents of the same compound in the solid state, is perhaps best illustrated by the
10 11 element carbon. Carbon exists in the form of diamond, graphite, lonsdaleite, C60
(buckminsterfullerene or buckyball), C540, C70, single-walled carbon nanotube and
amorphous carbon. In diamond, each carbon atom is bonded to four other carbon atoms
covalently in a tetrahedral arrangement. The overall structure is a 3-periodic diamondoid
(dia) network of carbon atoms featuring six-membered carbon rings in the stable chair
conformation that results in the hardness of diamond.12 This hardness makes diamond an
excellent abrasive and used industrially in cutting and drilling operations. In graphite,
each carbon atom is covalently bonded to three other carbon atoms in a plane, forming a
(6,3) honeycomb net. Each carbon atom has four valence electrons and contributes one
electron to a delocalized system of π-electron density above and below the plane,
3
allowing these delocalized electrons to move freely throughout the plane. Hence graphite
becomes a conductor of electricity along the planes of the carbon atoms. The layer
structure of graphite13 enables it as a lubricant. Using elemental carbon as an example,
diamond and graphite bring forth the contrast in properties generated by their distinct
spatial arrangements (crystal packing) of the carbon atoms.
1.4 Polymorphism of molecular crystals
The first example of polymorphism of molecular compounds was reported by
Liebig and Wöhler14 as early as 1832 when they described the slow cooling of a “boiling
hot” aqueous solution of benzamide which produced white silky needles that transformed to rhombic crystals. They were alerted by the changes in the morphology of the crystal.
The single crystal X-ray structure of benzamide (Form I)15 was reported in 1959. David16 and Blagden17 pursued the structure solution of benzamide (Form II) using powder X-ray diffraction techinques in 2005 until Form III18 was reported four years later. The polymorphism of benzamide was identified by the keen eye for detail of Liebig and
Wöhler but the lack of control in polymorphic selectivity from a crystallization process had been a barrier in the solid state characterization of the polymorphs.
4
Figure 1-1. Crystal Packing of Benzamide (Form I, top left, Form II, bottom left, Form III, bottom right) and the amide dimer supramolecular homosynthon present in all three polymorphs (top right).
In the crystal structures of benzamide Forms I, II and III, a supramolecular tape
established by the lateral stacking of the amide dimers, is present in all three polymorphs.
However, the relative orientation of these supramolecular tapes is different amongst the
three polymorphs and hence the cause of the polymorphic behaviour of benzamide. The
meticulous efforts to unravel the polymorphs of a simple molecule in benzamide,
highlights the alertness of the individual and the challenges in understanding and
controlling the crystallization conditions.
5
Figure 1-2. The conformations of ritonavir Form I (top) and Form II (bottom).
166 years later, the lack of control in polymorphic selectivity from a crystallization process was thrust onto centre stage. Ritonavir (HIV-1 protease inhibitor) is a Biopharmaceutical Classification System19 (BCS) Class 4 drug with low solubility and low permeability. One crystal form of ritonavir20 (Form I) was known since its development and production of 240 lots of Norvir capsules without the problem of phase transformation. Alarm was raised when several lots of the capsules failed a series of
6
dissolution experiments, powder X-ray diffraction revealed the appearance of a
polymorph (Form II). The crystal structures21 of Forms I and II reveal the compound exists in different conformations around the carbamate in the solid state. The subtle change in the conformation results in crystals with a decrease in aqueous solubility. In addition, the presence of Form II in the original capsule formulation decreases the bioavailability. The emergence of undesired Form II had an instant impact on the manufacturing and clinical fronts. Form II appeared according to Ostwald’s Law of
Stages but there was no crystallization strategy and lack of knowledge at that time to prevent its formation.
Table 1-1. Solubility of ritonavir polymorphs at 5°C.
EtOH/H2O 99/1 75/25 Form I (mg/mL) 90 170 Form II (mg/mL) 19 30
In hindsight, polymorphism is not the problem, the issue lies in the lack of 1)
control of the crystallization conditions and 2) a proactive approach22 to explore the
crystal form landscape of the API in the marketed product.
1.5 Concomitant polymorphism
To understand the relationship between structure and properties of crystals,
polymorphic systems are ideal since any changes in the properties of the crystal form is
invariably due to its structure (crystal packing), cēterīs paribus. Indeed, the intrigue of polymorphism is best captured in 5-methyl-2-[(2-nitrophenyl)amino]-3- thiophenecarbonitrile,23 also known as ROY for its red, orange and yellow crystals. To
7
date, it has ten polymorphs (1. R, 2. Y, 3. ON, 4. OP, 5. YN, 6. ORP, 7. RPL, 8. Y04, 9.
YT04 and 10. R05, numbered in order of discovery and named in terms of colour and morphology). Of these, seven polymorphs have been characterized by single crystal X-
ray crystallography at ambient conditions (20°C to 23°C) to elucidate the origins of its
polymorphic behaviour and difference in colour. X-ray analysis of ROY polymorphs
highlighted the torsion angle θ as an important variable, producing distinct conformations
of ROY in the crystal packing. π-conjugation increases between the thiophene and
benzene rings as the torsion angle θ nears zero, resulting in a red shift of the visible
absorption spectrum.
O O N H CN
N
S
Figure 1-3. Molecular structure of ROY.
Table 1-2. Melting points and torsion angles of ROY polymorphs.
Form R Y ON OP YN ORP YT04 mp (°C) 106.2 109.8 114.8 112.7 99 97 106.9 θ (°) 21.7 104.7 52.6 46.1 104.1 39.4 112.8
The pure melt of ROY yields several polymorphs simultaneously upon cooling to
near room temperature. Mixtures of polymorphs are also obtained from crystallization in methanol. All known polymorphs of ROY have been crystallized near ambient 8
conditions. The concomitant polymorphism24 of ROY makes it a challenging model
system to understand the relationship between nucleation and crystal growth of
polymorphs in general. Furthermore, their kinetic stability (at ambient conditions) allows
them to be isolated and studied for their stability relationships. The relative Gibbs free
energy of seven ROY polymorphs were calculated using data collected from differential
scanning calorimetry experiments25-26 to plot an energy versus temperature diagram and
reveal the stability order of ROY polymorphs and their monotropic or enantiotropic
relationships.27-28 The goal is to dictate polymorphic selectivity through a crystallization process and ultimately gain the control of selective crystallization of the desired polymorph in a complicated system.
1.6 Enantiotropy and Monotropy
The relative stability of two polymorphs depends on their Gibbs free energies.
G = H – TS
(G = Gibbs free energy, H = enthalpy, T = temperature in K, S = entropy)
When the stability order of polymorphs is invariant of temperature, the polymorphs are monotropic. When the stability order of polymorphs changes with temperature, they become enantiotropic polymorphs. The knowledge of the enantiotropic or monotropic relationship between different polymorphs requires the generation of energy versus temperature diagram of the polymorphic system. This diagram can be used
9
as a map to direct the crystallization process to achieve a desired polymorph at the expense of the undesired polymorph. For a dimorphic system, there are four possibilities:
1) The desired thermodynamically stable form is in a monotropic system. Phase
transformation will not occur to generate another form hence precautions are not
necessary to guard against such a transformation.
2) The desired thermodynamically stable form is in an enantiotropic system. Precautions
must be exercised to maintain the thermodynamic conditions at which the Gibbs free
energy of the desired polymorph is lower than that of the other.
3) The desired thermodynamically metastable form is in a monotropic system. A
kinetically controlled phase transformation will occur to generate the undesired
thermodynamically stable form. Precautions must be exercised to retard the kinetics
of the transformation by employing extreme conditions such as very low
temperatures, very dry conditions and storage in the dark.
4) The desired thermodynamically metastable form is in an enantiotropic system. The
generation of the energy versus temperature diagram of the polymorphic system will
reveal the temperature range at which the Gibbs free energy of the desired form is
lower than that of the other, to obtain and maintain this desired form.
10
1.7 Remarks
“There are many mysteries of nature that we have not solved. Hurricanes, for
example, continue to occur and often cause massive devastation. Meteorologists cannot
predict months in advance when and with what velocity a hurricane will strike a specific
community. Polymorphism is a parallel phenomenon. We know that it will probably happen. But not why or when. Unfortunately, there is nothing that we can do today to prevent a hurricane from striking any community or polymorphism from striking any drug.”29
Dr. Eugene Sun
This underscores the necessity for due diligence in solid form screening.30
11
Chapter 2. The Impact of Cocrystal on Aqueous Solubility
2.1 Preamble
Solubility enhancement31-32 of poorly-soluble APIs33-34 remains a scientific
challenge and poses a practical issue in the pharmaceutical industry. The emergence35 of pharmaceutical cocrystals has contributed another dimension to the diversity of crystal forms available for pharmaceutical development. The long-standing reliance of the pharmaceutical industry and regulatory authorities on crystal forms and the “spring-and- parachute”36-type dissolution profile uniquely exhibited by certain pharmaceutical cocrystals draw attention to an immediate question: How big is the impact of cocrystals on aqueous solubility? The scientific literature and in-house data on pharmaceutical cocrystals that are thermodynamically stable in water are reviewed and analyzed for trends in aqueous solubility and melting point between the cocrystal and the cocrystal formers. There is poor correlation between the aqueous solubility of cocrystal and cocrystal former with respect to the API. The log of the aqueous solubility ratio between cocrystal and API has a poor correlation with the melting point difference between cocrystal and API. Structure-property relationships between the cocrystal and the cocrystal formers remain elusive and the actual experiments are still necessary to investigate the desired physicochemical properties.
12
2.2 Biopharmaceutical Classification System (BCS)
A critical parameter deciding the fate of any API is its aqueous solubility. Hence
to increase drug solubility while maintaining a stable solid form is often an integral part
of a pharmaceutical development process. This goal is imperative since solubility and
permeability are the two criteria used to illustrate oral absorption of a drug according to
the BCS.19 BCS class II (low solubility, high permeability) drugs are limited in oral
absorption by their solubility. This class of drugs is currently estimated to account for
about 30% of commercial and developmental drugs37. BCS class I (high solubility, high
permeability) is the ideal scenario for any API to be in. Increased solubility can result in a
significant improvement of oral absorption, leading to higher bioavailability, pushing a
drug from BCS class II to BCS class I. This can be achieved via pharmaceutical
cocrystals38, which have emerged and established itself as a promising methodology to modify important physicochemical properties of poorly water soluble drugs, such as solubility, dissolution rate and bioavailability, to the extent that the pharmaceutical industry cannot afford not to explore. Indeed crystal form screening of APIs have traditionally been restricted to polymorphs, salts and solvates (including hydrates).
Pharmaceutical cocrystals are also possible for nonionizable39, weakly acidic40 and weakly basic41 drugs which prevent and restrict the opportunity of a salt screen
respectively, and present a viable option for solubility enhancement without changing the
molecular structure of the drug.
13
2.3 Noyes-Whitney Equation
The Noyes-Whitney equation42-43 dictates the dissolution profile of all substances,
at least until the dissolution of cocrystals was reported. It states “the rate at which a solid
substance dissolves in its own solution is proportional to the difference between the
concentration of that solution and the concentration of the saturated solution”. This has
practical relevance for the dissolution profile. A solid with high solubility will boast a
high initial rate of dissolution. A solid with low solubility will exhibit a low initial rate of
dissolution and take a longer time to reach maximum concentration. There will not be a
solid with low solubility but demonstrate a high initial rate of dissolution or vice versa.
With cocrystals, there can be a sudden spike in concentration (“spring-and-parachute”
effect) of the API followed by a precipitous dip to a level similar to that of the pure API.
This is achieved by a poorly water soluble antidepressant Prozac®.36 The powder
dissolution profiles of cocrystals of fluoxetine hydrochloride were measured and each
cocrystal has its unique dissolution properties. Obviously, there are several controls such
as temperature, stirring rate, particle size distribution (PSD), volume and type of
dissolution media. These factors are meant to mitigate the effects of diffusion
phenomenon and surface area. The solubility of cocrystals had been reported in a variety
of dissolution media, including 0.1 N HCl, fasted simulated intestinal fluids (FaSIF) and water. The dissolution media and context used for performing dissolution experiments can also change the outcome of the experiment. This was exemplified by the celecoxib44 nicotinamide cocrystal. Most studies reported the dissolution profile over time. Particle size control via sieving of samples was reported occasionally. There was also no mention of controls in some reports. This highlights the wide range of experimental parameters
14
that are adopted in solubility experiments which can be adjusted to achieve the necessary
information.
2.4 Thermodynamic versus apparent solubility
There are several pointers to consider when consulting solubility data45. The first is equilibrium versus apparent solubility measurements. Apparent solubility measurements are approximate data points usually based on one measurement at one time point. It is unknown if the solid material is thermodynamically stable in the system or if the system has reached equilibrium in the time frame of the experiment unless additional experiments are conducted to verify the phase purity of the material before and after each dissolution experiment. For equilibrium solubility, multiple data points are recorded at different time points to ensure the system has attained equilibrium, by observation of a plateau in the concentration-time plot, which is also referred to as a powder dissolution profile. Powder dissolution rates can be influenced by PSD since a smaller PSD affords a greater surface area in contact with the dissolution medium, given the same mass of material. The next factor is phase change during the experiment, as mentioned earlier about thermodynamic stability. When there is a change in the phase purity of the solid material, the resultant solubility data may be irrelevant to the starting material in the experiment. Phase transformation can be detected by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). They are typically indicated by the crystallization of a less soluble material after a dramatic plunge in concentration during the collection of solubility measurements at various time points. Hence the maximum
15
solubility observed over a certain time period is reported along with the time of
occurrence but this is not an equilibrium solubility measurement. An analysis of the solid
material remaining after the experiment is required to confirm any phase transformation.
Solubility studies had been conducted to correlate the aqueous solubilities of
cocrystals and their respective cocrystal formers. Success in these studies will pave the
way to a solubility-guided strategy46 towards cocrystal screening. Alternatively, the
origin of pharmaceutical cocrystals47 is the product of an approach based on the
understanding and implementation of supramolecular synthons.48 A solubility-guided
strategy towards cocrystal screening for solubility enhancement is indeed very attractive.
Should aqueous solubility become a transferable property, all cocrystal former libraries
will only include those with high aqueous solubility and significantly reduce the number
of cocrystal screening experiments.
2.5 Solubility and Melting Point
Solubility is a fixed thermodynamic property of a crystal form. From a
thermodynamic standpoint, the Gibbs free energy of solution is the summation of the lattice energy and solvation energy in an aqueous system. Going from a pure crystalline
API to a cocrystal, the Gibbs free energy of solution is obviously going to change since the cocrystal is a new composition of matter and not a physical mixture of two solids.
The hydration energy of both components (as a cocrystal or a physical mixture) is assumed to be a constant as they retain their molecular integrity in solution. But the lattice energy changes since the cocrystal is a new crystalline material. A stable crystal 16 form with high lattice energy is unlikely to disintegrate and dissolve in solution easily.
Likewise, a less stable crystal form with low lattice energy is more likely to disintegrate and dissolve in solution readily. Since melting point is a direct manifestation of the lattice energy and also an experimentally verifiable physical property of a crystalline solid that is easily obtainable, melting point may have a better correlation with the experimentally determined solubility measurements. In fact, if the inverse relationship between lattice energy and thermodynamic solubility is a simple one, solubility enhancement of an API upon cocrystal formation should be accompanied by melting point depression, observable by the difference in melting point between the cocrystal and the API.
To search for trends in solubilities of cocrystals, we undertook the endeavor to investigate the aqueous solubilities of cocrystals, eliminating systems where a solvent- mediated phase transformation occurred.
2.6 Trends in Aqueous Solubility of Cocrystals
Dissolution experiments of crystalline itraconazole (95% of all crystalline particles < 10 μm), commercial Sporanox® beads (amorphous itraconazole) and three itraconazole cocrystals (succinic acid, L-malic acid and L-tartaric acid) were conducted in solutions of 0.1 N HCl at 25°C. All the cocrystals demonstrated higher solubility than crystalline itraconazole. The solubility of the succinic acid cocrystal was about 2 × 10-4
M, while the solubilities of the L-malic acid and L-tartaric acid cocrystals were about 7 ×
-4 10 M which rivals the commercial amorphous Sporanox formulation. These cocrystals recorded a sustained increase in concentration ranging from 4- to 20-fold higher than that 17 of crystalline itraconazole49. This provides an early example of the solubility improvements that cocrystals can deliver.
Table 2-1. Solubility data for itraconazole cocrystals.b
Cocrystal [CCF] (mg/mL) [API] (M) [CC] (M) Itraconazole 76.9a ~(1/4)(2×10-4) ~2 × 10-4 Succinic acid Itraconazole 363.5a ~(1/20)(7×10-4) ~7 × 10-4 L-malic acid Itraconazole 1390a ~(1/20)(7×10-4) ~7 × 10-4 L-tartaric acid aValues are obtained from the Merck Index. bPhase transformation during the dissolution experiment is not reported.
The dissolution profiles of fluoxetine HCl36 and three fluoxetine HCl cocrystals
(benzoic acid, succinic acid and fumaric acid) were monitored in water at 20°C for 120 minutes using ultraviolet spectroscopy (UV) at 227 nm. The samples were sieved to achieve a PSD of 53-150 μm. About 800 mg of sample were introduced to 30 mL of water at a stirring rate of 144 rpm. Any remaining solids after the dissolution experiment were filtered, dried in vacuum and analyzed by powder x-ray diffraction (PXRD). The solubility of fluoxetine HCl was 11.4 mg/mL. The solubility of the benzoic acid cocrystal was lower at 5.6 mg/mL while the fumaric acid cocrystal was higher at 14.8 mg/mL. The succinic acid cocrystal recorded a peak solubility of 20.2 mg/mL after about 1 minute before decreasing to a concentration which nears that of fluoxetine HCl. The validity of these results is confirmed by PXRD analysis of the undissolved solids matching those of the starting phases for fluoxetine HCl, benzoic acid and fumaric acid cocrystals. PXRD also confirmed the identity of the undissolved solids after dissolution of the succinic acid cocrystal, to be fluoxetine HCl, highlighting that the cocrystal dissociated and 18
recrystallized to fluoxetine HCl under the experimental conditions. This series of three
cocrystals is unique in providing an example each of increasing (fumaric acid cocrystal)
and decreasing (benzoic acid cocrystal) the aqueous solubility as well as being the first
example (succinic acid cocrystal) of the “spring-and-parachute” effect.
Table 2-2. Solubility data for fluoxetine hydrochloride cocrystals.
Cocrystal [CCF] [CC] (mg/mL) Conversion CC mp (°C) (mg/mL) during experiment Fluoxetine HCl 3.4a 5.6 No 131.46 Benzoic acid Fluoxetine HCl 76.9a 20.2 Yes 134.08 Succinic acid Fluoxetine HCl 6.3a 14.8 No 161.06 Fumaric acid aValues are obtained from the Merck Index. [API]=11.4 mg/mL. API mp=157.18°C.
A developmental cancer candidate compound50 (Pfizer 1), a potent and selective
ErbB2 inhibitor, is a weak base with an aqueous solubility of 0.0008 μmol/mL. 20 crystal
forms of acid-base pairs were obtained after a salt screen. Three of these; a
sesquisuccinate (neutral, 0.79 μmol/mL), a dimalonate (mixed ionic and zwitterionic,
3.83 μmol/mL) and a dimaleate (salt, 10.4 μmol/mL), were selected for development. The
location of the protons is probed by X-ray structural analysis and confirmed by cross
polarization magic angle spinning (CPMAS) 15N nuclear magnetic resonance (NMR)
spectroscopy. There was no discussion on the experimental conditions involving solubility measurements. However, this is the first example of a cocrystal that exhibited an aqueous solubility approximating 3 orders of magnitude higher than that of the pure drug.
19
Table 2-3. Solubility data for Pfizer 1 succinic acid cocrystal.b
Cocrystal [CCF] (mg/mL) [CC] (μmol/mL) CC mp (°C) Pfizer 1 76.9a 0.79 143 Succinic acid aValue is obtained from the Merck Index. bPhase transformation during the dissolution experiment is not reported. [API]=0.0008 μmol/mL. API mp=167°C.
Norfloxacin51 is a poorly water soluble fluoroquinolone antibacterial drug. An
isonicotinamide cocrystal and three salts with succinic acid, malonic acid and maleic acid
were prepared and structurally characterized. Solubility studies were performed by
suspending about 21 mg of sample in 2.5 mL of water, maintained at 25°C (±1) in a
laboratory oven for 72 hours at a stirring rate of 300 rpm using absorbance measured at
276 nm. The succinic acid, malonic acid and maleic acid salts have an apparent solubility
of 6.60, 3.90 and 9.80 mg/mL. The apparent solubility of norfloxacin is 0.21 mg/mL
while that of the isonicotinamide cocrystal is 0.59 mg/mL. This cocrystal resulted in a
modest 3-fold increase in solubility.
Table 2-4. Solubility data for norfloxacin isonicotinamide cocrystal solvate.a
Cocrystal [CCF] (mg/mL) [CC] (mg/mL) CC mp (°C) Norfloxacin 192 0.59 180 Isonicotinamide Chloroform solvate aPhase transformation during the dissolution experiment is not reported. [API]=0.21 mg/mL. API mp=221°C.
