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1.  Crystal Structures of New Ammonium 5-Aminotetrazolates 
Crystals  2014;4(4):439-449.
The crystal structures of three salts of anionic 5-aminotetrazole are described. The tetramethylammonium salt (P1‒) forms hydrogen-bonded ribbons of anions which accept weak C–H⋯N contacts from the cations. The cystamine salt (C2/c) shows wave-shaped ribbons of anions linked by hydrogen bonds to screw-shaped dications. The tetramethylguanidine salt (P21/c) exhibits layers of anions hydrogen-bonded to the cations.
doi:10.3390/cryst4040439
PMCID: PMC4702350  PMID: 26753100
5-aminotetrazole; cystamine; tetramethylammonium; tetramethylguanidine
2.  Specific energy contributions from competing hydrogen-bonded structures in six polymorphs of phenobarbital 
Background
In solid state structures of organic molecules, identical sets of H-bond donor and acceptor functions can result in a range of distinct H-bond connectivity modes. Specifically, competing H-bond structures (HBSs) may differ in the quantitative proportion between one-point and multiple-point H-bond connections. For an assessment of such HBSs, the effects of their internal as well as external (packing) interactions need to be taken into consideration. The semi-classical density sums (SCDS-PIXEL) method, which enables the calculation of interaction energies for molecule–molecule pairs, was used to investigate six polymorphs of phenobarbital (Pbtl) with different quantitative proportions of one-point and two-point H-bond connections.
Results
The structures of polymorphs V and VI of Pbtl were determined from single crystal data. Two-point H-bond connections are inherently inflexible in their geometry and lie within a small PIXEL energy range (−45.7 to −49.7 kJ mol−1). One-point H-bond connections are geometrically less restricted and subsequently show large variations in their dispersion terms and total energies (−23.1 to −40.5 kJ mol−1). The comparison of sums of interaction energies in small clusters containing only the strongest intermolecular interactions showed an advantage for compact HBSs with multiple-point connections, whereas alternative HBSs based on one-point connections may enable more favourable overall packing interactions (i.e. V vs. III). Energy penalties associated with experimental intramolecular geometries relative to the global conformational energy minimum were calculated and used to correct total PIXEL energies. The estimated order of stabilities (based on PIXEL energies) is III > I > II > VI > X > V, with a difference of just 1.7 kJ mol−1 between the three most stable forms.
Conclusions
For an analysis of competing HBSs, one has to consider the contributions from internal H-bond and non-H-bond interactions, from the packing of multiple HBS instances and intramolecular energy penalties. A compact HBS based