AMG 51752, a transient receptor potential vanilloid 1 antagonist (TRPV1)
developed for the treatment of chronic pain, possesses an aqueous solubility of 5 μg/mL as the free base. A total of 21 cocrystals were reported on two occasions. Solubility
20 measurements were taken in fasted simulated intestinal fluid (FaSIF) at 25°C within a 24 hour timeframe. There was no reported control of particle size. Of these cocrystals, there are 6 cocrystals with trans-cinnamic acid, 2,5-dihydroxybenzoic acid, 2-hydroxycaproic acid, benzoic acid, benzamide and cinnamide, that did not undergo any phase transformation during the duration of the experiment. The solubilities of the cocrystals are 1, 2, 3, 21, 12.6 and 6.3 μg/mL respectively53-54. The benzoic acid cocrystal reported a four-fold increase in solubility.
Table 2-5. Solubility data for AMG517 cocrystals.
Cocrystal [CCF] [CC] (μg/mL) Conversion CC mp (°C) (mg/mL) during experiment AMG 517 0.23a 1 No 204 trans-cinnamic acid AMG 517 22b 2 No 229 2,5- dihydroxybenzoic acid AMG 517 32c 3 No 130 2-hydroxycaproic acid AMG 517 3.4d 21 No 146 Benzoic acid AMG 517 13.5d 12.6 No 164 Benzamide AMG517 1.37 6.3 No 184 Cinnamide aLiterature value. bValue is obtained from the Handbook of Aqueous Solubility Data. cValue is calculated from Scifinder. dValues are obtained from the Merck Index. [API]=5 µg/mL. API mp=230°C.
Ethenzamide, a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of moderate pain, forms polymorphic cocrystals55 with gentisic acid with three distinct crystalline modifications. Dissolution experiments were carried out at 25°C for ethenzamide and the three polymorphs. The equilibrium solubilities for ethenzamide and
21
the cocrystal (Form 1) were estimated to be 0.0344 and 0.0365 mg/mL. There was no
solubility enhancement in this example.
Table 2-6. Solubility data for ethenzamide gentisic acid cocrystal.b
Cocrystal [CCF] (mg/mL) [CC] (mg/mL) CC mp (°C) Ethenzamide 22a 0.0365 100.65 Gentisic acid Form I aValue obtained from the Handbook of Aqueous Solubility Data. bPhase transformation during the dissolution experiment is not reported. [Ethenzamide]=0.0344 mg/mL. Ethenzamide mp=132°C.
Hexamethylenebisacetamide is used in the treatment of myelodysplastic syndrome and resistant acute myelogenous leukemia. A pyridine derivative56 (A) was
prepared and forms five cocrystals with succinic acid, adipic acid, suberic acid, sebacic
acid and dodecanedioic acid. Crystal structure analysis reveals that the linear diacids
serve as spacer molecules such that the increase in length of the crystallographic c axis in
space group P1 is a reflection of the increasing number of carbon atoms from succinic
acid to dodecanedioic acid. As the melting point of the diacid decreases from succinic
acid to dodecanedioic acid, the cocrystals follow the same trend. The aqueous solubilities
of the cocrystals also decrease as the aqueous solubilities of the diacids decreases.
However, this is not a common occurrence and has been attributed to the crystal packing
of the cocrystals. Dissolution experiments were conducted with A and its five cocrystals
by stirring excess cocrystal solid phase in water (25°C). The concentration of A was
monitored by UV spectroscopy (λmax = 236.4 nm).
22
Table 2-7. Solubility data for cocrystals of hexamethylenebisacetamide derivative (A).a
Cocrystal [CCF] (mg/mL) [CC] (mg/mL) CC mp (°C) A·succinic acid 76.9 167.18 186 A·adipic acid 14.4 117.3 165 A·suberic acid 1.6 92.042 158 A·sebacic acid 1 12.109 148 A·dodecanedioic 0.03 7.2459 146 acid aPhase transformation during the dissolution experiment is not reported. [A]=70.24 mg/mL. A mp=181°C.
Lamotrigine is marketed as Lamictal® by GlaxoSmithKline for oral administration as a conventional or chewable tablet for the treatment of epilepsy and psychiatric disorders such as bipolar disorder. Ten crystal forms of lamotrigine were reported: lamotrigine methylparaben cocrystal form I (1:1) (1), lamotrigine
methylparaben cocrystal form II (1:1) (2), lamotrigine nicotinamide cocrystal (1:1) (3), lamotrigine nicotinamide cocrystal monohydrate (1:1:1) (4), lamotrigine saccharin salt
(1:1) (5), lamotrigine adipate salt (2:1) (6), lamotrigine malate salt (2:1) (7), lamotrigine nicotinate dimethanol solvate (1:1:2) (8), lamotrigine dimethanol solvate (1:2) (9) and lamotrigine ethanol monohydrate (1:1:1) (10). Dissolution experiments were performed on 2, 3, 4 and 5 in deionized water (25°C) and 0.1 M HCl (37°C). The samples were
sieved to achieve a PSD between 53 μm and 75 μm. 100 mg of samples were introduced
into 100 mL of water while 500 mg of samples were introduced into 50 mL of 0.1 M HCl.
The slurries were stirred at a rate about 200-300 rpm. Samples were filtered with a 0.45
μm syringe filter and the concentration was determined using UV spectroscopy. The
maximum concentration of 2, 3, 4, 5 and pure lamotrigine were 0.21, 0.30, 0.23, 0.45 and
0.28 mg/mL respectively. PXRD analysis of the remaining solid after dissolution
23
confirmed 2 and 5 were the same solid phase while 3 and 4 converted to a hydrated form
of lamotrigine57.
Table 2-8. Solubility data for lamotrigine cocrystals.
Cocrystal [CCF] [CC] (mg/mL) Conversion CC mp (°C) (mg/mL) during experiment Lamotrigine 2.5a 0.21b No 162.40 Methylparaben Form II Lamotrigine 1000a 0.30b Yes 167.23 Nicotinamide Lamotrigine 1000a 0.23b Yes 174.81 Nicotinamide Monohydrate aValues are obtained from the Merck Index. Maximum [API] observed=0.28 mg/mL. API mp=221°C.
The solubility of cytosine cocrystals58 with oxalic acid, malonic acid and succinic
acid were measured by gravimetric method at 15, 25, 40 and 60 °C. The solubility of
cytosine and its oxalic acid, malonic acid and succinic acid cocrystals were about 6, 4, 20 and 7 mg/mL respectively.
Table 2-9. Solubility data for cytosine cocrystals.b
Cocrystal [CCF] (mg/mL) [CC] (mg/mL) CC mp (°C) Cytosine 98.1a ~4 270.2 Oxalic acid Cytosine 1538a ~20 219.2 Malonic acid Cytosine 76.9a ~7 249.5 Succinic acid aValues are obtained from the Merck Index. [API]=7.69 mg/mL.a bPhase transformation during the dissolution experiment is not reported. API mp=320°C(dec.).
24
Pterostilbene is a dimethylated analogue of resveratrol59 that forms cocrystals
with caffeine and carbamazepine. Three cocrystals60 were obtained: caffeine pterostilbene cocrystal (Form I and Form II) and carbamazepine pterostilbene cocrystal. Dissolution experiments were performed for caffeine pterostilbene cocrystal (Form I) and the
carbamazepine pterostilbene cocrystal by slurrying in water for 72 hours. Samples were
filtered with a 0.2 µm nylon filter and analyzed via a 96 well quartz plate using UV
spectroscopy at 275 nm for carbamazepine.
Table 2-10. Solubility data for pterostilbene cocrystals.
Cocrystal [CCF] [CC] (mg/mL) Conversion CC mp (°C) (mg/mL) during experiment CBZ 0.021 0.0085 No 134 Pterostilbene Caffeine 0.021 0.56 Yes 114 Pterostilbene Form I [CBZ]=0.056 mg/mL. CBZ mp=190°C.
25
In-house studies
Table 2-11. Molecular structures of phenolic acids used in this study and their three letter code.
OH O HO HO
O O OH HO HO OH OH HO SAL PCA GAL H3CO OH O O O
HO OH HO OH OH
H3CO SYR 1HY COU O HO O H3CO O OH O O HO OH HO HO OH OH
HO OH OH CFA FER CGA
Tables 2-11 to 2-15 represent different categories of molecules based on different functional groups to facilitate cocrystal screening and preparation via a supramolecular heterosynthon approach. In-house dissolution experiments were performed for cocrystals of epigallocatechin-gallate, protocatechuic acid, coumaric acid, caffeic acid, gallic acid, ferulic acid, caffeine and (±)baclofen. All samples were prepared and sieved with ASTM standard sieve to achieve a PSD between 53 μm and 75 μm. The dissolution experiments were done in water at room temperature with the exception of (±)baclofen cocrystals at
26
36.9°C. Residual solids at the end of the dissolution experiments were analyzed with powder X-ray diffraction to ensure the integrity of the cocrystal solid phase.
Table 2-12. Polyphenols used in this study and their three letter code.
OH OH OH O HO OH HO HO O O OH O HO O HO OH O HO O OH OH OH O O OH O OH HO
OH O
OH EGCG QUE ELA ETG
Table 2-13. Pyridines, Purines and their three letter code.
O O O
NH2 N NH2 NH2 H N N N NAM INM INZ O O O
H N N N N N HN
N N O N N O N O N
CAF TPH TBR
27
Table 2-14. Zwitterions and their three letter code.
+ O O NH3 Cl O +HN
+ - - HN O O O- NAC INA BAC
Table 2-15. Molecules with carbonyl groups and their three letter code.
O O O O HN NH HN NH H2N NH2 NH
O O N O H CAP URE GAH CYA
Many of these cocrystals routinely contain two components that can be considered as APIs in their own right based on their pharmacological properties. Thus the description of API and cocrystal former becomes interchangeable. For the correlation of the properties of the cocrystals, CCF1 will be used to denote the API while CCF2 will be denoted as the cocrystal former.
Table 2-16. Aqueous solubility and melting point for target molecules.
CCF1 [CCF1] (mg/mL) CCF1 mp (°C) Epigallocatechin gallate (EGCG) 23.6 140 Protocatechuic acid (PCA) 10.67 200 Coumaric acid (COU) 0.789 210 Caffeic acid (CFA) 0.485 223 Gallic acid (GAL) 11.49 258 Ferulic acid (FER) 0.6 168 Caffeine (CAF) 21.7 238 (±)-baclofen (BAC) 5 206
28
Table 2-17. Solubility data for in-house cocrystals.
Cocrystal Refcode [CCF2] (mg/mL) [CC] (mg/mL) CC mp (°C) (CCF1CCF2) EGCGNAM 1000 2.9 90 EGCGINM 192 1.32 155 EGCGINA 5.2 1.23 190 PCACAP 4560 17.21 131 PCAINM 192 7.74 195 PCATPH 8.3 1.02 254 PCANAM 1000 2.94 201 COUNAM 1000 1.078 159 COUINM (I) 192 1.15 172 COUINM (II) 192 1.12 165.5 COUCAF 22 0.314 184 COUTHP 8 1.157 223 COUTHB.H2O 0.5 0.294 228 COUURE 1200 1.52 123.5 COUINZ 12.5 1.096 178 COUTHB 0.5 0.2812 228 CFAINM 192 1.9415 151 CFAGAH 142 1.2613 221 CFAINZ 12.5 1.0616 185 GALINM 192 2.4 202 GALTBR 0.5 0.5 271 GALNAC 17 8 211 GALGAH 142 4.7 260 FERINM 192 1.8 152 FERNAM 1000 1.4 126 FERTBR 0.5 0.6 192 CAFCYA 2.7 9.69 228 CAFELA 0.0038 0.07 300 CAFCOU 0.789 1.1 178 CAFFER 0.6 2.85 146 CAFSAL 2 3.5 146 CAF1HY 0.5 0.19 190 CAFETG 4 0.54 144 CAFCGA 25 11.9 131 CAFGAL 11 5.7 244 CAFCFA 0.485 0.671 199 CAFSYR 5.7 1.17 180 CAFQUR 0.0026 8.55 244 QURCAF 22 13.3 244 BACGAL(36.9°C) 26.4 9.37 178 BACFER(36.9°C) 1.76 1.943 154 CCF1 denotes API. CCF2 denotes cocrystal former.
29
Figure 2-1. Significance of quadrants Q1, Q2, Q3 and Q4 in log plot of solubility ratios. CCF1 denotes API. CCF2 denotes cocrystal former.
Plotting the solubility ratio of cocrystal to API against the solubility ratio of cocrystal former to API on a logarithmic scale, any negative value implies a solubility ratio of less than 1. When a more soluble cocrystal former (compared to API) leads to a more soluble cocrystal, these data points are captured in quadrant Q1. When the solubility of the cocrystal decreases with a less soluble cocrystal former (compared to
API), they are represented in quadrant Q3. Of particular concern are the data points in quadrants Q2 and Q4. Quadrant Q2 depicts cocrystals that reveal a decrease in aqueous solubility of the cocrystal despite a cocrystal former with an aqueous solubility higher
30 than that of the API. Albeit with a less soluble cocrystal former, if the solubility of the cocrystal records an increase, they are found in quadrant Q4.
Figure 2-2. Solubility plot of in-house cocrystals.
First and foremost, without a logarithmic scale, most data points are within an order of magnitude. A logarithmic plot enables a spread of the individual data points. For the quercetin caffeine cocrystal (QUECAF), the dissolution experiment was performed with caffeine as the analyte of interest. Since the cocrystal is thermodynamically stable in water, therefore the molar concentration of both components (caffeine and quercetin) has to be the same to arrive at 13.3 mg/mL. Datapoints in Q1 and Q3 suggest that solubility
31
is a transferable property from the cocrystal former to the cocrystal. However, the
presence of several data points in Q2 suggests this is not the case.
Figure 2-3. Solubility plot of literature cocrystals.
The solubility plot of cocrystals from the scientific literature tells a similar story.
While the examples of the Pfizer cancer drug succinic acid cocrystal and the cis-itraconazole cocrystals are encouraging, the AMG517 cocrystals undoubtedly refutes the notion that a more soluble cocrystal former (compared to API) translates to a more soluble cocrystal. Figure 2-3 reveals data points in every quadrant. Clearly, the solubility of the cocrystal is not predictable based on the solubility of the cocrystal former.
32
Figure 2-4. Relationship between cocrystal solubility and cocrystal former solubility with respect to the API.
The resultant plot in Figure 2-4 features a cluster of datapoints near the origin with a few notable exceptions such as QUECAF, the Pfizer cancer drug succinic acid cocrystal and the cis-itraconazole cocrystals. Solubility is not a transferable physicochemical property. No longer can one be contented with a restricted cocrystal former library that favours high aqueous solubility of cocrystal former to boost the aqueous solubility of cocrystals. Furthermore, the opportunity cost of missing the cocrystal with desired aqueous solubility after substantial research and development
33
efforts, is too high. That aqueous solubility is not predictable means that every cocrystal
potentially features utility in advantageous solubility and expands the searchable space61 of APIs but the solubility data has to be available. While a solubility-guided approach to cocrystal screening is not advisable, the formation of a cocrystal, using a supramolecular synthon approach, is more reliable by employing persistent supramolecular heterosynthons62-64. Although the desired aqueous solubilities of the cocrystals are not
predictable, they are by all means achievable after due diligence.
As mentioned earlier in this chapter, a crystal form with high lattice energy is unlikely to disintegrate and dissolve in solution readily, manifested by a high melting point which is an easily obtainable, experimentally verifiable physical property of a crystalline solid. Hence solubility enhancement upon cocrystal formation should be accompanied by melting point depression (∆mp = CC mp – API mp) reflected in the melting point of the cocrystal relative to the API, i.e. ∆mp < 0 for solubility enhancement and vice versa.
34
Figure 2-5. The relationship between change in melting point (CC mp - CCF1 mp) and the log of solubility ratio of cocrystal and API. CCF1 denote API.
Indeed, if the inverse relationship between lattice energy and thermodynamic solubility upon cocrystal formation is a simple one, all data points in figure 2-5 should only occupy the top left and bottom right quadrants. That most of the data points in figure 2-5 fall in the lower half suggests that melting point depression may be a common phenomenon among the cocrystals discussed herein. There may be a higher probability of obtaining a cocrystal with a lower melting point than a higher melting point. Hence if a crystal form of a solid with a lower melting point is necessary without covalent modifications to the API, cocrystals represent viable options.
35
2.7 Conclusion
The “spring-and-parachute” effect has been a unique feature of pharmaceutical cocrystals that are not stable in an aqueous environment. As the dissolution profile of more cocrystal systems become publicly available, we can expect to witness more examples of such systems. That the “spring-and-parachute” effect features a precipitous plunge to a concentration level similar to that of the pure API, is not necessarily a bad one. Similar dissolution profiles are presented by amorphous solids since the initial boost in solubility (due to the metastable amorphous form) will decline once the conversion of the amorphous solid (into a crystalline form) commences. However, that the pharmaceutical cocrystal is a crystalline solid implies it possesses all the advantages that a crystal form has to offer. Compared to amorphous solids, crystalline solids are preferred from a manufacturing and regulatory perspective due to a number of factors such as purity, stability and reproducibility. Furthermore, formulation strategies such as the judicious choice of excipients can control the kinetics of the conversion process, in the same way that amorphous solids are stabilized by excipients.
Is solubility a transferable physicochemical property of a crystalline solid? The results presented herein suggest that this is not the case. Several cocrystals are observed to be less water soluble upon cocrystal formation with cocrystal formers possessing a favourable solubility ratio (>1) with respect to the API. 20.3% (13/64) of the data points in this study fall into this category. Given the lack of publicly available dissolution and solubility data of cocrystals, calculation of this percentage may not be statistically
36
representative. The lack of predictability of the desired physicochemical properties points
to a need for a cocrystal former library to be exhaustive and include cocrystal formers with a wide range of aqueous solubilities. In the same manner that the cocrystals were overlooked after initial salt screens, due diligence should be taken not to miss the targeted cocrystals.
37
Chapter 3. Molecular Cocrystals: Crystal Forms of Ellagic Acid
3.1 Preamble
Crystal form (cocrystals, polymorphs, salts, hydrates and solvates) diversity is and
will continue to be a contentious issue for the pharmaceutical industry.65-66 That the crystal form of an API dramatically impacts its aqueous solubility (a fixed thermodynamic property) is illustrated by the histamine H2-receptor antagonist ranitidine
hydrochloride and HIV protease inhibitor ritonavir. For more than a century, the
dissolution rate of a solid has been shown to be directly dependent on its solubility,42-43 cēterīs paribus. A century later, it remains impossible to predict the properties of a solid, given its molecular structure.67 If delivery and absorption of an API are limited by its
aqueous solubility, aqueous solubility then becomes a critical parameter linking bioavailability and pharmacokinetics of an API. Since the majority of APIs are BCS
Class II (low solubility and high permeability) compounds, crystal form screening, optimization and selection have thus received more efforts, attention and investment.
Given that the dissolution rate, aqueous solubility and crystal form of an API are intricately linked, it remains a scientific challenge to understand the nature of crystal packing forces and their impact upon physicochemical properties of different crystal forms. Indeed, the selection68 of an optimal crystal form of an API is an indispensable
part of the drug development program.
Developing a crystalline form of an API has other advantages. Crystallization has
been employed routinely in the pharmaceutical industry to separate, isolate and purify
38
drug molecules to yield a high purity product with reliable reproducibility and is a
scalable process for manufacturing purposes. Compared to amorphous solids, a stable
crystal form is highly desirable from manufacturing, handling and regulatory
perspectives. In addition, the recent introduction69 of pharmaceutical cocrystals has
expanded the patentable space of an API.61 Their novelty and utility is illustrated by the
fact that they profoundly modify the physicochemical properties of the parent API.
Pharmaceutical cocrystals can be defined as multiple component crystals in which at least
one component is molecular and a solid at room temperature (the pharmaceutically
acceptable cocrystal former) and forms a supramolecular synthon with a molecular or
ionic API. They have added another dimension to the diversity of possible crystal forms
(traditionally restricted to polymorphs, salts, solvates and hydrates) and augmented the
drug discovery funnel. With a myriad of possible crystal forms waiting to be discovered,
it is not surprising that pharmaceutical scientists have resorted to high throughput
screening (HTS) techniques to assist them in their endeavor.
Screening techniques such as solvent drop grinding, SonicSlurry™, HTS
evaporation experiments, and reaction crystallization are some of the routine screening
tools. Using carbamazepine, these four screening techniques identified a total of 27 solid
phases with 18 carboxylic acids as cocrystal formers.70 50 piroxicam cocrystals71 were
identified in screening experiments using 23 carboxylic acids. 18 carboxylic acids were
combined with meloxicam to produce 19 cocrystals.72 Other examples of API carboxylic
acid cocrystals include itraconazole,49 fluoxetine hydrochloride,36 developmental sodium
channel blocker,73 fluconazole,74 caffeine,75 theophylline,75 gabapentin,76 AMG517,52 minoxidil77 and ethenzamide.55, 78-79 Many carboxylic acids are included in a Generally
39
Recognised As Safe80 (GRAS) list and are thus routinely engaged as pharmaceutically acceptable cocrystal formers. However, pharmaceutically acceptable cocrystal formers must go beyond carboxylic acids to truly diversify the crystal forms available to APIs.
For instance, polyphenols possess potent hydrogen bonding functional groups capable of molecular recognition. Furthermore, they are present in our diet81 in the fruits, tea82 and wine83 that are commonly consumed and often exhibit pharmacological properties as well. Obviously, they have to be pharmaceutically acceptable even though the toxicology84 profile may not be thoroughly investigated. Indeed, this has been demonstrated with pterostilbene as a cocrystal former to prepare cocrystals with caffeine and carbamazepine.60
Figure 3-1. The phenol-carbonyl supramolecular heterosynthon is featured in the cocrystals of (caffeine)•(pterostilbene) (left) and (carbamazepine)•(pterostilbene) (right).
Ellagic acid85 is a naturally occurring polyphenolic nutraceutical86-87 derived from the hydrolysis of ellagitannins88 and it is abundant in pomegranates and raspberries.
According to DeFelice, a nutraceutical is defined as “a food (or part of a food) that
40
provides medical or health benefits, including the prevention and/or treatment of a
disease. It has been widely studied for its pharmacological properties.89-90 However, it is
reported to possess an aqueous solubility of only 3.8 μg/ml91 at 25°C. This has restricted
recent nutritional research to focus on the pharmacokinetics of pomegranate juice/extract rather than pure ellagic acid in healthy subjects,92-96 since its poor aqueous solubility
limits bioavailability. In two separate pharmacokinetic studies administrating pomegranate extract and pomegranate juice in healthy human subjects, ellagic acid was
97-98 detected in human plasma with a maximum concentration (Cmax) of about 33 ng/mL at a time of maximum concentration (Tmax) of 1 hour after ingestion. The poor aqueous
solubility of ellagic acid has impeded its potential as a therapeutic molecule. There is a
need to improve the aqueous solubility of ellagic acid from a clinical perspective.
Although a number of pharmacokinetic studies have been focused on ellagic acid, little
information on its solid state chemistry has been reported in the open literature. That
ellagic acid possesses extremely low aqueous solubility makes it a worthy candidate for
cocrystal formation since aqueous solubility is a critical physicochemical property that
can decide the fate of an API.
41
Table 3-1. Molecular Structures of Ellagic Acid and Group 1 Basic Cocrystal Formers with their three letter code.
O O O HO O
OH HO NH2 NH2
O OH N O N ELA NAM INM O O
H N N N N
HNN O N N O N N
CAF TPH DMP
Table 3-2. Group 2 Zwitterionic Cocrystal Formers with their three letter code.
O O + H2 N NH+ O- O- SAR DMG
Table 3-3. Group 3 Neutral Cocrystal Formers with their three letter code.
O O
NH
H2N NH2
CAP URE
42
Table 3-4. Solvates of Ellagic Acid.
O O O OH
N N S HO
NMP DMA DMSO (±)PG
With this in mind, we explore the crystal form landscape of ellagic acid.
Amenable to crystal engineering design principles, ellagic acid has an imbalance of
hydrogen bond donors over acceptors, which suggests that perhaps it may be prone
towards cocrystal formation and/or solvation by molecules with superior hydrogen bond
acceptor capabilities. Its molecular planarity and rigidity also makes it an attractive
crystal engineering target. To date, three crystal structures of ellagic acid (anhydrate,
dihydrate and tetrakis(pyridine) solvate) were reported in the Cambridge Structural
Database99 (CSD). Cocrystals of ellagic acid had addressed supramolecular
heterosynthons64 (between phenols and carboxylates) and structure-stability relationships100 (thermal stability of cocrystal hydrates). A grouped library of successful
cocrystal formers include (1) nicotinamide, isonicotinamide, caffeine, theophylline, 3,5-
dimethylpyrazole, (2) sarcosine, N,N-dimethylglycine, (3) ε-caprolactam and urea. Group
1 involves cocrystal formers with basic pyridine, imidazole and pyrazole moieties. Group
2 contains zwitterionic cocrystal formers having negatively-charged carboxylate moieties. Group 3 features the neutral carbonyl group. Other crystal forms of ellagic acid include solvates from N,N-dimethylacetamide (DMA), N-Methyl-2-pyrrolidone (NMP),
dimethylsulfoxide (DMSO) and (±)propylene glycol (PG). Although the discovery of
43
solvates was serendipitous, the supramolecular synthons observed in these structures
nevertheless render themselves useful in the design of cocrystals.
3.1.1 CSD Survey of Ellagic Acid
ELLAGC KUVBEI
VA S Y E U Figure 3-2. Crystal forms of ellagic acid: anhydrate (top left), dihydrate (top right) and tetrakis(pyridine) solvate (bottom).
Analysis of existing crystal structures represents the first step in a crystal engineering experiment.101 A survey of the CSD for crystal forms of ellagic acid returned
three hits, an anhydrate101 (Refcode: ELLAGC), a dihydrate102 (KUVBEI) and tetrakis(pyridine) solvate103 (VASYEU). In the crystal structure of anhydrous ellagic
acid, ellagic acid molecules are arranged into a chain by phenol-phenol supramolecular
homosynthon. Adjacent chains are cross-linked by phenol-carbonyl supramolecular 44 heterosynthon to generate a flat sheet. Adjacent sheets are π-stacked to complete the crystal packing. In the dihydrate, water molecules insert themselves between ellagic acid molecules so that the chains are sustained by OH•••O(water) interactions. Adjacent chains are linked by OH•••O(water) and OH(water)•••O=C interactions. Similarly, adjacent sheets are reinforced by π-stacking104 interactions. The crystal structure of the tetrakis(pyridine) solvate of ellagic acid reveals a discrete supermolecule105 assembled from one ellagic acid molecule and four pyridine solvent molecules linked via phenol- pyridine supramolecular heterosynthon. The presence of the tetrakis(pyridine) solvate suggests the phenol-pyridine supramolecular heterosynthon is more robust than the phenol-phenol supramolecular homosynthon and should be exploited for cocrystal formation.
3.1.2 Cocrystals of Polyphenols with Group 1 Basic Cocrystal Formers (Pyridine,
Imidazole, Pyrazole)
The supramolecular heterosynthons responsible for the formation of cocrystals between phenols and pyridine/imidazole/pyrazole has been documented. The dominant phenol-pyridine supramolecular heterosynthon has been employed by the groups of
MacGillivray, Nangia and Zaworotko in constructing cocrystals of polyphenols.
MacGillivray106 et al. used resorcinol as a template to align trans-1,2-bis(4- pyridyl)ethylene into a photoreactive supermolecule for the [2+2] photodimerization of trans-1,2-bis(4-pyridyl)ethylene (which is otherwise photostable) to yield rctt-tetrakis(4- pyridyl)cyclobutane.
45
Figure 3-3. The phenol-pyridine supramolecular heterosynthon aligns two olefins into a discrete photoreactive supermolecule105 (top). A projection of the discrete photoproduct on the ac plane (bottom).
Peddy et al. prepared a series of cocrystals of phenols with isonicotinamide107 that exhibit the phenol-pyridine supramolecular heterosynthon. To demonstrate the preference of phenols for pyridines over cyano groups in a competitive hydrogen bonding environment, Bis et al. prepared and characterized a series of cocrystals with persistent
phenol-pyridine supramolecular heterosynthon63 in the presence of cyano groups. That the phenol-pyridine supramolecular heterosynthon is superior to the phenol-cyano supramolecular heterosynthon is confirmed when mixtures of starting materials were obtained from experiments to obtain cocrystals of 3-hydroxypyridine or 5- hydroxyisoquinoline with cyano derivatives.
46
Figure 3-4. A chain of alternating caffeine molecules and methyl gallate molecules in (caffeine)·(methyl gallate) cocrystal (top), alternating pairs of methyl gallate and theophylline dimer forms a flat sheet in the (theophylline)·(methyl gallate) cocrystal (bottom).
Substituted xanthines (such as caffeine and theophylline) are biologically active
molecules that feature basic imidazoles, and are potent corystal formers for acidic
molecules. Trask et al. reported a series of cocrystals with caffeine108 and theophylline109 using a homologous series of dicarboxylic acids (oxalic acid, malonic acid, maleic acid, succinic acid110 and glutaric acid). Coincidently, both caffeine/theophylline oxalic acid
cocrystals were stable to hydration at 98% RH for a period of seven weeks, confirmed by
powder X-ray diffraction. Weakly acidic phenols are equally adept in interacting with
substituted xanthines111, demonstrated by their methyl gallate cocrystals.40, 112 The crystal 47
packing of the cocrystal helps to improve the mechanical properties compared to caffeine
due to the introduction of a slip system. The ability of pyrazoles to form cocrystals with polyphenols was illustrated through 3,5-dimethypyrazole and phloroglucinol.113
3.1.3 Cocrystals of Polyphenols with Group 2 Zwitterionic Cocrystal Formers
Zwitterions such as the proteinogenic amino acids are perhaps the best cocrystal formers in terms of their toxicology profile, cost and ready availability. In general, a zwitterion is a dipolar ion that carries both a positive and negative charge114 and has a total net charge of zero.115 They had been used in the resolution of optical isomers
involving cocrystals of homochiral mandelic acid. (S)-alanine116 and (R)-cysteine117 can be used to resolve racemic mandelic acid. (S)-mandelic acid is able to resolve racemic 2- aminobutyric acid and phenylalanine through fractional crystallization. Importantly, (S)- mandelic acid is used to resolve racemic pregabalin118 (active ingredient in LYRICA® that is used to treat neuropathic pain) on an industrial scale. Examples of zwitterionic cocrystals exist in the CSD.119-127 The utility of carboxylates in cocrystal formation has expanded the scope of zwitterionic cocrystals beyond carboxylic acids to include
100 molecules with weakly acidic hydroxyl moieties , as exemplified by polyphenols and L-
ascorbic acid.
48
Figure 3-5. A 1:1 cocrystal of L-ascorbic acid and sarcosine sustained by carboxylate-hydroxyl supramolecular heterosynthon.
3.1.4 Cocrystals of Polyphenols with Group 3 Neutral Cocrystal Formers
(Carbonyl)
Figure 3-6. ε-caprolactam molecules exist as dimers and bridge resorcinol molecules.
The carbonyl group is a component of many organic functional groups such as the carboxylic acid, primary, secondary and tertiary amides, aldehyde, ketone, ester, lactone and lactam. While the supramolecular chemistry of carboxylic acids, primary and
49 secondary amides have been explored, the same cannot be said of the other functional groups. Using ε-caprolactam and urea, we probe the propensity of the carbonyl group to engage in hydrogen bonding interaction with polyphenols. Urea is a small organic molecule that is prone to forming urea inclusion128-129 compounds. Supramolecular heterocatemers130 have been constructed from polyphenols (such as 4,4’-biphenol and resorcinol) and ε-caprolactam to highlight their role in cocrystal design.
3.2 Results and Discussion
Cocrystals, cocrystal solvates/hydrates and solvates of ellagic acid were prepared and fully characterized. The synthesis of these cocrystals demonstrated the utility of polyphenols as cocrystal formers for a wide variety of functional groups, such as, pyridine, imidazole, pyrazole, zwitterions and carbonyl groups.
3.2.1 Crystal Forms of Ellagic Acid with Group 1 Basic Cocrystal Formers
(Pyridine, Imidazole, Pyrazole)
ELANAM: The crystal structure of ELANAM reveals it is a 1:2 cocrystal of ellagic acid and nicotinamide. ELANAM exhibits hydrogen bonding between the pyridyl group of nicotinamide and the phenolic moieties of ellagic acid [OH•••N: 2.630(5) Å].
The neutral nature of nicotinamide is supported by the C-N-C angle of 116.35° in the pyridyl group. Two nicotinamide molecules adopt the amide dimer. The phenol-pyridine supramolecular heterosynthon63, 107, 131 and the amide dimer supramolecular
50
homosynthon132-134 [NH•••O: 3.040(7) Å] generate an undulating tape. Two ellagic acid
molecules sandwich the amide dimer with the carbonyl and phenolic moieties to form a
(10) trimer [OH•••O: 2.694(6) Å and NH•••O: 2.953(7) Å]. The trimeric interaction
(figure 2-6) links the undulating tapes together to yield the overall crystal packing.
Figure 3-7. The undulating ELANAM tapes are crosslinked by sandwiching the amide dimer with a pair of ellagic acid molecules.
ELAINM: Three crystal forms of ELAINM were obtained: a variable hydrate, a
NMP solvate and DMA solvate.
Crystal structure analysis of ELAINM•1.7H2O reveals one ellagic acid molecule,
two isonicotinamide molecules and disordered water molecules in the unit cell.
ELAINM•1.7H2O exhibits hydrogen bonding between the pyridyl group of
isonicotinamide and the phenolic moieties of ellagic acid [OH•••N: 2.611(2) Å]. The
51
neutral nature of isonicotinamide is supported by the C-N-C angle of 118.07° in the pyridyl moiety. Two isonicotinamide molecules exist as dimers through amide dimer supramolecular homosynthons [NH•••O: 2.988(3) Å]. The phenol-pyridine supramolecular heterosynthon and the amide dimer supramolecular homosynthon generate a tape (figure 2-7). The amide dimer also acts as both a hydrogen bond donor and acceptor towards the carbonyl [NH•••O: 2.930(3) Å] and phenolic moieties of ellagic
acid [OH•••O: 2.749(2) Å] to form a (10) trimer that links adjacent chains. Disordered water molecules occupy channels parallel to the crystallographic a axis.
Figure 3-8. Crystal packing of ELAINM·1.7H2O reveals isonicotinamide dimers with lateral hydrogen bonding to phenolic and carbonyl moieties of ellagic acid. Water molecules (shown as large vdw spheres) occupy channels parallel to the crystallographic a axis.
The crystal structure of ELAINM•4NMP reveals it is a tetrakis(NMP) solvate of the 1:2 cocrystal of ellagic acid and isonicotinamide. Isonicotinamide molecules exist as 52
dimers via the amide dimer supramolecular homosynthon [NH•••O: 2.923(4) Å]. The pyridyl group interacts with the phenolic moiety [OH•••N distance of 2.647(4) Å] to form
a linear chain. The crystal structure is sustained by the phenol-pyridine and amide-amide
supramolecular synthons. Along the periphery of the chain, four NMP molecules are
positioned to engage the two remaining hydrogen bond donors (from ellagic acid) via phenol-carbonyl supramolecular heterosynthon [OH•••O: 2.615(4) Å], and another two dangling N-H donors [from the amide dimer, NH•••O: 2.827(5) Å].
Figure 3-9. The supramolecular tape in ELAINM has excess hydrogen bond donors from phenolic moieties of ellagic acid and amide dimer of isonicotinamide, attracting the NMP solvent molecules (top) and DMA solvent molecules (bottom).
53
The crystal structure of ELAINM•4DMA reveals a 1:2:4 ellagic acid,
isonicotinamide and DMA cocrystal solvate in which two of the four DMA molecules are crystallographically disordered. ELAINM•4DMA is isostructural with ELAINM•4NMP.
Isonicotinamide molecules are dimers via the amide dimer supramolecular homosynthon
[NH•••O: 2.895(3) Å]. The pyridyl group interacts with the phenolic moiety [OH•••N:
2.647(3) Å] to form a linear chain. Along the periphery of the chain, four DMA
molecules are positioned to engage the two remaining hydrogen bond donors (from
ellagic acid) via phenol-carbonyl supramolecular heterosynthon [OH•••O: 2.608(3) Å],
and another two dangling N-H donors [from the amide dimer, NH•••O: 2.792(7) Å].
54
Figure 3-10. Crystal Packing in ELACAF·H2O reveals hydrogen bonding between ELA and CAF molecules (top). Water molecules reinforce the hydrogen bonding interaction between adjacent sheets (bottom).
ELACAF•H2O: Analysis of the crystal structure reveals that ELACAF•H2O contains two ellagic acid molecules, two caffeine molecules and two water molecules in the unit cell. The phenolic moieties of ellagic acid act as hydrogen bond donors to the basic imidazole [OH•••N: 2.702(4) Å] and carbonyl moieties of caffeine molecules
[OH•••O: 2.708(3) Å] so as to form straight chains of alternating ellagic acid and caffeine molecules. Adjacent chains are linked via OH(ELA)•••O=C(CAF) hydrogen bonds
[2.708(3) Å] and water molecules [2.608(3) Å and 2.854(4) Å] that hydrogen bond to two
55
ELA molecules, thereby forming a sheet [Figure 3-10(top)]. Adjacent sheets are
crosslinked by hydrogen bonds between water molecules and carbonyl oxygen atoms of
ellagic acid [2.920(4) Å]. The water molecules are in isolated environments.
ELATPH: Two crystal forms of ELATPH were obtained: a partial hydrate and a
DMA solvate.
Figure 3-11. A projection of ELATPH·0.13H2O on the ac plane (top), a chain is constructed in ELATPH·2DMA (bottom).
The X-ray structure of ELATPH•0.13H2O reveals a 1:2 cocrystal of ellagic acid
and theophylline. Theophylline molecules exist as (10) dimers [N-H•••O: 2.714(2) Å], allowing the remaining carbonyls from the dimer to engage the phenolic moieties of ellagic acid [OH•••O: 2.757(2) Å] to form a straight chain. This straight chain is crosslinked at an angle with adjacent straight chains via phenol-imidazole supramolecular heterosynthon [N-H•••O: 2.711(2) Å] to generate stacks of crosses. Traces of water are present in the X-ray crystal structure represented by the isolated red spheres in figure 56
3-11(top). The water molecules hydrogen bond with the carbonyls [OH•••O: 2.611 Å] of
ellagic acid and theophylline [OH•••O: 2.785Å].
In ELATPH•2DMA, theophylline molecules exist as dimers [N-H•••O:
2.804(3) Å], allowing the imidazole nitrogen of theophylline to interact with the phenolic
moieties [OH•••N: 2.849(3) Å] and establish a linear chain. Similarly, the crystal
structure is sustained by the phenol-imidazole supramolecular heterosynthon and the
theophylline dimer. Two disordered DMA molecules are located along the periphery of
the chain to satisfy the two remaining hydrogen bond donors (from ellagic acid) via phenol-carbonyl supramolecular heterosynthon [OH•••O: 2.548(4) Å].
Figure 3-12. A discrete assembly is established in ELADMP.
ELADMP: X-ray structural analysis reveals a 1:2 cocrystal of ellagic acid and
3,5-dimethylpyrazole. Centrosymmetric 3,5-dimethylpyrazole molecules sandwich an
ellagic acid molecule via OH(phenol)•••N(pyrazole) interaction [OH•••N: 2.588(4) Å] 57
and NH(pyrazole) •••O=C(lactone) interaction [NH•••O: 2.973(4) Å] to form a
supermolecule. The remaining phenolic moieties engage in T-shaped OH•••π [OH•••π:
3.263(5) Å] interactions135 with adjacent 3,5-dimethylpyrazole molecules to generate a
herringbone arrangement.
3.2.2 Crystal Forms of Ellagic Acid with Group 2 Zwitterionic Cocrystal Formers
ELASAR: The crystal structure of ELASAR reveals that the 1:1 cocrystal of ellagic acid and sarcosine is sustained by charge-assisted O-H•••O supramolecular
heterosynthon [2.594(2) Å and 2.630(2) Å] to form (18) tetramers [figure 3-13(top)].
Each carboxylate moiety of sarcosine interacts with four ellagic acid molecules whereas
each ammonium moiety forms a charge-assisted N-H•••O supramolecular heterosynthon
[2.905(3) and 3.025(3) Å] with the phenolic moieties of two ellagic acid molecules. The ellagic acid molecules are π-stacked in a slipped orientation [figure 3-13 (bottom)].
58
Figure 3-13. The phenol-carboxylate supramolecular heterosynthon (top), π- stacking interactions in the crystal packing of ELASAR (bottom)
ELADMG: The 1:1 cocrystal of ellagic acid and N,N-dimethylgycine also
exhibits the (18) tetramer [OH•••O: 2.649(1) Å and 2.903(2) Å] [figure 3-14(left)].
The ammonium moiety of N,N-dimethylglycine interacts with one phenolic moiety
[NH•••O: 2.887(2) Å] whereas the ellagic acid molecules are π-stacked in a staggered orientation [figure 3-14(right)].
59
Figure 3-14. The phenol-carboxylate supramolecular heterosynthon (left), π- stacking interactions reinforce the crystal packing forces in ELADMG (right)
3.2.3 Crystal Forms of Ellagic Acid with Group 3 Neutral Cocrystal Formers
(Carbonyl)
ELACAP: The X-ray crystal structure reveals it is a 1:2 cocrystal of ellagic acid
and ε-caprolactam. The phenolic moieties act as hydrogen bond donors towards the carbonyls of ε-caprolactam [OH•••O: 2.696(9) Å and 2.724(9) Å]. The carbonyl groups of ellagic acid act as hydrogen bond acceptors towards the NH of ε-caprolactam
[NH•••O: 2.903(10) Å]. The two supramolecular heterosynthons generate a 3-periodic network of supramolecular heterocatemers.
60
Figure 3-15. A supramolecular heterocatemer is assembled in ELACAP.
ELAURE•2NMP: Analysis of the crystal structure reveals a bis(NMP) solvate of
a 1:2 cocrystal of ellagic acid and urea. The phenol-carbonyl supramolecular
heterosynthon is prevalent with all phenolic moieties interacting with the carbonyl of two
crystallographically independent urea [OH•••O: 2.543(5) Å and 2.684(4) Å] and NMP
molecules [OH•••O: 2.581(4) Å and 2.657(5) Å]. Centrosymmetric urea dimers [NH•••O:
2.899(6) Å] bridge four ellagic acid molecules [NH•••O: 2.983(5) Å and 3.058(5) Å]
from different staggered layers. Channels are generated along the crystallographic a axis
to accommodate chains of hydrogen bonded urea molecules [NH•••O: 2.922(5) Å and
61
2.959(6) Å]. NMP molecules are present to interact with the remaining hydrogen bond donors from ellagic acid.
Figure 3-16. A chain of hydrogen bonded urea molecules occupy channels down the crystallographic a axis in the crystal packing of ELAURE·2NMP.
3.2.4 Solvates of Ellagic Acid
Additional crystal forms of ellagic acid were obtained in the form of solvates using DMA, NMP, DMSO and (±)-PG. The crystal packing of some of these solvates resembles that of the dihydrate and tetrakis(pyridine) solvate of ellagic acid.
62
Figure 3-17. The similarity in crystal packing between the ELADMA4 solvate and the tetrakis(pyridine) solvate (inset).
ELADMA4: The tetrakis(DMA) solvate is sustained by phenol-carbonyl supramolecular heterosynthon between the phenolic moieties of one ellagic acid molecule with four DMA molecules [OH•••O: 2.6148(16) Å and 2.5770(16) Å]. This crystal structure resembles that of the tetrakis(pyridine) solvate (Refcode: VASYEU) with slightly further hydrogen bonding distances [OH•••N: 2.622(3) Å and 2.795(4) Å] compared to the tetrakis(DMA) solvate. A discrete assembly is formed and the overall crystal packing is a herringbone arrangement.
63
Figure 3-18. The similarity in crystal packing between the ELADMA2 solvate and the dihydrate (inset).
ELADMA2: The bis(DMA) solvate of ellagic acid is sustained by phenol- carbonyl supramolecular heterosynthon, with the phenolic moieties of two adjacent
ellagic acid molecules bridged by two DMA molecules to form a (14) tetramer
[OH•••O: 2.6696(14) Å and 2.8393(14) Å]. This unit propagates into a linear chain and resembles the crystal packing of ellagic acid dihydrate (Refcode: KUVBEI). In the crystal structure of ellagic acid dihydrate, the crystal packing forces were maximized with water molecules bridging adjacent chains via OH(water)•••O=C(lactone) interaction, reinforced by π-stacking interaction. The same is not possible for this DMA solvate since
DMA does not possess labile protons available for hydrogen bonding and the comparatively bigger DMA molecules (relative to H2O molecules) caused adjacent chains to be displaced such that π-stacking interactions cannot be made efficiently.
64
Figure 3-19. DMSO molecules tether ELA molecules into a straight chain.
ELADMSO2: The bis(DMSO) solvate is sustained by phenol-sulfoxide
supramolecular heterosynthon [OH•••O=S: 2.674(3) Å and 2.695(3) Å]. Two adjacent
ellagic acid molecules are tethered by two bridging DMSO molecules to form a (14) tetramer. This unit propagates linearly into a chain and the crystal packing resembles that of both the bis(DMA) solvate and ellagic acid dihydrate. Here, π-stacking interactions reinforced the crystal packing forces.
65
Figure 3-20. A projection of ELANMP2 on the ac plane.
ELANMP2: The bis(NMP) solvate is sustained by phenol-carbonyl supramolecular heterosynthon where the phenolic moieties of two ellagic acid molecules are bridged by one NMP molecule [OH•••O: 2.697(4) Å and 2.745(4) Å]. Unlike the bis(DMA) solvate and bis(DMSO) solvate, the phenolic moieties do not hydrogen bond in a concerted manner to the same two NMP molecules to avoid the formation of another chain structure. Instead, the NMP molecules are bridging ellagic acid molecules to generate a supramolecular heterocatemer packed in a herringbone arrangement.
66
Figure 3-21. (±)PG molecules align the ellagic acid molecules.
ELAPG2: The bis(±)PG solvate is sustained by OH(phenol)•••OH(aliphatic alcohol) and OH(aliphatic alcohol)•••O=C(lactone) interactions at 2.660(3) Å and
2.734(3) Å respectively. PG molecules of opposite chirality bridge adjacent ellagic acid molecules into π-stacks, with the shortest distance of two ellagic acid planes at 3.280 Å.
3.3 Conclusion
17 crystal forms (5 cocrystals, 7 cocrystal solvates/hydrates and 5 solvates) of ellagic acid have been presented herein. It seems ellagic acid is particularly prone to solvation. Although they are usually discovered serendipitously, the supramolecular synthons observed in these structures can still render themselves useful in the design of cocrystals. Unlike calixarenes136 and cyclodextrins137 that act as hosts to accommodate
67
guest molecules in their cavities, ellagic acid does not possess any molecular feature to
suggest a tendency towards small molecule uptake such as solvent molecules. The
solvated/hydrated crystal structures reveal they are neither inclusion compounds, i.e. the
crystal packing does not generate pockets of empty spaces to trap molecules of
appropriate volume. As mentioned at the start of this chapter, the imbalance of hydrogen
bond donors over acceptors implies that given the opportunity, ellagic acid will prefer to
accommodate a hydrogen bond acceptor in its local environment to satisfy its hydrogen
bonding requirements. Furthermore, the lactone functional group is not known to be a
target in crystal engineering studies, i.e., a stronger hydrogen bond acceptor will engage
in hydrogen bonding interaction with the phenolic moieties. Hence, it is not surprising
that the phenol-carbonyl(lactone) interaction is only observed in the crystal structure of
anhydrous ellagic acid. However, in the presence of molecules with superior hydrogen bonding acceptor capabilities, the phenolic moieties participate in hydrogen bonding readily, disrupting the crystal packing of anhydrous ellagic acid. The crystal structures of the five cocrystal solvates/hydrates are a further testament of this imbalance of hydrogen bond donors over acceptors. Referring to the isonicotinamide and theophylline cocrystal solvates, there remains an excess of hydrogen bond donors after the formation of the phenol-pyridine supramolecular heterosynthon and the phenol-imidazole supramolecular heterosynthon. Hence the solvent molecules are included in the crystal lattice around the periphery of the established unit.
Examination of the crystal form landscape of ellagic acid has demonstrated that it has a preference for molecules capable of hydrogen bond acceptor properties in its local environment. Pyridines, imidazoles, pyrazole, zwitterions and carbonyl groups have been
68
manipulated to yield the cocrystals. The results presented herein further our
understanding of the supramolecular chemistry of polyphenols, confirm the feasibility of polyphenols to serve as cocrystal formers for a diverse variety of functional groups and demonstrate the phenol-carbonyl supramolecular heterosynthon to be reliable and useful in a predictable manner. The crystal structure of anhydrous ellagic acid reveals linear chains of ellagic acid molecules (established by forming a catechol dimer), crosslinked via OH···O=C(lactone) interaction and reinforced by π-stacking interactions. The DMA
and NMP solvates of ellagic acid suggest that tertiary amides are perhaps better hydrogen bond acceptors than lactones. The crystal structures of the cocrystal solvates highlight the
synergistic cooperation exhibited among the phenol-pyridine supramolecular
heterosynthon, phenol-imidazole supramolecular heterosynthon and the phenol-carbonyl
supramolecular heterosynthon. That the solvents are included in the crystal lattice,
despite the phenol-pyridine supramolecular heterosynthon and phenol-imidazole
supramolecular heterosynthon playing a critical role in the self-assembly of the cocrystal
solvates, implies that the phenol-carbonyl supramolecular heterosynthon is robust,
especially when there is an excess of hydrogen bond donors such as in the presence of a
polyphenol. The synergism demonstrated between the phenol-pyridine supramolecular
heterosynthon and phenol-imidazole supramolecular heterosynthon with the phenol-
carbonyl supramolecular heterosynthon (in the cocrystal solvates) suggests the possibility
of a ternary cocrystal and adds another level of complexity to the possible structures that
can be constructed.
In conclusion, the crystal forms (cocrystals, cocrystal solvates/hydrates and
solvates) of ellagic acid are achieved by a variety of supramolecular heterosynthons
69 formed between polyphenols with pyridines, imidazoles, pyrazole, carboxylates and carbonyl moieties. The propensity of polyphenolic molecules to engage in molecular recognition events, leading to the formation of supramolecular heterosynthons, has been the subject of intense scrutiny. The delineation of supramolecular synthons into a hierarchy has undoubtedly unleashed the power of the supramolecular heterosynthon approach to the crystal engineering of cocrystals. The synergism exhibited among supramolecular heterosynthons is a coveted attribute in a hydrogen bonding cooperative environment. That APIs routinely contain multiple functional groups enables polyphenols to play a role as cocrystal formers in the crystal form screening of APIs. This information is relevant to the pharmaceutical, food and nutrition industry in their crystal form screening since polyphenols are found in a variety of food sources (tea, wine, fruits) with known toxicology profile. Indeed, the range of pharmaceutically acceptable cocrystal formers available for crystal form screening would be considerably broadened if polyphenols were to be included in cocrystal former libraries.
3.4 Materials and Methods
Ellagic acid dihydrate was purchased from TCI America (Lot. 6LHXG) and used as received. Ellagic acid dihydrate from other suppliers may not reproduce these results if they are not easily soluble in pyridine, DMA and NMP.
70
3.4.1 Synthesis of Crystal Forms of Ellagic Acid
ELANAM: Ellagic acid dihydrate (20.0 mg, 0.06 mmol) was dissolved in 0.5 mL
of NMP with heat. Nicotinamide (144.0 mg, 11.8 mmol) was dissolved in 0.5 mL of
deionised water with heat. The contents were mixed and left for slow evaporation.
Yellow plate-like crystals (15.6 mg, 288°C) were harvested after a week.
ELAINM•1.7H2O: Ellagic acid dihydrate (20.0 mg, 0.06 mmol) was dissolved in
2 mL of DMA. Isonicotinamide (290 mg, 2.37 mmol) was dissolved in 1 mL of deionised
water. Both contents were mixed to give a light brown solution and left for slow
evaporation. Yellow plate-like crystals (18.1 mg, mp 300°C) were harvested after one
month.
ELAINM•4NMP: Ellagic acid dihydrate (20.0 mg, 0.06 mmol) and isonicotinamide (80.0 mg, 0.66 mmol) were dissolved in 1 mL of NMP with heat. The yellow solution was left for slow evaporation. Yellow crystals (16.6 mg, 290°C) were harvested overnight.
ELACAF•H2O: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) and caffeine
(29.0 mg, 2.37 mmol) were added to 5 mL of (±)1,2-propanediol/ethanol (6:4 volume
ratio) and heated on a hotplate until boiling occurred. The contents were cooled to room
temperature and filtered to obtain a yellow solution. The solution was left to stand.
Yellow oval plate-like crystals (3.9 mg, mp, 300°C) were harvested after a week.
ELATPH•0.13H2O: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) and anhydrous
theophylline (27.0 mg, 0.15 mmol) were added to 5 mL of ethanol with heat until boiling
71
occurred. The contents were cooled to room temperature and filtered to obtain a yellow
solution. The solution was left for slow evaporation. Yellow plate-like crystals (11.1 mg,
326°C) were harvested the next day.
ELATPH•2DMA: Ellagic acid dihydrate (50.0 mg, 0.15 mmol) and and anhydrous theophylline (134.0 mg, 0.75 mmol) were dissolved in 2 mL of DMA with heat. The solution was left for slow evaporation. Yellow plate-like crystals (63.7 mg,
326°C) were harvested after a week.
ELADMP: Ellagic acid dihydrate (5.0 mg, 0.015 mmol) was dissolved in 5 mL of hot (±)PG. 3,5-dimethylpyrazole (143.0 mg, 15 mmol) were added. The solution was left for slow evaporation. Yellow needle-like crystals (2.9 mg, 237°C) were harvested after one month.
ELASAR: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) was dissolved in 5 mL of hot methanol. Sarcosine (10.0 mg, 0.11 mmol) was dissolved in 5 mL of hot methanol.
Both contents were mixed to give a yellow solution and left for slow evaporation. Yellow plate-like crystals (6.5 mg, 320oC) were harvested after two days.
ELADMG: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) was dissolved in 5 mL of hot methanol. N,N-dimethylglycine (10.0 mg, 0.11 mmol) was dissolved in 5 mL of hot methanol. Both contents were mixed to give a yellow solution and left for slow evaporation. Yellow plate-like crystals (5.6 mg, 293°C) were harvested after two days.
ELACAP: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) and ε-caprolactam
(268.0 mg, 2.37 mmol) were added to 5 mL of isopropanol with heat. The content was
72 filtered to obtain a yellow solution. It was allowed to slowly evaporate at room temperature. Yellow triangular plate-like crystals (6.2 mg, 276°C) were harvested after a month.
ELAURE•2NMP: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) and urea
(27.0 mg, 0.45 mmol) were dissolved in 2 mL NMP/H2O (1:1 volume ratio) with heat.
The solution was left to stand in air. Yellow block crystals (9.3 mg, 200°C) were harvested after a week.
ELADMA4: Ellagic acid dihydrate (50.0 mg, 0.15 mmol) was dissolved in 1 mL of DMA. The brown solution was left for slow evaporation. Colourless block crystals
(45.0 mg) were harvested after a week.
ELADMA2: Ellagic acid dihydrate (20.0 mg, 0.06 mmol) and oxalic acid
(107.0 mg, 1.18 mmol) was dissolved in 1 mL of DMA with heat. The brown solution was left to stand in air. Yellow block crystals (10.2 mg) were harvested after a week.
ELADMSO2: Ellagic acid dihydrate (10.0 mg, 0.03 mmol) was dissolved in 1 mL of DMSO with heat. The brown solution was left for slow evaporation. Yellow plate-like crystals (9.9 mg) were harvested after three days.
ELANMP2: Ellagic acid dihydrate (50.0 mg, 0.15 mmol) was dissolved in 1 mL of NMP. The brown solution was left for slow evaporation. Yellow plate-like crystals
(42.0 mg) were harvested after a week.
73
ELAPG2: Ellagic acid dihydrate (10.0 mg, 0.15 mmol) was dissolved in 2 mL of
(±)PG with heat. The yellow solution was filtered and left for slow evaporation. Yellow
block crystals (5.0 mg) were harvested after a week.
3.4.2 Crystal Form Characterization
Single crystals suitable for X-ray diffraction were selected using an optical microscope. The X-ray diffraction data were collected using Bruker-AXS
SMART-APEX/APEXII CCD diffractometer with monochromatized Cu Kα radiation (λ
= 1.54178Å) for all crystal samples, except for ELATPH•0.13H2O with
monochromatized Mo Kα radiation (λ = 0.71073Å). Indexing was performed using
SMART v5.62537a or using APEX 2008v1-0.37b Frames were integrated with SaintPlus
7.5138 software package. Absorption correction was performed by multiscan method
implemented in SADABS. The structures were solved using SHELXS-97 (Direct
methods) and refined using SHELXL-97 (full matrix nonlinear least-squares) contained
in SHELXTL v6.1040 and WinGX v1.70.0141-43 program packages. All non-hydrogen
atoms were refined anisotropically.
A Bruker AXS D8 X-ray powder diffractometer was used for all PXRD
measurements with experimental parameters as follows: Cu Kα radiation (λ = 1.54056 Å);
40 kV and 30 mA; detector type: scintillation type; scanning interval: 3° - 40° 2θ; time
per step: 0.5 s. The experimental PXRD patterns and calculated PXRD patterns from
single crystal structures were compared to confirm the composition of bulk materials.
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Thermal analysis was performed on a TA Instruments DSC 2920 differential scanning calorimeter. Aluminum pans were used for all samples and the instrument was
calibrated using an indium standard. For reference, an empty pan sealed in the same way
as the sample was used. Using inert nitrogen conditions, the samples were heated in the
DSC cell from 30°C to 350°C at a rate of 10°C/min.
A Perkin-Elmer STA 6000 Simultaneous Thermal Analyzer was used to conduct thermogravimetric analysis. Open alumina crucibles were used to heat the samples from
30°C to 350°C at a rate of 10°C/min under a nitrogen stream.
Characterization of the cocrystals by fourier transform infrared spectroscopy
(FTIR) was accomplished with a Nicolet Avatar 320 FT-IR instrument. Sample amounts of 1-2 mg were used, and spectra were measured over the range of 4000-400 cm-1 and
analyzed using EZ Omnic software.
75
Table 3-5. Selected hydrogen bond parameters for ellagic acid cocrystals.
Compound Hydrogen bond d (H···A) / Å D (D···A) / Å θ / ° N(7)-H(71)•••O(7)#2 2.17 3.044 (7) 176.5 N(7)-H(72)•••O(15) 2.07 2.939 (7) 169.1 ELANAM O(17)-H(17)•••N(1)#3 1.59 (6) 2.634 (5) 174 (5) O(11)-H(11)•••O(7)#2 1.85 2.694 (6) 179.3 #1 -x,-y,-z #2 -x+1,-y,-z+2 #3 x-1/2,-y+1/2,z-3/2 O(2)-H(2)•••N(1)#3 1.58 (5) 2.588 (4) 163 (4) ELADMP N(2)-H(1)•••O(4)#2 1.90 (5) 2.973 (4) 173 (4) #1 -x+2,-y+1,-z+1 #2 x,-y+1/2,z-1/2 #3 x,-y+1/2,z+1/2 N(1)-H(1N)•••O(7) 1.99 (2) 2.905 (3) 163 (3) N(1)-H(2N)•••O(8)#1 2.24 (2) 3.006 (3) 142 (3) O(6)-H(6)•••O(10)#2 1.79 2.595 (3) 160.6 ELASAR O(7)-H(7)•••O(9)#3 1.80 2.594 (2) 156.7 O(8)-H(8)•••O(9)#4 1.93 2.714 (2) 154.5 #1 x,y,z+1 #2 x,y-1,z-1 #3 -x,-y+1,-z+1 #4 -x,-y+1,-z O(5)-H(3)•••O(10)#1 1.72 (2) 2.649 (1) 174 (2) O(6)-H(4)•••O(9)#2 1.86 (2) 2.682 (1) 157 (2) O(1)-H(1)•••O(9)#3 2.17 (2) 2.903 (2) 149 (2) ELADMG O(2)-H(2)•••O(10)#4 1.63 (2) 2.587 (1) 170 (2) N(1)-H(5)•••O(5)#5 2.09 (2) 2.887 (2) 144 (2) #1 -x+1/2,-y+1/2,-z #2 x,y+1,z #3 x+1/2,y+1/2,z #4 -x+1,-y+1,-z #5 -x+1/2,y-1/2,-z+1/2 O(11)-H(11)•••O(1) 1.96 (11) 2.724 (9) 160 (11) N(1)-H(1N)•••O(17)#2 2.15 (11) 2.903 (10) 130 (8) ELACAP O(12)-H(12)•••O(1)#4 1.98 (8) 2.696 (9) 171(9) #1 -x+1,-y+1,-z+1 #2 x-1/2,-y-1/2,z-1/2 #3 -x+1/2,y-1/2,-z+1/2 #4 -x+1/2,y+1/2,-z+1/2
76
Table 3-6. Selected hydrogen bond parameters for ellagic acid cocrystal solvates/hydrates.
d (H···A) / D (D···A) / Compound Hydrogen bond θ / ° Å Å O(3)-H(3)•••O(11)#1 1.91 2.749 (2) 177.1 O(4)-H(4)•••N(11) 1.86 2.611 (2) 147.8 ELAINM•1.7H2O N(12)-H(12N)•••O(1)#2 2.03 (3) 2.930 (3) 174 (3) N(12)-H(13N)•••O(11)#3 2.06 (3) 2.988 (3) 173 (3) #1 -x-1,-y+1,-z #2 -x,-y+1,-z+1 #3 -x-2,-y+2,-z N(4)-H(16)•••O(7)#4 2.01 (5) 2.923 (4) 176 (5) O(4)-H(17)•••N(3)#3 1.78 (6) 2.647 (4) 147 (5) ELAINM•4NMP N(4)-H(10)•••O(1)#2 1.97 (5) 2.827 (5) 166 (4) O(3)-H(15)•••O(2)#3 1.72 (6) 2.615 (4) 166 (5) #1 -x+2,-y+1,-z+1 #2 x+1,y,z+1 #3 x-1,y,z #4 1-x,2-y,2-z N(2)-H(2A)•••O(1)#2 2.04 2.895 (3) 172.4 N(2)-H(2B)•••O(51) 2.01 2.792 (7) 150.2 ELAINM•4DMA O(3)-H(3)•••N(1) 1.916 (2) 2.647 (3) 148.1 (1) O(4)-H(4)•••O(6) 1.790 (2) 2.608 (3) 177.3 (1) #1 -x+1,-y+1,-z+2 #2 -x,-y+2,-z+1 O(2)-H(2)•••N(4)#1 1.93 2.702 (4) 151.7 O(4)-H(4)•••O(6)#2 1.90 2.708 (3) 161.3 O(7)-H(7)•••O(1W)#3 1.78 2.608 (3) 167.2 ELACAF•H2O O(8)-H(8)•••O(5)#4 1.93 2.701 (3) 152.4 O(1W)-H(1W)•••O(3)#3 2.08 (2) 2.920 (4) 164 (4) O(1W)-H(2W)•••O(9) 1.99 (2) 2.854 (4) 162 (4) #1 x+1,y,z-1 #2 x,y,z-1 #3 x-1,y,z #4 x,y+1,z N(4)-H(4)•••O(4)#2 1.80 (2) 2.714 (2) 169 (2) O(11)-H(111)•••O(2)#3 1.86 (3) 2.757 (2) 171 (2) ELATPH•0.13H2O O(12)-H(121)•••N(3)#4 1.82 (4) 2.711 (2) 166 (3) #1 -x+1,-y,-z+1 #2 -x+2,-y,-z+2 #3 -x+1/2,y-1/2,-z+3/2 #4 -x+1,-y,-z+2 O(3)-H(3)•••N(13)#2 2.09 2.849 (3) 154.7 O(4)-H(4)•••O(21)#3 1.75 2.548 (4) 165.6 ELATPH•2DMA N(14)-H(14A)•••O(11)#4 1.95 2.804 (3) 170.0 #1 -x+2,-y+1,-z+1 #2 x-1,y,z #3 x,y-1,z #4 -x+1,-y,-z
77
O(2)-H(2)•••O(11)#1 1.81 (6) 2.543 (5) 169 (7) O(6)-H(11)•••O(12)#2 1.99 (7) 2.684 (4) 160 (7) O(5)-H(10)•••O(10)#3 1.39 (8) 2.581 (4) 166 (7) O(1)-H(1)•••O(9)#4 2.05 (6) 2.657 (5) 164 (7) N(3)-H(3A)•••O(11)#5 2.061 (3) 2.899 (6) 164.6 (3) ELAURE•2NMP N(4)-H(4B)•••O(6)#5 2.348 (3) 2.983 (5) 130.9 (3) N(3)-H(3B)•••O(8)#5 2.256 (3) 3.058 (5) 155.4 (3) N(2)-H(2A)•••O(12) 2.064 (3) 2.922 (5) 175.9 (3) N(1)-H(1A)•••O(12)#3 2.248 (3) 2.959 (6) 139.9 (3) #1 x,1+y,z #2 x,-1+y,z #3 -1+x,y,z #4 1-x,1-y,-z #5 1-x,-y,-z
Table 3-7. Selected hydrogen bond parameters for ellagic acid solvates.
d (H···A) / D (D···A) / Compound Hydrogen bond θ / ° Å Å O(3)-H(20)•••O(2)#2 1.70 2.5770 (16) 170.4 ELADMA4 O(4)-H(21)•••O(1)#2 2.01 2.6148 (16) 129.9 #1 -x,-y+2,-z #2 -x+1,y+1/2,-z+1/2 O(1)-H(1)•••O(5)#2 1.83 2.6696 (14) 172.8 ELADMA2 O(2)-H(2)•••O(5) 2.08 2.8393 (14) 149.9 #1 -x,-y+2,-z+2 #2 -x+1,-y+1,-z+2 O(11)-H(11)•••O(1)#2 1.87 (5) 2.674 (3) 169 (5) ELADMSO2 O(12)-H(12)•••O(1)#3 1.97 (5) 2.695 (3) 153 (5) #1 -x+1,-y+2,-z+1 #2 x+1,y,z #3 -x+2,-y+1,-z+1 O(1)-H(1)•••O(5)#2 2.09 (6) 2.745 (4) 150 (6) ELANMP2 O(2)-H(2)•••O(5)#3 2.01 (6) 2.697 (4) 172 (8) #1 -x+1,-y,-z #2 x,y+1,z #3 -x+1/2,y+1/2,-z+1/2 O(21)-H(21)•••O(14)#2 1.99 (5) 2.734 (3) 166 (5) O(12)-H(12)•••O(22)#3 1.84 (5) 2.660 (3) 164 (4) ELAPG2 O(11)-H(11)•••O(21)#4 1.75 (5) 2.602 (3) 171 (5) #1 -x+1,-y+1,-z #2 x,y+1,z #3 x+1,y-1,z #4 x+1,y,z
78
Table 3-8. Crystallographic data for ellagic acid cocrystals.
ELANAM ELADMP ELASAR ELADMG ELACAP Formula C26H18N4O10 C24H22N4O8 C17H13NO10 C18H15NO10 C26H28N2O10 MW 546.44 494.46 391.28 405.31 528.51 Crystal Monoclinic Monoclinic Triclinic Monoclinic Monoclinic system Space group P21/n P21/c P1 C2/c P21/n a (Å) 7.035 (3) 4.9393 (6) 7.6115 (2) 20.7781 (4) 12.452 (3) b (Å) 22.963 (6) 18.155 (2) 9.4592 (2) 12.4012 (2) 6.0627 (15) c (Å) 7.290 (2) 12.1795 (12) 11.5037 (3) 13.0557 (2) 15.624 (4) (deg) 90 90 105.294 (2) 90 90 (deg) 106.50 (2) 93.451 (7) 109.068 (2) 107.333 (1) 91.562 (10) (deg) 90 90 91.848 (2) 90 90 V /Å3 1129.2 (6) 1090.2 (2) 748.69 (3) 3211.34(9) 1179.1 (5) -3 Dc/mg m 1.607 1.506 1.736 1.677 1.489 Z 2 2 2 8 2 3.85 to 4.38 to 4.25 to 4.20 to 4.48 to 2 range 39.04 68.14 63.65 65.08 42.87 Nref./Npara. 623 / 172 1916 / 178 2369 / 263 2695 / 285 753 / 212 T /K 100 (2) 100 (2) 100 (2) 100 (2) 100 (2) R 1 0.0375 0.0636 0.0431 0.0313 0.0515 [I>2sigma(I)]
wR2 0.0771 0.1404 0.1032 0.0844 0.1346 GOF 1.011 1.002 1.001 1.030 1.065 Abs coef. 1.077 0.972 1.269 1.206 0.974
79
Table 3-9. Crystallographic data for ellagic acid cocrystal solvates/hydrates.
ELAINM ELAINM ELAINM ELACAF
•1.7H2O •4NMP •4DMA •H2O Formula C26H21.4N4O11.7 C46H54N8O14 C42H54N8O14 C22H18N4O11 MW 574.65 942.97 894.93 514.40 Crystal system Triclinic Triclinic Triclinic Triclinic Space group P1 P1 P1 P1 a (Å) 3.6207 (2) 6.6365 (2) 6.6402 (4) 9.705(3) b (Å) 12.4908 (6) 10.6281 (3) 10.4995 (6) 10.926(5) c (Å) 13.5227 (6) 16.1445 (4) 16.2469 (8) 11.469(7) (deg) 72.641 (3) 87.391 (2) 86.469 (3) 104.74(3) (deg) 89.258 (3) 87.722 (2) 86.959 (3) 95.68(3) (deg) 83.979 (3) 78.243 (2) 78.012 (3) 113.80(3) V /Å3 580.39 (5) 1113.14 (5) 580.39 (5) 1047.9 (9) -3 Dc/mg m 1.644 1.407 1.345 1.630 Z 1 1 1 2 2 range 3.42 to 65.36 2.74 to 67.72 2.73 to 68.33 4.09 to 65.36 Nref./Npara. 1916 / 210 3735 / 395 3710 / 354 3301 / 349 T /K 100(2) 100(2) 100(2) 100(2) R1 [I>2sigma(I)] 0.0439 0.0798 0.0593 0.0549 wR2 0.1093 0.2067 0.1638 0.1380 GOF 1.037 1.052 1.052 1.013 Abs coef. 1.136 0.881 0.855 1.150 ELATPH ELATPH ELAURE •0.07H2O •2DMA •2NMP Formula C28H2N8O12.13 C36H40N10O14 C52H64N12O24 MW 664.62 836.75 620.57 Crystal system Monoclinic Triclinic Triclinic Space group P21/n P1 P1 a (Å) 11.636 (3) 4.543 (3) 7.1468 (7) b (Å) 6.8183 (19) 12.373 (6) 13.1766 (11) c (Å) 16.868 (5) 17.486 (8) 14.7365 (12) (deg) 90 104.923 (8) 88.038 (5) (deg) 95.607 (6) 94.003 (13) 79.457 (6) (deg) 90 93.217 (12) 86.578 (6) V /Å3 1331.9 (6) 944.6 (8) 1361.5 (2) -3 Dc/mg m 1.657 1.471 1.514 Z 2 1 2 2 range 2.04 to 25.03 2.63 to 65.49 3.05 to 67.71 Nref./Npara. 2339 / 271 3207 / 296 4548 / 416 T /K 100(2) 100(2) 100 (2) R1 [I>2sigma(I)] 0.0474 0.0576 0.0916 wR2 0.1108 0.1438 0.1966 GOF 1.099 1.013 1.459 Abs coef. 0.133 0.979 1.035
80
Table 3-10. Crystallographic data for ellagic acid solvates.
ELADMA4 ELADMA2 ELADMSO2 ELANMP2 ELAPG2 Formula C30H42N4O12 C22H24N2O10 C18H18O10S2 C24H24N2O12 C20H22O12 MW 650.68 476.43 458.44 500.46 454.38 Crystal Monoclinic Triclinic Triclinic Monoclinic Triclinic system Space group P21/c P1 P1 P21/n P1 a (Å) 11.2531 (1) 7.0277 (1) 5.040 (2) 12.7369 (6) 5.0201 (4) b (Å) 7.9074 (1) 7.8128 (1) 10.095 (5) 6.1858 (3) 7.2345 (5) c (Å) 18. 9832 (3) 10.8493 (2) 10.304 (4) 14.1230 (8) 13.8053 (10) (deg) 90 90.697 (1) 71.61 (3) 90 74.893 (5) (deg) 109.448 (1) 107.440 (1) 77.13 (3) 96.182 (4) 87.069 (5) (deg) 90 113.140 (1) 76.07 (3) 90 77.273 (6) V /Å3 1592.80 (4) 516.822 (14) 476.7 (3) 1106.25 (10) 472.15 (6) -3 Dc/mg m 1.357 1.531 1.597 1.502 1.598 Z 2 1 1 2 1 2 range 4.17 to 68.23 4.32 to 66.26 4.58 to 65.03 4.44 to 65.63 3.32 to 63.64 Nref./Npara. 2843 / 214 1716 / 159 1520 / 146 1878 / 172 1459 / 162 T /K 100 (2) 100 (2) 100 (2) 100 (2) 100 (2) R 1 0.0460 0.0374 0.0440 0.0687 0.0464 [I>2sigma(I)] wR2 0.1279 0.1077 0.1066 0.2169 0.1058 GOF 1.088 1.106 1.025 1.389 1.060 Abs coef. 0.887 1.041 3.065 1.005 1.157
81
Chapter 4. Ionic Cocrystals: Crystal Forms of Lithium Salts
4.1 Preamble
Bipolar disorder138 affects more than one percent of the population, is a disabling
mental illness characterized by alternating “mood swings” between periods of elevated or
irritable mood (mania) and periods of depression. These mood swings can be very abrupt with occasional suicidal tendencies. There are three types of bipolar disorder (type I, II and cyclothymic), differing only in the severity of the mood swings. Type I involves at least one manic or mixed episode (mania and depression occurring simultaneously) and one or more depressive episodes, that lasts for at least 7 days in a regular alternating pattern. Untreated patients average 4 episodes of mood swings each year with untreated mania lasting at least one week to months while depressive episodes can last 6 to 12 months. Type II involves major depressive episodes with occasional hypomania episodes, lasting at least 4 days. Patients suffer from significantly more depressive episodes with shorter periods of well-being between episodes compared to type I patients, leading to a higher risk for suicidal tendencies. Cyclothymic disorder is less severe compared to types
I and II but is more chronic. It can deteriorate to type I or II in some patients or remain a mild chronic condition. In addition, there is bipolar disorder not otherwise specified
(NOS) that does not fit into the three categories and bipolar disorder with rapid cycling.
Bipolar disorder with rapid cycling is a temporary condition with at least 4 rapid alternating manic, hypomania or depressive episodes in a year.139
82
Lithium (especially carbonate and citrate salts) remains the “gold standard” for
the treatment of bipolar disorder and the prevention of relapses in patients.140 Further, it is
the only medication that consistently reduces suicidality in recurrent unipolar major
depressive disorder and in bipolar disorder.141 Lithium is readily absorbed from the gastrointestinal tract and attains its maximum concentration between ½ to 3 hours.
However, lithium treatment suffers from a narrow therapeutic index with a therapeutic
serum level between 0.5 mM to 1.5 mM. Lithium intoxication occurs with a serum level
of ≥ 2.0 mM. Animal studies with adult male Sprague-Dawley rats indicate lithium takes
about 2 hours (Tmax) to achieve maximum serum concentration (Cmax) but 24 hours for
maximum brain concentration.142 That lithium experiences difficulty in crossing the
blood brain barrier coupled with the narrow therapeutic index, means any patient on
lithium treatment for bipolar disorder must be monitored constantly to guard against
lithium intoxication. From a clinical perspective, the Cmax in blood serum should best be
quickly followed by the Cmax in brain, i.e., the time difference between the Tmax for blood serum and brain should be minimal.
4.1.1 Amino acids as the ideal cocrystal formers
A pharmaceutical cocrystal143 is a cocrystal in which a pharmaceutically
acceptable cocrystal former forms a supramolecular synthon48 with an API. That there are
active transporters to facilitate the movement of amino acids across the blood brain barrier144 implies that intuitively, amino acids may be the appropriate cocrystal formers to target ionic cocrystals145 of lithium salts. Furthermore, amino acids as dipolar zwitterions
83
are ideally suited to engage the lithium cation via the negatively-charged carboxylate
while the positively-charged ammonium interact with the counteranion, thus segregating
the lithium cation from its counteranion by acting as a spacer. In an aqueous
environment, the carboxylic acid moiety of the amino acid undergoes deprotonation
readily with simultaneous protonation of the amine moiety. In essence, the amino acid is
a zwitterion that is dipolar with a positive-charged ammonium group and a negative-
charged carboxylate moiety and has a total net charge of zero. The carboxylate moiety
will bind strongly to the lithium cation due to its oxophilic character, leaving the
ammonium group to hydrogen bond with the counteranion. Lithium chloride is the
primary objective since the chloride anion is abundant in stomach acid. In addition, other
pharmaceutically acceptable anions such as bromide and nitrate will also be studied.
- - - 4.1.2 CSD survey of ionic cocrystals of LiX (X = Cl , Br and NO3 ) and amino
acids
The coordination chemistry of the lithium146 cation has been reviewed to provide
in-depth analysis of the bond length, geometry, coordination number and solvent of
crystallization of lithium complexes based on X-ray crystallographic data. The
coordination numbers of lithium complexes range from 4 to 8. But it prefers the 4-
coordinate tetrahedral coordination mode which is the most frequently encountered. The
lithium cation is defined as a hard acid.147-149 Thus lithium cations are expected to bond to the oxygen atoms of ligands. A survey of the Cambridge Structural Database (CSD) on
lithium chloride/bromide/nitrate complexes with amino acids and peptides reveals the
84 coordination of the bridging carboxylates onto lithium cations while hydrogen bonding interaction between the anions and the ammonium groups serves to reinforce the crystal packing forces.
Table 4-1. Ionic cocrystals of lithium salts from the CSD.
Lithium Salt Amino Acid Lithium: Amino CSD Refcode Acid Stoichiometry Glycine 1:1 HEFWUK150 LiCl GLY-GLY 1:1 HEFXEV150 L-proline 1:1 YOXBET151 ALA-GLY 1:1 ALGLYL152 LiBr GLY-GLY 1:1 GLYGLB GLY-GLY-GLY 1:1 GLYLIB 153 LiNO3 Glycine 1:1 ALUNEA Glycine 1:2 ROZTUW154
Figure 4-1. A chain of fused six-atom rings in HEFWUK (top) and alternating eight-atom and four-atom rings in ALUNEA (bottom). 85
Analysis of these crystal structures reveals the lithium cations in the 4-coordinate
tetrahedral coordination environment. The carboxylates bridge adjacent lithium cations to
form either a chain of fused six-atom rings or a chain of alternating eight-atom and four-
atom rings. This is a dominant feature in the 1:1 ionic cocrystals of lithium salts and
amino acids discussed in this chapter.
- - - 4.1.3 1:2 ionic cocrystals of LiX (X = Cl , Br and NO3 ) and amino acids as
structural analogues of zeolites and silica
The interest in developing ionic cocrystals of lithium salts is two-fold. From a materials design perspective, lithium is the lightest metal in the periodic table that prefers to adopt a 4-coordinate tetrahedral environment. The attention is drawn to zeolites
(aluminosilicates) and silica (SiO2) as manifestations of tetrahedral nodes to create a rich
diversity of 3-periodic architectures. Synthetic inorganic zeolites typically consist of
oxide anions that link tetrahedral aluminum or silicon cations (nodes) in a 2:1 ratio.155
The key to the existence of microporosity in zeolites is that the oxide linkers are angular
(M-O-M angles typically range from 140° to 165°), thereby facilitating the generation of a wide range of topologies that are based upon rings, fused rings and polyhedral cages.
86
Frequency of occurrence given in parentheses Figure 4-2. Secondary building units (SBUs) in zeolites.
Which particular topology exists for a given chemical composition is typically controlled by reaction conditions, counterions and/or structure directing agents156
(SDAs). The absence of counterions, SDAs or the use of a linear linker more typically manifests the tetrahedral node in the form of a diamondoid (dia) net157-158 that, unlike most zeolitic topologies, can interpenetrate to mitigate the creation of free space.
The ground rules for generating zeolitic and/or dia networks are therefore self- evident and they have been validated across a remarkably diverse range of tetrahedral nodes (e.g. phosphates159, transition metal cations160-162, metal clusters163) and linkers
(including purely organic ligands that form coordination bonds164 or hydrogen bonds165-
167). Coordination polymers that exploit the diversity of tetrahedral moieties and angular 87
or linear organic ligands have recently afforded new levels of scale that includes new
classes of zeolitic structures with hitherto unattainable levels of porosity. Such zeolitic
metal-organic materials are exemplified by zeolitic imidazolate frameworks168-170 (ZIFs), boron imidazolate frameworks171 (BIFs), zeolite-like metal-organic frameworks172
(ZMOFs) and the zeolite NPO sustained by metal-carboxylate clusters only (denoted as
CPM = crystalline porous material)173. ZIFs are based upon imidazolate ligands that
subtend an angle of ca. 145° whereas the prototypal ZMOFs use 4,5-imidazole-
dicarboxylate174 and pyrimidine-based ligands175-176 in the presence of SDAs to
coordinate to 8-coordinate metals such as In and Cd. BIFs are inherently of low density
because they are based upon tetrahedral boron atoms.
88
Figure 4-3. Synthetic zeolite based on imidazolates, LTA (top left), RHO, (top right), RHO (BIF-9-Li, bottom left), SOD (bottom right). Yellow spheres highlight the empty polyhedral cages.
Tetrahedral nodes are also found in several crystalline forms (polymorphs) of
silica (SiO2). Among them, quartz is the only stable form under ambient conditions.
Under normal pressure conditions, α-quartz (trigonal polymorph) converts to β-quartz
(hexagonal polymorph) at 573°C which further converts to β-tridymite (hexagonal polymorph) at 870°C. β-tridymite exhibits the rarely encountered lonsdaleite177-178 (lon)
89
net. At 1470°C, β-tridymite converts to β-cristobalite (cubic polymorph) which exhibits the dia net and finally melts at 1705°C.179 The multitude of 3-periodic architectures from zeolites and silica has been constructed from heavy atoms. That low density is a desirable property means that lithium, the lightest metal in the periodic table, is a particularly attractive target to serve as a tetrahedral node in either zeolitic or dia networks.
Figure 4-4. Polymorphs of silica, β-cristobalite (top left), β-tridymite (top right), β- quartz, (bottom left), faujasite (bottom right).
90
Lithium forms many air and water stable coordination environments and not all
existing zeolitic metal-organic materials are water stable. In this context, a prototypal
structure was reported by Pinkerton et al., who isolated a lithium-based zeolitic ABW
network with hexachlorotantalum anion embedded in what was described as a three-
dimensional Li-Cl-dioxane network180. However, this compound is extremely moisture
sensitive. Bu and coworkers addressed the challenge elegantly in BIFs by employing both
lithium and boron with imidazolates in BIF-9-Li, a compound with RHO topology181.
Other approaches to low density porous materials based upon lithium include the following: Robson et al. reported a microporous lithium isonicotinate with square channels182; Henderson and coworkers isolated a pillared bilayer and a diamondoid net
with solvated lithium aryloxides183; Parise et al. reported a MOF based on lithium and
2,5-pyridinedicarboxylic acid that loses porosity upon solvent removal184.
A new and general strategy to build lithium based zeolitic metal-organic materials
(LiZMOMs) and lithium based diamondoid metal-organic materials (LiDMOMs) by
exploiting the Li-carboxylate-Li linkages that can be formed when amino acid zwitterions
form cocrystals with lithium salts is described. The strategy described herein is based
upon generating compounds in which there is a stoichiometric ratio of one lithium cation
and two carboxylate anions. That carboxylate moieties can sustain dia nets is exemplified
in a series of divalent metal formates that naturally possess the required 2:1 ratio of linker
to node185-186. Indeed, such structures can even exhibit the rarely encountered
lonsdaleite177-178 (lon) topology. However, that lithium is monovalent means that the
requisite 2:1 ratio of linker to node will be very difficult to achieve with anionic linkers.
Again, Bu and coworkers circumvented this issue by supplementing neutral lithium
91 imidazolates with neutral bifunctional N-donor ligands.187 The charge of the linker will not be an issue by using the carboxylate moieties in amino acids, i.e. neutral zwitterions, to bridge two lithium cations. The target is a new class of compound: 2:1 cocrystals of amino acids and inorganic lithium salts. The use of amino acids provides numerous advantages and opportunities: 1) many amino acids are commercially available and they are typically inexpensive; 2) Figure 5 reveals that lithium- carboxylate-lithium angles offer the requisite diversity needed to generate a wide range of extended structures; 3) the lithium-carboxylate bond is robust even in the presence of water; 4) amino acids possess functionalized side chains that facilitates fine-tuning of the resulting structures through pre-synthetic methods; 5) the abundance of homochiral amino acids means that homochiral crystals with optical activity and bulk polarity are guaranteed; 6) most amino acids are soluble in water, therefore facilitating green synthesis; 7) the charge of the network is inverted compared to zeolites because the framework is cationic and the required counterions are anions, i.e. anion exchange becomes feasible. The remarkable range of Li-carboxylate-Li angles stems partly from the tendency of the carboxylate ligand to exhibit either endodentate or exodentate bridging modes.
92
40
30
20 Frequency
10
0 60 80 100 120 140 160 180 Li-C-Li bridging angle
Figure 4-5. Distribution of the Li-C-Li angle in crystal structures that contain lithium cations bridged by carboxylate moieties (data obtained using CSD version 5.31).
4.2 Results and Discussion
Table 4-2. Table of zwitterionic cocrystal formers.
O O O + H2 + N NH+ N O- O- O- SAR DMG BTN O O O
+H N N 3 + + - - H2 H3N O O O- BAL ABA PRO
The amino acids listed in table 4-2 are combined with lithium salts in two distinct stoichiometries to achieve a wide variety of ionic cocrystals.
93
4.2.1 1:1 ionic cocrystals of LiX and amino acids: A discrete supermolecule and
linear chains
A series of 1:1 ionic cocrystals and cocrystal hydrates of lithium salts (lithium
chloride, LIC, lithium bromide, LIB and lithium nitrate, LIN) and amino acids (sarcosine,
SAR, N,N-dimethylglycine DMG, betaine, BTN, β-alanine, BAL, 4-aminobutyric acid and L-proline, PRO) are synthesized and characterized. A discrete assembly and 1- periodic chains were obtained from these 1:1 cocrystals and cocrystal hydrates.
Figure 4-6. A chain of fused six-atom rings is observed in LICSAR.
LICSAR: The crystal structure reveals that LICSAR is a 1:1 lithium chloride and
sarcosine cocrystal monohydrate. Each lithium cation is bridged by three carboxylates
[Li-O: 1.895(12) Å, 1.932(13) Å and 1.959(13) Å] with one coordinated water molecule
[Li-O: 1.960(12) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused six-atom rings. Adjacent chains are linked by hydrogen bonding interaction
94
between the chloride anions and the ammonium groups [NH•••Cl: 3.145(5) Å and
3.114(5) Å] and OH(water) •••O(carboxylate) interaction [2.951(7) Å].
Figure 4-7. The nitrate anions coordinate to the lithium cations in LINSAR.
LINSAR: Analysis of the crystal structure reveals a 1:1 cocrystal of lithium
nitrate and sarcosine. Each lithium cation is bridged by three carboxylates [Li-O:
1.939(4) Å, 1.952(4) Å and 1.956(5) Å] with one coordinated nitrate anion [Li-O:
2.017(5) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused six-atom ring. Adjacent chains are linked by hydrogen bonding interaction between the
nitrate anions and the ammonium groups [NH•••O: 2.896(3) Å and 2.918(3) Å].
95
Figure 4-8. Li2(DMG)2 clusters are hydrogen bonded into a 1-periodic structure.
LICDMG: The X-ray structure reveals a dihydrate of a 1:1 cocrystal of lithium
chloride and N,N-dimethylglycine. Each lithium cation is bridged by the same pair of carboxylates [Li-O: 1.926(3) Å and 1.932(2) Å] with two coordinated water molecules
[Li-O: 1.909(3) Å and 1.943(3) Å] to establish a discrete supermolecular assembly.
OH(water)•••O(carboxylate) [2.7543(14) Å] interactions align these discrete units into a linear chain. The chloride anions act as hydrogen bond acceptors towards three water molecules [OH•••Cl: 3.1264(12) Å, 3.1452(12) and 3.1686(11) Å] and an ammonium group [NH•••Cl: 3.2204(12) Å] to tether adjacent chains together.
96
Figure 4-9. The nitrate anions are coordinated to the lithium cations in LINDMG.
LINDMG: The crystal structure reveals a 1:1 cocrystal of lithium nitrate and N,N- dimethylglycine.. Each lithium cation is bridged by three carboxylates [Li-O: 1.919(3) Å,
1.934(3) Å and 1.937(3) Å] with one coordinated nitrate anion [Li-O: 1.977(3) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused six-atom ring.
Adjacent chains are linked by hydrogen bonding interaction between the nitrate anions and the ammonium groups [NH•••O: 2.8349(1) Å].
Figure 4-10. An undulating chain is constructed by bridging discrete (LiCl)2·(H2O)2 clusters with betaine zwitterions.
97
LICBTN: The X-ray structure reveals a 2:1 lithium chloride and betaine cocrystal
dihydrate. Each lithium cation is coordinated by a bridging carboxylate [Li-O: 1.849(5) Å
and 1.865(6) Å], two water molecules [Li-O: 1.997(5) Å, 2.023(5) Å and 2.011(5) Å] and
a coordinated chloride anion [Li-Cl: 2.319(4) Å and 2.329(4) Å]. Two lithium cations and
two bridging water molecules form a four-atom ring cluster. The four-atom ring cluster
alternates with bridging carboxylates to form an undulating chain. Each chloride anion accepts two hydrogen bonds from bridging water molecules [OH•••Cl: 3.065(2) Å,
3.117(2) Å, 3.120(2) Å and 3.178(2) Å] to crosslink adjacent chains. Crystals of LICBTN
deliquesce within minutes and do not allow further analysis to be possible.
Figure 4-11. A chain of fused alternating eight-atom rings and four-atom rings in LICBAL-anhydrate.
LICBAL-anhydrate: X-ray analysis reveals a 1:1 cocrystal of lithium chloride and
β-alanine. Each lithium cation is bridged by three carboxylates [Li-O: 1.915(3) Å,
1.920(3) Å and 1.942(3) Å] with a coordinated chloride anion [Li-Cl: 2.304(3) Å] to attain tetrahedral coordination environment. An eight-atom ring is constructed from two 98
lithium cations and two bridging carboxylates. Adjacent eight-atom rings are connected by forming a four-atom ring to yield a chain. Adjacent chains are linked by hydrogen bonding interaction between the ammonium groups with chloride anions [NH•••Cl:
3.1983(14) Å and 3.2433(14) Å] and adjacent carboxylates [NH•••O: 2.8251(17) Å].
Figure 4-12. Water molecules coordinate to the lithium cations in LICBAL.
LICBAL: The crystal structure reveals a 1:1 lithium chloride and β-alanine
cocrystal monohydrate. Each lithium cation is bridged by three carboxylates [Li-O:
1.928(3) Å, 1.933(3) Å and 1.943(3) Å] with one coordinated water molecule [Li-O:
2.002(3) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused
six-atom rings. Adjacent chains are linked by hydrogen bonding interaction between the
chloride anions and the ammonium groups. Each chloride anion acts as hydrogen bond
acceptors towards two water molecules [OH•••Cl: 3.1262(17) Å and 3.2458(14) Å] and
two ammonium groups [NH•••Cl: 3.222(2) Å and 3.2475(15) Å].
99
Figure 4-13. The chloride anions are coordinated to the lithium cations in LICABA.
LICABA: Analysis of the crystal structure reveals a 1:1 cocrystal of lithium
chloride and 4-aminobuytric acid. Each lithium cation is bridged by three carboxylates
[Li-O: 1.900(3) Å, 1.965(3) Å and 1.976(3) Å] with one coordinated chloride anion [Li-
Cl: 2.289(2) Å] to achieve the tetrahedral coordination geometry. It forms a chain of fused six-atom rings. Adjacent chains are crosslinked by hydrogen bonding interaction
between the ammonium groups acting as hydrogen bond donors towards neighbouring
chloride anions [NH•••Cl: 3.1516(13) Å and 3.1886(13) Å] and adjacent carboxylates
[NH•••O: 2.7970(16) Å].
LICPRO: The crystal structure reveals a 1:1 lithium chloride and L-proline cocrystal monohydrate. Each lithium cation is bridged by three carboxylates [Li-O:
1.956(5) Å, 1.962(7) Å and 1.993(8) Å] with one coordinated water molecule [Li-O:
100
1.996(5) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused six-atom rings. Adjacent chains are crosslinked by hydrogen bonding interaction between
the chloride anions and the ammonium groups. Each chloride anion acts as hydrogen
bond acceptors towards two water molecules [OH•••Cl: 3.194(3) Å and 3.234(3) Å] and
two ammonium groups [NH•••Cl: 3.187(3) Å].
Figure 4-14. A chain of fused six-atom rings in LICPRO (top) and LIBPRO (bottom).
101
LIBPRO: X-ray analysis reveals a monohydrate of 1:1 cocrystal of lithium
bromide and L-proline. Each lithium cation is bridged by three carboxylates [Li-O:
1.937(4) Å, 1.941(4) Å, 1.950(5), 1.970(6) and 1.987(6) Å] with one coordinated water molecule [Li-O: 1.939(4) Å and 1.971(4) Å] to fulfill the 4-coordinate tetrahedral environment. It forms a chain of fused six-atom rings. Adjacent chains are linked by hydrogen bonding interaction between the bromide anions and the ammonium groups.
Each bromide anion acts as hydrogen bond acceptors towards two water molecules
[OH•••Br: 3.312(3) Å, 3.322(3) Å, 3.345(3) Å and 3.353(3) Å] and two ammonium groups [NH•••Br: 3.277(3) Å, 3.289(3) Å and 3.326(3) Å].
Figure 4-15. An adamantane cage (left) is constructed with L-proline zwitterions and nitrate anions as bridging ligands, hexagonal channels in the dia net (right) are occupied by the pyrrolidinium ring of the zwitterions to mitigate interpenetration.
LINPRO: The X-ray structure reveals a 1:1 lithium nitrate and L-proline cocrystal.
Each lithium cation is bridged by two carboxylates [Li-O: 1.882(3) Å and 1.888(3) Å]
102
and two nitrate anions [Li-O: 1.974(3) Å and 1.998(3) Å] to form a neutral mixed ligand
dia net with distorted hexagonal channels exhibiting diameters ranging from 5.095 Å to
9.288 Å, populated by the pyrrolidinium ring of the zwitterions [figure 4-15(right)]. The
framework is reinforced by hydrogen bonding between the ammonium of an amino acid
with an adjacent carboxylate [N-H···O: 2.898(2) Å] of another amino acid and a
neighbouring nitrate anion [N-H···O: 2.842(2) Å]. The presence of pairs of zwitterions in
these hexagonal channels interacting with the framework renders interpenetration
impossible.
4.2.2 1:2 ionic cocrystals of LiX and amino acids: Square grids, Diamondoids and
a Zeolitic ABW net
In principle, 1:2 cocrystals of lithium salts and amino acids fit the criteria for
formation of dia and/or zeolitic frameworks. However, another structural feature of zeolites is the presence of one or more rings, typically 4-, 6- or 8-membered MnOn rings.
4-membered Li4(carboxylate)4 rings have previously been observed in a 1:2 cocrystal of
lithium nitrate and glycine demonstrating a square grid network154 (Refcode ROZTUW,
Li-C-Li angles 115.88°, 117.83°). With the structural prerequisites for self-assembly of zeolitic and/or dia networks in mind, a series of 1:2 ionic cocrystals of lithium salts (LIC,
LIB and LIN) and amino acids (SAR, DMG, BTN and PRO) are synthesized and characterized. Cocrystals of the desired stoichiometry were prepared by slow evaporation of aqueous solutions of LIC, LIB or LIN and two equivalents of the amino acid at ca.
80oC. These cocrystals are stable to at least 200C and are freely soluble in water.
103
Crystallographic analysis of the products revealed that three distinct networks were observed: square grids based upon only 4-membered Li4(carboxylate)4 rings; diamondoid networks based upon only Li6(carboxylate)6 rings; a zeolitic ABW network based upon 4- membered, 6-membered and 8-membered Lin(carboxylate)n (n=4, 6 and 8) rings.
(a) (b) (c)
Figure 4-16. Structural diversity in the networks formed by 1:2 cocrystals of lithium salts with amino acids: (a) square grids; (b) diamondoid LiDMOM nets; (c) zeolitic ABW topology in the first LiZMOM. Hydrogen atoms and counteranions are omitted for clarity.
Figure 4-17. Undulating square grid (left) and bilayered packing arrangement (right) in LICSAR2.
104
LICSAR2: Each lithium cation is bridged by four carboxylates [Li-O: 1.905(3) Å,
1.916(3) Å, 1.928(3) Å and 1.966(3) Å] to form an undulating square grid [figure
4.17(left)], while the opposite ends of the amino acids point away (above and below) from the square grid to establish a bilayer packing arrangement [figure 4.17(right)]. The chloride anions reside at the interface of the ammonium groups, sustained by N-H···Cl
[3.1011(1) Å, 3.1549(1) Å] interactions. These square cavities are about 5.0 Å by 6.0 Å and form undulating sheets that stack in a roughly eclipsed manner.
Figure 4-18. Undulating square grid (left) and bilayered packing arrangement (right) in LINBTN2.
LINBTN2: Each lithium cation is bridged by four carboxylates [Li-O: 1.931(3) Å,
1.933(3) Å, 1.958(3) Å and 1.973(3) Å] to form an undulating square grid [figure 4-
18(left)], while the opposite ends of the amino acids point away (above and below) from the square grid to establish a bilayer packing arrangement [figure 4-18(right)]. The nitrate anions reside at the interface of the ammonium groups, sustained by C-H···O [3.154(2) Å 105
to 3.606(2) Å] interactions. These square cavities are about 5.5 Å by 5.7 Å and form
undulating sheets that stack in a roughly eclipsed manner.
Figure 4-19. Hexagonal channels in dia nets of LICDMG2 (left) and LIBDMG2 (right).
LICDMG2: Each lithium cation is bridged by four carboxylates [Li-O distances:
1.898(3)Å and 1.910(3)Å] to form a cationic dia net with hexagonal channels exhibiting diameters ranging from 10.6 Å to 12.0 Å, populated by the chloride anions [figure 4-19
(left)]. The framework is reinforced by hydrogen bonding between the carboxylate of one amino acid and the ammonium of an adjacent amino acid [N-H···O, 2.742(2) Å]. The presence of pairs of chloride anions [C-H···Cl, 3.628(3) Å, 3.633(2) Å and 3.635(2) Å] in these hexagonal channels interacting with neighbouring methyl groups renders interpenetration impossible.
106
LIBDMG2: Each lithium cation is bridged by four carboxylates [Li-O: 1.908(3) Å and 1.942(3) Å] to form a cationic dia net with hexagonal channels exhibiting diameters ranging from 10.7 Å to 12.1 Å, populated by the bromide anions [figure 4-19(right)]. The framework is reinforced by hydrogen bonding between the carboxylate of one amino acid and the ammonium of an adjacent amino acid [N-H···O, 2.747(2) Å]. The presence of pairs of bromide anions [C-H···Br, 3.716(3) Å, 3.731(2) Å and 3.772(2) Å] in these hexagonal channels interacting with neighbouring methyl groups renders interpenetration impossible. LIBDMG2 is isostructural with LICDMG2.
LICPRO2: Each lithium cation is bridged by four carboxylates [Li-O: 1.9341(18)
Å and 1.9536(19) Å] to form a cationic dia net with hexagonal channels exhibiting diameters ranging from 10.1 Å to 12.5 Å, populated by the chloride anions [figure 4-
20(left)]. The framework is reinforced by hydrogen bonding between the carboxylate of one amino acid and the ammonium of an adjacent amino acid [N-H···O, 2.7404(15) Å].
The presence of pairs of chloride anions [N-H···Cl, 3.1322(12) Å] in these hexagonal channels interacting with neighbouring ammonium groups renders interpenetration impossible.
107
Figure 4-20. Hexagonal channels in dia nets of LICPRO2 (left) and LIBPRO2 (right).
LIBPRO2: Each lithium cation is bridged by four carboxylates [Li-O: 1.939(2) Å
and 1.974(3) Å] to form a cationic dia net with hexagonal channels exhibiting diameters ranging from 10.2 Å to 12.6 Å, populated by the bromide anions [figure 4-20(right)]. The framework is reinforced by hydrogen bonding between the carboxylate of one amino acid and the ammonium of an adjacent amino acid [N-H···O, 2.737(2) Å]. The presence of pairs of bromide anions [N-H···Br: 3.2769(15) Å] in these hexagonal channels interacting with neighbouring ammonium groups renders interpenetration impossible.
LIBPRO2 is isostructural with LICPRO2.
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Figure 4-21. Hexagonal channels in LINPRO2 (dia, top) and octagonal channels in LINPRO2 (ABW, bottom).
LINPRO2 (dia): Each lithium cation is bridged by four carboxylates [Li-O:
1.921(12) Å, 1.937(12) Å, 1.959(13) Å and 1.965(12) Å] to form a cationic dia net with hexagonal channels exhibiting diameters ranging from 10.6 Å to 12.3 Å, populated by the
109
nitrate anions [figure 4-21(top)]. The framework is reinforced by hydrogen bonding
between the carboxylate of one amino acid and the ammonium of an adjacent amino acid
[N-H···O, 2.751(5) Å, 2.762(5) Å]. The presence of pairs of nitrate anions [N-H···O,
2.741(6) Å, 2.870(6) Å, 3.046(6) Å] in these hexagonal channels interacting with
neighbouring ammonium groups renders interpenetration impossible.
LINPRO2 (ABW): A combination of Li4(carboxylate)4 and Li8(carboxylate)8 rings generate channels that lie parallel to the crystallographic a axis. When viewed down the crystallographic c axis, the presence of Li6(carboxylate)6 rings is evident. Li-O bond distances in the range of 1.913(3) Å -1.976(3) Å occur in the 4- and 8-membered rings while Li-O bond distances in the range of 1.920(2) Å -1.976(3) Å are observed in the 6- membered rings. Pairs of nitrate anions occupy the 8-membered ring channels and they
are crystallographically ordered through N-H···O hydrogen bonding interactions
[2.735(8)Å, 2.885(8)Å, 3.005(8)Å]. The dimensions of the largest 8-membered ring channel are about twice that of an ABW zeolite as illustrated in figure 4-22.
Although the ABW form of LINPRO2 is stable at elevated temperatures, it converts to the diamondoid form, LINPRO2(dia), upon standing in mother liquor under ambient conditions. Grinding of the plate-like crystals of LINPRO2(ABW) also results in conversion to LINPRO2(dia) as determined by powder X-ray diffraction (PXRD).
Interestingly, ABW zeolite has been observed as an intermediate phase in inorganic zeolite synthesis188.
110
Figure 4-22. Significant expansion of dimensions occurs because of the ditopic carboxylate linker in the ABW-type LiZMOM LINPRO2 when compared to prototypal ABW zeolite.
Whereas the Li-carboxylate bond distances observed in the structures reported
herein exhibit a relatively narrow range, the Li-carboxylate-Li angles range from 117.78o
o [Li4(carboxylate)4 ring in LICSAR2] to 180 [Li8(carboxylate)8 ring in LINPRO2(ABW)] and are detailed in Table 4-3. The majority of angles cluster around 150o, intermediate between those for linear and tetrahedral geometry, which is consistent with what would be needed to form a wider range of zeolitic structures.
111
Table 4-3. Analysis of Li-C-Li angles forming 4-, 6- and 8-membered ring motifs.
4-membered ring 6-membered ring 8-membered ring
motif motif motif LICSAR2 117.78°, 157.08° LINBTN2 122.77°, 144.37° LICDMG2 153.27° LIBDMG2 153.27° LICPRO2 156.00° LIBPRO2 155.50° LINPRO2 (dia) 154.84°, 158.77° 148.72°, 155.18°, 122.13°, 148.72°, LINPRO2 (ABW) 122.13°, 148.72° 158.97° 155.18°, 158.97° ABW 149.4°, 156.8° 156.8°, 156.9°, 180° 149.4°, 180°
4.3 Conclusion
19 crystal forms (13 cocrystals and 6 cocrystal hydrates) of lithium salts (chloride,
bromide, nitrate) have been presented herein. Hydration appears to be a phenomenon in
these ionic cocrystals, in particular, the 1:1 cocrystals. That the 1:1 cocrystals with
lithium nitrate and the 1:2 cocrystals escape hydration suggests that perhaps hydration is
predictable in this situation. Given their ubiquity, relevance and that many hydrates are
discovered due to the adventitious water molecules, it should be unsurprising that a
number of researchers have addressed the frequency189, formation190 and the water
environment of organic crystalline hydrates191-194 and crystalline hydrates have been classified according to their structure or energetics.194 Morris and Rodriguez-Hornedo195 proposed a classification system whereby hydrates are subdivided into three classes (1) channel hydrates in which water molecules interact with each other to form tunnels within the crystal lattice, (2) isolated site hydrates in which water molecules are not
112
directly hydrogen bonded to each other, (3) metal ion associated hydrates in which water
molecules form strong interactions with transition metals or alkali metals. The 1:1 cocrystal hydrates fall into the third category where water molecules are coordinated to lithium cations, as evidenced from the crystal structures. The isolation and characterization of both the anhydrate and hydrate will be advantageous to discern the hydration trend. In fact, both the anhydrate and monohydrate of LICBAL are isolable.
Whereas a coordinated chloride anion [Li-Cl: 2.304 (3) Å] is observed in the anhydrate, a water molecule displaces the chloride and coordinates to the lithium cation [Li-O:
2.002(3) Å] in the monohydrate. A comparison of the respective Li-Cl distance and Li-O distance confirms the strength of the Li-O bond over the Li-Cl bond. This is expected from the oxophilic character of the lithium cation and also explains why lithium chloride is a hygroscopic solid. The coordination sphere of lithium cations is surrounded by 4 oxygen atoms in the 1:1 cocrystals with lithium nitrate and the 1:2 cocrystals and therefore hydration cease in the solid state.
These crystal forms of lithium salts have generated a rich diversity of structure types from 0-periodic to 3-periodic. All 1:1 cocrystals are assembled into 1-periodic chains, including a discrete supermolecule that is hydrogen bonded into a chain in
LICDMG. The only exception is LINPRO which exists as a mixed ligand dia net, where the nitrate anion plays the same role of a bridging ligand as the carboxylate moiety of the zwitterion. The architectures constructed from 1:2 cocrystals feature 2-periodic and 3- periodic nets, composed of 4-, 6- and 8-membered Lin(carboxylate)n (n=4, 6, 8) rings,
reminiscent of square grids, dia nets and a zeolitic ABW net. This approach consists of
one-step synthesis from readily available starting materials and should be general because
113 of the modular nature of these compounds and the ready availability of amino acids and counteranions. The use of larger anions and/or templates coupled with the expected diversity of Li-carboxylate-Li angles will envisage a range of LiZMOMs that parallels the structural diversity seen in inorganic zeolites and zeolitic metal-organic materials.
4.4 Materials and Methods
All chemicals purchased were used as received without further purification.
4.4.1 Synthesis of Crystal Forms of Lithium Salts
LICSAR: Lithium chloride (100.0 mg, 2.36 mmol) and sarcosine (211.0 mg,
2.36 mmol) were dissolved in 0.5 mL of deionised water and left for slow evaporation.
Colourless plate-like crystals (200 mg, m.p. 245°C) were harvested after three days.
LINSAR: Lithium nitrate (413.4 mg, 6.0 mmol) and sarcosine (534.5 mg,
6.0 mmol) were dissolved in 1 mL of deionised water. It was maintained on the hot plate until crystals emerged from the hot solution. Colorless crystals (368.4 mg, 208°C) were collected from the hot solution.
LICDMG: Lithium chloride (50.0 mg, 1.18 mmol) and N,N-dimethylglycine
(122.0 mg, 1.18 mmol) were dissolved in 0.75 mL of hot deionised water. It was left for slow evaporation. Colourless block crystals (101 mg, 272°C) were harvested after one month.
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LINDMG: Lithium nitrate (413.4 mg, 6.0 mmol) and N,N-dimethylglycine
(618 mg, 6.0 mmol) were dissolved in 3 mL of hot deionised water. It was maintained on the hot plate until crystals emerged from the hot solution. Colorless plates (595 mg,
202°C) were collected from the hot solution.
LICBTN: Lithium chloride (1.00 g, 23.6 mmol) and betaine (2.76 g, 23.6 mmol) were dissolved in 1 mL of hot deionised water. . It was maintained on the hot plate until crystals emerged from the hot solution. Colorless block crystals were collected from the hot solution. The crystals were very hygroscopic and deliquesced into liquid rapidly once out of the mother liquor.
LICBAL-anhydrate: Lithium chloride (1.00 g, 23.6 mmol) and β-alanine (2.11 g,
23.6 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot plate until crystals emerged from the hot solution. Colourless rod crystals (2143 mg,
252°C) were collected from the hot solution.
LICBAL: Lithium chloride (1.00 g, 23.6 mmol) and β-alanine (2.11 g,
23.6 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot plate until crystals emerged from the hot solution. The contents were allowed to cool. The mother liquor was decanted and 0.5 mL of deionised water was added. The colourless plate crystals (1910 mg, 252°C) were harvested the next day.
LICABA: Lithium chloride (1.00 g, 23.6 mmol) and 4-aminobutyric acid (2.44 g,
23.6 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot
plate until crystals emerged from the hot solution. Colourless rod crystals (2244 mg,
241°C) were collected from the hot solution. 115
LICPRO: Lithium chloride (200.0 mg, 4.72 mmol) and L-proline (544.0 mg,
4.72 mmol) were dissolved in 0.75 mL of deionised water and left for slow evaporation.
Colourless plate crystals (609 mg, 281°C) were harvested after three days.
LIBPRO: Lithium bromide (1.00 g, 11.5 mmol) and L-proline (1.33 g, 11.5 mmol)
were dissolved in 2 mL of hot deionised water. It was maintained on the hot plate until
crystals emerged from the hot solution. Colourless block crystals (1427 mg, 280°C) were
harvested from the hot solution.
LINPRO: Lithium nitrate (413.4 mg, 6.0 mmol) and L-proline (690.0 mg,
0.599 mmol) were dissolved in 1.5 mL of deionised water and was maintained on the hot
plate until crystals emerged from the hot solution. Colorless plates (473.8 mg, 232°C)
were collected from the hot solution.
LICSAR2: Lithium chloride (0.5 g, 11.8 mmol) and sarcosine (3.15 g, 35.4 mmol)
were dissolved in 2 mL of hot deionised water. It was maintained on the hot plate until
crystals emerged from the solution. Colourless block crystals (1213 mg, 247oC) were
harvested from the hot solution.
LINBTN2: Lithium nitrate (413.4 mg, 6.0 mmol) and betaine (1405.6 mg,
12.0 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot
plate until crystals emerged from the hot solution. Colorless plates (357 mg, 286oC) were
collected from the hot solution.
LICDMG2: Lithium chloride (0.5 g, 11.8 mmol) and N,N-dimethylglycine
(2.44 g, 23.6 mmol) were dissolved in 3 mL of hot deionised water. It was maintained on
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the hot plate until crystals emerged from the hot solution. Colourless block crystals
(1488 mg) were collected from the hot solution.
LIBDMG2: Lithium bromide (0.5 g, 5.76 mmol) and N,N-dimethylglycine
(1.19 g, 11.5 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot plate until crystals emerged from the hot solution. Colourless block crystals
(696 mg, 289ºC) were collected from the hot solution.
LICPRO2: Lithium chloride (0.50 g, 11.8 mmol) and L-proline (2.72 g,
23.6 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot
plate until crystals emerged from the hot solution. Colourless block crystals (1266 mg,
250oC) were harvested from the hot solution.
LIBPRO2: Lithium bromide (0.50 g, 5.76 mmol) and L-proline (1.33 g,
11.5 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot
plate until crystals emerged from the hot solution. Colourless block crystals (861 mg,
257oC) were collected from the hot solution.
LINPRO2: Lithium nitrate (413.4 mg, 6.0 mmol) and L-proline (1381.2 mg,
12.0 mmol) were dissolved in 2 mL of hot deionised water. It was maintained on the hot
plate until crystals emerged from the hot solution. Colorless plates (LINPRO2, ABW)
were collected from the hot solution which converted to rhombohedral crystals
(LINPRO2, dia, 603 mg) once they are removed from the hot plate.
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4.4.2 Crystal Form Characterization
Single crystals suitable for X-ray diffraction were selected using an optical microscope. The X-ray diffraction data were collected using Bruker-AXS
SMART-APEX/APEXII CCD diffractometer with monochromatized Cu Kα radiation (λ
= 1.54178 Å) for all crystal samples. Indexing was performed using SMART v5.62537a
or using APEX 2008v1-0.37b Frames were integrated with SaintPlus 7.5138 software package. Absorption correction was performed by multiscan method implemented in
SADABS.39 The structures were solved using SHELXS-97 (Direct methods) and refined using SHELXL-97 (full matrix nonlinear least-squares) contained in SHELXTL v6.1040 and WinGX v1.70.0141-43 program packages. All non-hydrogen atoms were refined anisotropically.
A Bruker AXS D8 X-ray powder diffractometer was used for all PXRD measurements with experimental parameters as follows: Cu Kα radiation (λ = 1.54056 Å);
40 kV and 30 mA; detector type: scintillation type; scanning interval: 3° - 40° 2θ; time
per step: 0.5 s. The experimental PXRD patterns and calculated PXRD patterns from
single crystal structures were compared to confirm the composition of bulk materials.
Thermal analysis was performed on a TA Instruments DSC 2920 differential scanning calorimeter. Aluminum pans were used for all samples and the instrument was
calibrated using an indium standard. For reference, an empty pan sealed in the same way
as the sample was used. Using inert nitrogen conditions, the samples were heated in the
DSC cell from 30°C to 300°C at a rate of 10°C/min.
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A Perkin-Elmer STA 6000 Simultaneous Thermal Analyzer was used to conduct thermogravimetric analysis. Open alumina crucibles were used to heat the samples from
30°C to 300°C at a rate of 10°C/min under a nitrogen stream.
Characterization of the cocrystals by FTIR was accomplished with a Nicolet
Avatar 320 FT-IR instrument. Sample amounts of 1-2 mg were used, and spectra were measured over the range of 4000-400 cm-1 and analyzed using EZ Omnic software.
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Table 4-4. Selected hydrogen bond parameters for 1:1 ionic cocrystals.
Compound Hydrogen bond d (H···A) / Å D (D···A) / Å θ / ° O(3)-H(1O)•••O(2)#1 2.305 (5) 2.951 (7) 170.6 (5) N(6)-H(1N)•••Cl(1)#7 2.249 (2) 3.145 (5) 168.9 (3) N(6)-H(2N)•••Cl(1) 2.224 (2) 3.114 (5) 167.1 (3) LICSAR #1 x+1,y,z #2 x+1/2,-y+1/2,-z+2 #3 x+1,y-1,z #4 x-1,y,z #5 x-1/2,-y+1/2,-z+2 #6 x-1,y+1,z #7 x,y+1,z N(1)H(1B)•••O(3) 2.012 (2) 2.896 (3) 167.2 (1) LINSAR N(1)H(1A)•••O(3) 2.197 (2) 2.918 (3) 136.8 (1) N(1)-H(1)•••Cl(1)#2 2.430 (19) 3.2204 (12) 148.8 (15) O(1)-H(2)•••Cl(1)#3 2.41 (3) 3.1452 (12) 175 (2) O(2)-H(5)•••O(3)#2 1.96 (3) 2.7543 (14) 174 (2) LICDMG O(2)-H(4)•••Cl(1)#2 2.38 (2) 3.1686 (11) 169 (2) O(1)-H(3)•••Cl(1)#4 2.29 (3) 3.1264 (12) 177 (2) #1 -x,-y,-z+1 #2 x-1,y,z #3 -x+1,-y+1,-z+2 #4 x-1,y-1,z LINDMG N(1)H(7)•••O(5) 1.9912 2.8349 (1) 158.49 O(4)-H(3)•••Cl(1)#3 2.47 (5) 3.178 (2) 165 (5) O(3)-H(2)•••Cl(2)#4 2.30 (3) 3.120 (2) 168 (3) O(4)-H(4)•••Cl(2)#5 2.37(5) 3.117 (2) 163 (4) LICBTN O(3)-H(1)•••Cl(1)#6 2.33 (5) 3.065 (2) 168 (4) #1 -x+1,-y,z+1/2 #2 -x+1,-y,z-1/2 #3 x-1/2,-y-1/2,z #4 x+1/2,-y+1/2,z #5 x,y-1,z #6 x,y+1,z N(1)-H(1A)•••Cl(1)#4 2.62 3.2433 (14) 128.3 N(1)-H(1B)•••Cl(1)#5 2.32 3.1983 (14) 168.6 LICBAL- N(1)-H(1C)•••O(2)#4 1.95 2.8251 (17) 167.2 anhydrate #1 -x,-y+2,-z+1 #2 -x+1,-y+2,-z+1 #3 -x+1/2,y-1/2,-z+1/2 #4 x+1/2,-y+3/2,z+1/2 #5 x-1/2,-y+3/2,z+1/2 O(1)-H(1)•••Cl(1)#5 2.41 (3) 3.2458 (14) 179 (2) O(1)-H(2)•••Cl(1)#6 2.36 (3) 3.1262 (17) 170 (3) N(1)-H(4)•••Cl(1)#7 2.53 (2) 3.2475 (15) 135.9 (18) N(1)-H(3)•••O(3) 2.44 (4) 2.980 (2) 120 (3) LICBAL N(1)-H(5)•••Cl(1)#9 2.38 (3) 3.222 (2) 167 (3) #1 -x+5/2,y+1/2,-z+1/2 #2 x,y+1,z #3 x,y-1,z #4 -x+5/2,y-1/2,-z+1/2 #5 x+1,y,z #6 x+1,y-1,z #7 -x+1,-y+1,-z+1 #8 x-1,y+1,z #9 -x+1,-y,-z+1 N(1)-H(1A)•••Cl(1)#5 2.32 3.1516 (13) 155.9 N(1)-H(1B)•••Cl(1)#6 2.33 3.1886 (13) 163.0 N(1)-H(1C)•••O(2)#7 1.92 2.7970 (16) 166.6 LICABA #1 x,y+1,z #2 -x+5/2,y+1/2,-z+1/2 #3 x,y-1,z #4 -x+5/2,y-1/2,-z+1/2 #5 -x+2,y+1,-z+1/2 #6 x-1/2,-y+1/2,z-1/2 #7 -x+2,-y+2,-z
120
O(3)-H(11)•••Cl(1)#5 2.32 3.234 (3) 161.1 O(3)-H(12)•••Cl(1)#6 2.23 3.194 (3) 171.6 N(1)-H(1)•••Cl(1) 2.42 3.187 (3) 144.6 LICPRO N(1)-H(2)•••Cl(1)#4 2.69 3.336 (3) 128.5 #1 -x+1,y-1/2,-z+2 #2 x,y-1,z #3 -x+1,y+1/2,-z+2 #4 x,y+1,z #5 -x+1,y+1/2,-z+1 #6 -x+1,y-1/2,-z+1 O(17)-H(17A)•••Br(2) 2.63 (6) 3.345 (3) 167 (6) O(17)H(17B)•••Br(2) 2.40 (5) 3.312 (3) 168 (4) O(18)-H(18B)•••Br(1) 2.64 (6) 3.353 (3) 163 (6) LIBPRO O(18)-H(18A)•••Br(1) 2.42 (4) 3.322 (3) 177 (3) N(16)-H(16B)•••Br(1) 2.76 (3) 3.326 (3) 123 (2) N(16)H(16A)•••Br(1) 2.47 (4) 3.277 (3) 154 (3) N(8)-H(8A)•••Br(2) 2.53 (4) 3.289 (3) 144 (3) N(1)-H(1A)•••O(12)#5 1.95 (2) 2.842 (2) 165 (2) N(1)-H(1B)•••O(1)#2 2.02 (2) 2.898 (2) 161 (2) LINPRO #1 x-1/2,-y+3/2,-z #2 -x+2,y-1/2,-z+1/2 #3 -x+2,y+1/2,-z+1/2 #4 x+1/2,-y+3/2,-z #5 -x+5/2,-y+1,z+1/2
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Table 4-5. Selected hydrogen bond parameters for 1:2 ionic cocrystals.
Compound Hydrogen bond d (H···A) / Å D (D···A) / Å θ / ° N(1)-H(1A)•••Cl(1)#5 2.195 (2) 3.1011 (1) 159.9 (1) N(1)-H(1B)•••Cl(1)#6 2.281 (2) 3.1549 (1) 166.4 (1) N(2)-H(4A)•••O(3)#4 1.85 (2) 2.7244 (2) 164.4 (2) LICSAR2 N(2)-H(4B)•••O(2)#4 2.01 (2) 2.8878 (2) 161.6 (2) #1 -x+5/2,y+1/2,z #2 -x+5/2,y-1/2,z #3 x+1/2,-y+1/2,-z+1 #4 x-1/2,-y+1/2,-z+1 #5 x+1,y,z #6 x+1/2,y,-z+1/2 N(1)-H(1N)•••O(2)#1 1.79 2.742 (2) 168.5 LICDMG2 #1 x-1/4,-y+1/4,z-1/4 N(1)-H(1)•••O(2)#5 1.85 2.747 (2) 161.3 LIBDMG2 #1 -x+3/4,y+1/4,z-1/4 #2 -x+1/2,-y+1/2,z #3 x-1/4,-y+3/4,z+1/4 #4 -x+3/4,y-1/4,z+1/4 #5 x+1/4,-y+3/4,z-1/4 N(1)-H(1B)•••Cl(1)#1 2.22 3.1322 (12) 172.9 LICPRO2 N(1)-H(1A)•••O(2)#2 1.82 2.7404 (15) 175.4 #1 x,y+1,z #2 x-1/2,-y+3/2,-z+3/4 N(1)-H(1A)•••Br(1)#1 2.36 3.2769 (15) 174.6 LIBPRO2 N(1)-H(1B)•••O(1)#2 1.82 2.737 (2) 175.1 #1 x,y-1,z #2 x+1/2,-y+1/2,-z-1/4 N(3)-H(3A)•••O(2)#5 1.93 2.741 (6) 145.8 N(3)-H(3B)•••O(5)#1 1.85 2.762 (5) 170.3 N(4)-H(4A)•••O(4)#3 1.85 2.751 (5) 167.0 LINPRO2 N(4)-H(4B)•••O(2)#6 2.26 2.870 (6) 123.2 (dia) N(4)-H(4B)•••O(1)#6 2.13 3.046 (6) 171.2 #1 x-1/2,-y+3/2,-z+1 #2 -x+2,y-1/2,-z+1/2 #3 -x+2,y+1/2,-z+1/2 #4 x+1/2,-y+3/2,-z+1 #5 -x+3/2,-y+1,z-1/2 #6 -x+5/2,-y+2,z-1/2 N(3)-H(3C)•••O(4)#1 1.88 2.791 (2) 170.4 N(3)-H(3D)•••O(13)#2 1.92 2.830 (2) 168.9 N(3)-H(3D)•••O(14)#2 2.37 3.054 (2) 131.0 N(1)-H(1A)•••O(11)#3 2.10 2.998 (2) 166.4 N(1)-H(1B)•••O(12)#2 2.36 3.010 (2) 127.4 N(1)-H(1B)•••O(10)#2 2.36 3.060 (2) 132.5 LINPRO2 N(2)-H(2C)•••O(1) 1.91 2.783 (2) 156.9 (ABW) N(2)-H(2C)•••O(3) 2.19 2.688 (2) 113.1 N(2)-H(2D)•••O(8)#4 1.81 2.722 (2) 169.2 N(4)-H(21A)•••O(10) 2.03 2.849 (2) 147.0 N(4)-H(21A)•••O(9) 2.31 2.971 (2) 128.8 N(4)-H(21B)•••O(5) 1.87 2.775 (2) 166.3 #1 -x,y+1/2,-z+1/2 #2 -x+1,y+1/2,-z+1/2 #3 -x+1/2,-y+2,z+1/2 #4 x-1/2,-y+3/2,-z+1
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Table 4-6. Crystallographic data for 1:1 ionic cocrystals.
LICSAR LINSAR LICDMG LINDMG Formula C3H9ClLiNO3 C3H7LiN2O5 C4H13ClLiNO4 C4H9LiN2O5 MW 149.50 158.05 181.54 172.07 Crystal system Orthorhombic Orthorhombic Triclinic Orthorhombic
Space group P212121 P212121 P1 Fdd2 a (Å) 4.9169 (2) 5.0816 (5) 7.2090 (1) 21.7388 (6) b (Å) 5.2917 (2) 10.7057 (9) 7.5745 (2) 29.0098 (8) c (Å) 27.938 (1) 12.5344 (10) 9.0100 (2) 4.9930 (2) (deg) 90 90 110.746 (1) 90 (deg) 90 90 93.170 (1) 90 (deg) 90 90 103.709 (1) 90 V /Å3 726.91 (5) 681.9 (1) 441.698 (16) 3148.78 (18) -3 Dc/mg m 1.366 1.539 1.365 1.452 Z 4 4 2 16 2 range 3.16 to 67.46 5.43 to 66.13 5.31 to 65.96 5.08 to 67.58 Nref./Npara. 1288 / 85 1153 / 101 1466 / 123 1190 / 145 T /K 100 (2) 100 (2) 100 (2) 100 (2) R1 [I>2sigma(I)] 0.0672 0.0384 0.0293 0.0269 wR2 0.1717 0.1079 0.0828 0.0812 GOF 1.188 0.869 1.393 0.744 Abs coef. 4.186 1.259 3.624 1.137 LICBAL- LICBTN LICBAL LICABA anhydrate Formula C5H15Cl2Li2NO2 C3H7ClLiNO2 C3H9ClLiNO3 C4H9ClLiNO2 MW 237.91 131.47 149.50 145.51 Crystal system Orthorhomic Monoclinic Monoclinic Monoclinic Space group Pna21 P21/n P21/n C2/c a (Å) 11.8788 (4) 5.0510 (2) 6.6716 (9) 20.0021 (4) b (Å) 6.1712 (2) 13.2649 (5) 5.0400 (8) 4.8815 (1) c (Å) 15.3296 (5) 8.9413 (3) 19.816 (3) 17.0417 (6) (deg) 90 90 90 90 (deg) 90 96.721 (2) 95.888 (7) 124.929 (1) (deg) 90 90 90 90 V /Å3 1123.76 (6) 594.96 (4) 662.78 (16) 1364.21 (6) -3 Dc/mg m 1.407 1.468 1.498 1.417 Z 2 4 4 8 2 range 5.77 to 67.63 6.00 to 67.81 4.49 to 67.91 5.39 to 68.66 Nref./Npara. 1790 / 146 1045 / 74 1156 / 102 1214 / 83 T /K 100 (2) 100 (2) 100 (2) 100 (2) R1 [I>2sigma(I)] 0.0333 0.0284 0.0292 0.0299 wR2 0.0757 0.0776 0.0841 0.0780 GOF 1.080 1.361 1.516 1.104 Abs coef. 5.104 4.909 4.591 4.335
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Table 4-7. Crystallographic data for 1:1 ionic cocrystals (continued).
LICPRO LIBPRO LINPRO Formula C5H11ClLiNO3 C5H11BrLiNO3 C5H9LiN2O5 MW 175.54 220.00 184.08 Crystal system Monoclinic Monoclinic Orthorhombic Space group P21 P21 P212121 a (Å) 7.7692 (12) 11.2473 (3) 9.0947 (4) b (Å) 5.1020 (9) 5.1316 (1) 9.2876 (5) c (Å) 10.3795 (16) 14.9547 (4) 9.5743 (5) (deg) 90 90 90 (deg) 105.458 (9) 104.395 (1) 90 (deg) 90 90 90 V /Å3 396.54 (11) 836.04 (4) 808.72 (7) -3 Dc/mg m 1.470 1.748 1.512 Z 2 4 4 2 range 4.42 to 66.91 3.05 to 67.98 6.64 to 67.56 Nref./Npara. 1097 / 100 2675 / 231 1406 / 124 T /K 100 (2) 100 (2) 100 (2) R1 [I>2sigma(I)] 0.0312 0.0200 0.0290 wR2 0.0862 0.0502 0.0739 GOF 1.147 1.102 1.052 Abs coef. 3.928 6.386 1.151
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Table 4-8. Crystallographic data of 1:2 ionic cocrystals.
LICSAR2 LINBTN2 LICDMG2 LIBDMG2 Formula C6H14ClLiN2O4 C10H22LiN3O7 C8H18ClLiN2O4 C8H18BrLiN2O4 MW 220.58 303.25 248.63 293.09 Crystal system Orthorhombic Monoclinic Orthorhombic Orthorhombic Space group Pbca P21/c Fdd2 Fdd2 a (Å) 9.5197 (1) 16.0472 (16) 14.0427 (5) 14.0912 (2) b (Å) 9.9275 (1) 8.4767 (10) 14.6533 (5) 14.9035 (2) c (Å) 21.7783 (2) 10.8836 (11) 12.4822 (4) 12.5426 (2) (deg) 90 90 90 90 (deg) 90 103.731 (6) 90 90 (deg) 90 90 90 90 V /Å3 2058.20 (4) 1438.2 (3) 2568.49 (15) 2634.05 (7) -3 Dc/mg m 1.424 1.401 1.286 1.478 Z 8 4 8 8 2 range 4.06 to 67.95 2.83 to 66.56 5.62 to 68.02 5.58 to 66.35 Nref./Npara. 1838 / 145 2484 / 196 1080 / 76 1114 / 77 T /K 100 (2) 100 (2) 100 (2) 100 (2) R1 [I>2sigma(I)] 0.0274 0.0408 0.0312 0.0178 wR2 0.0786 0.1134 0.0726 0.0464 GOF 1.031 1.023 0.994 1.089 Abs coef. 3.248 0.992 2.660 4.282 LINPRO2 LICPRO2 LIBPRO2 LINPRO2 (dia) (ABW) Formula C10H18ClLiN2O4 C10H18BrLiN2O4 C10H18LiN3O7 C10H18LiN3O7 MW 272.65 317.11 299.21 299.21 Crystal system Tetragonal Tetragonal Orthorhombic Orthorhombic Space group P41212 P41212 P212121 P212121 a (Å) 9.0791 (1) 9.1703 (3) 9.5219 (9) 11.0448 (3) b (Å) 9.0791 (1) 9.1703 (3) 9.5664 (9) 12.0393 (3) c (Å) 15.4104 (2) 15.5694 (14) 15.0812 (12) 20.2019 (5) (deg) 90 90 90 90 (deg) 90 90 90 90 (deg) 90 90 90 90 V /Å3 1270.28 (3) 1309.30 (14) 1373.8 (2) 2686.28 (12) -3 Dc/mg m 1.426 1.609 1.447 1.480 Z 4 4 4 8 2 range 5.66 to 67.91 5.60 to 68.18 2.93 to 65.90 4.27 to 65.93 Nref./Npara. 1150 / 84 1182 / 83 2347 / 191 4505 / 379 T /K 100 (2) 100 (2) 100 (2) 100 (2) R1 [I>2sigma(I)] 0.0229 0.0181 0.0576 0.0314 wR2 0.0662 0.0447 0.1454 0.0799 GOF 1.022 1.078 1.046 1.045 Abs coef. 2.745 4.362 1.038 1.061
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Chapter 5. Conclusions and Future Directions
5.1 Conclusions
The power of the supramolecular heterosynthon approach to generate cocrystals is once again demonstrated using ellagic acid. 17 crystal forms (5 cocrystals, 7 cocrystal solvates/hydrates and 5 solvates) of ellagic acid have been isolated and characterized by solid state analytical techniques. The crystal forms of ellagic acid reveal its compatibility with a diverse variety of functional groups in pyridine, imidazole, pyrazole, carboxylate and carbonyl moieties. The discovery of ellagic acid solvates while serendipitous is not totally unexpected since ellagic acid has an imbalance of hydrogen bond donors over acceptors and thus demonstrates its affinity for solvent molecules with superior hydrogen bond acceptor capabilities. Solvation/hydration persists after cocrystal formation if the imbalance remains. This obeys Etter’s first rule of hydrogen bonding196 that “all good
proton donors and acceptors are used in hydrogen bonding”, as originally put forth by
Donohue197, is satisfied. Hence the synergistic incorporation of the phenol-carbonyl supramolecular heterosynthon resulted in the cocrystal solvates of ellagic acid with isonicotinamide and theophylline. This synergism put polyphenols such as ellagic acid in a favourable position to be included in a cocrystal former library for cocrystal screening experiments since APIs routinely contain multiple functional groups.
The motivation to diversify the crystal forms of lithium salts stems from the pharmacological properties of lithium that consistently reduce suicidality in recurrent unipolar major depressive disorder and in bipolar disorder. To engineer ionic cocrystals
126
of lithium salts, the coordination chemistry of the lithium cation has been immensely
helpful. The oxophilic character of lithium points to oxygen based ligands such as the
carboxylate as a good cocrystal former. That the carboxylate is negatively-charged means
the carboxylate moiety has to be derived from an amino acid so that it is an overall
neutral molecule. In addition, that there are active transporters to facilitate the movement
of amino acids across the blood brain barrier implies that intuitively, amino acids may be
the appropriate cocrystal formers to target ionic cocrystals of lithium salts and potentially
facilitate the passage of the lithium cations across the blood brain barrier.
The choice of the lithium-to-amino acid stoichiometry dictates the periodicity of
the crystal structure. Equimolar quantities of lithium salts and amino acids yield 1-
periodic structures with the exception of LICDMG (a discrete supermolecule that is hydrogen bonded into a 1-periodic chain) and LINPRO (a mixed ligand 3-periodic dia net). The construction of 2-periodic and 3-periodic nets is instead observed in 1:2 cocrystals of lithium salts and amino acids to generate cationic square grids, dia nets and a zeolitic ABW net. These architectures are characterized by the formation of 4-, 6- and
8-membered Lin(carboxylate)n (n=4, 6, 8) rings with a wide range of Li-carboxylate-Li
angles. Dia nets are prone to interpenetration but the presence of pairs of counterions and
the bulkiness of the amino acid substituents precludes interpenetration in the LiDMOMs.
The zeolitic ABW net is the first example of a LiZMOM and features the combination of
4-, 6- and 8-membered Lin(carboxylate)n (n=4, 6, 8) rings. The modular nature of these
compounds coupled with larger anions will envisage a range of LiZMOMs that parallels the structural diversity seen in inorganic zeolites and zeolitic metal-organic materials.
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5.2 Future Directons
While the phenol-pyridine, phenol-imidazole, phenol-pyrazole and phenol-
carboxylate supramolecular heterosynthons have been the target of crystal engineering studies, the phenol-carbonyl supramolecular heterosynthon is still relatively unexplored.
While ε-caprolactam (supramolecularly similar to a carboxylic acid) and urea are not the best models for a carbonyl group such as a ketone, the phenol-carbonyl supramolecular heterosynthon is observed nonetheless.
Figure 5-1. Triclinic modification of quinhydrone.
That the phenol-carbonyl supramolecular heterosynthon is not exploited in
cocrystal design is perhaps surprising since it is featured in the prototypal cocrystal in
quinhydrone198 (1:1 cocrystal of quinone and hydroquninone) by Wöhler in 1844.
Further, benzophenone was used to prepare a cocrystal with diphenylamine.199 These cocrystals were discovered without the benefit of single crystal X-ray crystallography.
128
The power of X-ray crystallography200-201 undoubtedly elucidates the carbonyl group to
be the hydrogen bond acceptor for these cocrystals. Perhaps ellagic acid can form a
cocrystal with benzophenone. In line with using pharmaceutically acceptable cocrystal
formers, flavone202 may be an excellent choice.
Figure 5-2. Carbonyl as the hydrogen bond acceptor in the cocrystal of diphenylamine and benzophenone.
All 1:1 cocrystals of lithium nitrate and amino acids are capable of generating mixed ligand dia nets or square grids but only LINPRO is observed as a mixed ligand dia net. Nature tunes the polymorphic selectivity of silica by varying temperature. Perhaps a similar approach can be used to hunt for other mixed ligand dia nets or square grids.
While these may be of pure academic interest, the ability to control the crystal structure is an example of crystal engineering at this finest and is potentially useful to the control of
129
polymorphic selectivity. However, that the mapping of the phase diagram does not
guarantee the preparation and isolation of a particular crystal form203 must not discourage
us in our endeavours but serve as the motivational tool to refine our skills and better our
knowledge at crystallization.
5.3 Crystal Engineering and Crystallization
“… crystal engineering, which is defined 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…”204
Gautam R. Desiraju
“…, the last step (precipitating good single crystals) remains a black art.”205
Philip Ball
“… there is still a great deal of black art (art, not magic!) and I might add skill, experience and chemical intuition in making them”206
Joel Bernstein
I close with some noteworthy quotes. I have not deliberated on crystal
engineering207 thus far, even though crystal engineering is reflected in the title of this dissertation. Using Desiraju’s definition of crystal engineering, the understanding of intermolecular (non-covalent and ionic) interactions have been documented and are exploited to design the molecular and ionic cocrystals presented in this dissertation. I can identify with the comments by Bernstein (in response to Ball) that undoubtedly mirrors one of the toughest challenges I had to overcome. The variety of organic, inorganic and hybrid solids is ever increasing. Crystal engineering is a science but crystallization
130 remains an art, but no longer a dark art. The concerted operation of the art of crystallization and the craft of crystal engineering is imminent to achieve the final prize, the desired crystalline material.
131
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158
Appendices
159
Appendix 1. Solid state characterization data for ELANAM
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
98 96 94 92 90
88 3350.41 86 84 82 80 78 %T 76 74 845.52 1188.81 1701.59 72 972.56 1327.28
70 1438.25 1601.32 1673.94
68 923. 16 66
64 776. 65 1098.37 638. 57 692.40 62 1039.45 60 58
4000 3000 2000 1000 753. 47 Wavenumber s ( cm- 1)
160
Appendix 2. Solid state characterization data for ELAINM•1.7H2O
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
328k EAINTA dihydrate 100
98
96 3591.77 94
92 3350.95 3175.91 90
88
86 1722.53 84 1555.94 %T 82 1268.46 1211.61 80 1225.52 1603.30 78 1584.78 1421.13 1682.51 774.90 923.36 76 852.72 678.77 74 1189.71 72 640.74 1339.91 1047.78 1106.39 651.64 70 1010.67
68
66
4000 3000 2000 1000 752.36 Wav enumbers (cm-1)
161
Appendix 3. Solid state characterization data for ELAINM•4NMP
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
100
98
96
94
92
90
88 1691.03
86 1505.48 885.21 %T 84 1725.44 915.75 1413.38 1556.54
82 812.85 1008.69 1180.67 1304.11 80 1605.96
78 1443.17 761.10 1092.50 76 1343.43
74 657.49 1666.07 1046.03 72
70
4000 3000 2000 1000 638.18 Wavenumber s (cm- 1)
162
Appendix 4. Solid state characterization data for ELAINM•4DMA
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
163
Appendix 5. Solid state characterization data for ELACAF•H2O
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
98
96
94
92
90
88 3262.45
86
84
82
%T 80
78 1583.46 76
74 921.40 1195.73 1443.62 72 1619.23
70 1322.28 1635.51 741. 12 68 1697.59 1175.67
66 1103.16 1042.55 1029.80 64 759. 47 62 4000 3000 2000 1000 Wa v en umb er s ( c m- 1)
164
Appendix 6. Solid state characterization data for ELATPH•0.13H2O
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity Relative 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45
98 96 94 92 90 88 86 3062.10 2861.43
84 2981.07
82 3356.38 80
%T 78 76 74 1736.39
72 1692.92 916. 72 1161.00
70 1179.63 831. 97
68 1440.64
66 619. 40 1559.43
64 1636.74 1092.59 744. 30 1334.37 1319.62 1617.93 62 756. 59 608. 48 60 58
4000 3000 2000 10001042.82 Wavenumbers (cm-1)
165
Appendix 7. Solid state characterization data for ELATPH•2DMA
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
166
Appendix 8. Solid state characterization data for ELADMP
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
100 319e EADPZ
95
90
85 1376.15 3455.21 80 3259.64 1478.31 75 1450.38 1268.79 1417.82 70 1387.81 1604.07 %T 1573.82 964. 81 65 1019.73 1298.78 663. 66 1150.52 1710.62
769. 69 1104.21
60 869. 72 1061.40 626. 48
55 1041.92 728. 76 601. 71 919. 52 1333.42 50 1201.88
45
40 782. 63
4000 3000 2000 1000 753.01 Wavenumbers (cm-1)
167
Appendix 9. Solid state characterization data for ELASAR
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
98
96
94
92
90 3108.23
88
86 %T 84 961.22
82 1504.48 1449.32
80 812.95 641.21 1037.21 1723.90 1221.88
78 1738.45 1584.44 861.67
76 1404.95 1271.76 601.71 753.78 74 739.34 1057.85 879.96 911.48 674.26 653.70 1363.50 1339.64 1175.92 72
4000 3000 2000 10001084.52 Wavenumbers (cm-1)
168
Appendix 10. Solid state characterization data for ELADMG
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0 0 5 10 15 20 25 30 35 40 45 2
100
98
96
94
92 3125.22
90 1505.73 88
86 1256.23 %T 957.17 809.73 1456.25 1210.05 995.70 84 636.49
1433.74 1403.18 82 740.88 1305.83 1733.67 80 863.38 1592.94
78 753.04 914.11 690.76 76 1172.06
74 1090.40 1042.67
72
4000 3000 2000 1340.26 1000 Wav enumbers (cm-1)
169
Appendix 11. Solid state characterization data for ELACAP
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8 Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
95
90
85 2932.36 3333.50 80 605 22 %T 75 661.62
70 868.02 920. 59 1714.93
65 1437.98 1583.86 719.31 1609.43
60 759.17 1107.36 1185.83
55 1043.08
3000 2000 1328.24 1000 Wa ven umb er s ( c m- 1)
170
Appendix 12. Solid state characterization data for ELAURE•2NMP
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
171
Appendix 13. Solid state characterization data for ELADMA4
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
172
Appendix 14. Solid state characterization data for ELADMA2
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
173
Appendix 15. Solid state characterization data for ELADMSO2
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0
0 5 10 15 20 25 30 35 40 45 2
174
Appendix 16. Solid state characterization data for ELANMP2
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
175
Appendix 17. Solid state characterization data for ELAPG2
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
176
Appendix 18. Solid state characterization data for LICSAR
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0
0 5 10 15 20 25 30 35 40 45 2
177
Appendix 19. Solid state characterization data for LINSAR
2.0
1.8
1.6
1.4 Experimental
1.2
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
178
Appendix 20. Solid state characterization data for LICDMG
2.0
1.8
1.6 Experimental 1.4
1.2
1.0
0.8
Relative Intensity 0.6
0.4 Calculated 0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
104 LiDMGH2O50122 102 100 98 96 94 1291.80 92 3036.82 1167.06 1227.75 90 928. 14 88 1318.61 1013.39
86 856. 89 723.50 1473.32 %T 84 969.77 1448.52 82 1409.10 3412.09 80 990.98 3372.33
78 667. 71 76 1368.12 1423.84 74
72 1636.11 70 68 66 618.54
4000 3000 2000 1000 Wav en umber s ( cm- 1)
179
Appendix 21. Solid state characterization data for LINDMG
2.0
1.8
1.6
1.4 Experimental
1.2
1.0
0.8
Relative Intensity 0.6
0.4 Calculated 0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
180
Appendix 22. Solid state characterization data for LICBAL-anhydrate
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity Relative 0.6
0.4
0.2 Calculated
0.0
0 5 10 15 20 25 30 35 40 45 2
110 T418g LITbetaALA 150degC
105
100 3395.37
95
90 3132.11 1043.49
85 3000.91 970. 47 700. 84
%T 80 838. 56 1322.28 75 1492.11 1294.37 798. 16
70 1382.19 1457.18 65
60 1578.93
55
4000 3000 2000 1426.20 1000 Wavenumbers (cm-1)
181
Appendix 23. Solid state characterization data for LICBAL
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4 Calculated 0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
125f LITBAH 105
100
95
90 949. 17
85 1250.40 3039.76 1649.82
80 874. 32 %T 1124.22 1294.87 3392.66 75 1042.76 1084.66 70 659. 84 1383.16
65 1321.02
60 837. 86 1456.18 1400.26 55
50 1590.10
4000 3000 2000 1422.28 1000 Wavenumbers (cm-1)
182
Appendix 24. Solid state characterization data for LICABA
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity Relative 0.6
0.4 Calculated 0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
105 T4 18 h LITGABA
100
95
90
85
80 1242.40
75 1261.86 70 2927.02 3064.27 668.65 1611.06 %T 2985.04
65 1341.98
60 2959.58 984.06 961.46 1477.37 1149.38 55 756.65 699. 65
50 1438.08 45
40
35 1403.97
30
4000 3000 2000 1546.32 1000 Wa venumb er s ( cm- 1)
183
Appendix 25. Solid state characterization data for LICPRO
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4 Calculated 0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
184
Appendix 26. Solid state characterization data for LIBPRO
2.0
1.8
1.6
1.4 Experimental
1.2
1.0
0.8
Relative Intensity Relative 0.6
0.4 Calculated
0.2
0.0
0 5 10 15 20 25 30 35 40 45 2
103 145t LIBPRO 102
101
100
99
98 3085.99
97 3186.44 1229.56 1276.95 908.63
96 970. 25 945. 24 1473.06 95 3416.85 1167.34 1447.90 3392.70
94 1030.44 775. 74 922.43 %T 93
92 1368.13 653. 15
91 1522.35
90 844. 70
89 1421.74
88 1327.14 87
86
85
4000 3000 2000 1613.53 1000 Wavenumbers (cm-1)
185
Appendix 27. Solid state characterization data for LINPRO
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0
0 5 10 15 20 25 30 35 40 45 2
186
Appendix 28. Solid state characterization data for LICSAR2
2.0
1.8
1.6 Experimental 1.4
1.2
1.0
0.8
Relative Intensity 0.6
0.4 Calculated 0.2
0.0 0 5 10 15 20 25 30 35 40 45 2
145a LICSAR2
102
100
98 626.53 894.31 1137.33 2444.12 2930.08 1496.22
96 2787.79 2705.65 1670.22 611. 77 964. 43 935. 43
94 1052.32 1447.49 1471.36 %T 1265.40
92
90 866.41
88 1306.61 710. 52
86 1606.10
84
4000 3000 2000 1406.97 1000 Wavenumbers (cm-1)
187
Appendix 29. Solid state characterization data for LINBTN2
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0
0 5 10 15 20 25 30 35 40 45 2
188
Appendix 30. Solid state characterization data for LICDMG2
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
189
Appendix 31. Solid state characterization data for LIBDMG2
2.0
1.8
1.6
1.4
1.2
1.0 Experimental
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
146n LIBDMG2 102
100
98
96
94
92 1143.82 90 1170.95 1473.73 967. 12 88 1003.39 867. 69 %T 86
84 1282.30
82 1420.98 931. 42 706. 03
80 1332.63 1383.30 78
76
74
72
4000 3000 2000 1605.11 1000 Wa v en umb er s ( c m- 1)
190
Appendix 32. Solid state characterization data for LICPRO2
2.0
1.8
1.6
1.4
1.2 Experimental
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
191
Appendix 33. Solid state characterization data for LIBPRO2
2.0
1.8
1.6
1.4 Experimental 1.2
1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated
0.0 0 5 10 15 20 25 30 35 40 45 2
105 142e LIBPRO2
100
95 3401.27
90 2204.97 908. 28 1078.86 2657.35 85 989. 50 1191.88 2754.82 762.99 2572.37 1449.80 2498.98
80 854. 27 1644.49 %T 2926.57 1049.02 802.07 75 958. 43 710. 59 1622.27 70 1291.35
65 1381.07 603. 70
60 1335.51 55
50 1593.25
4000 3000 2000 1401.66 1000 Wavenumbers (cm-1)
192
Appendix 34. Solid state characterization data for LINPRO2 (dia)
2.0
1.8
1.6
1.4
1.2 Experimental 1.0
0.8
Relative Intensity 0.6
0.4
0.2 Calculated 0.0
0 5 10 15 20 25 30 35 40 45 2
193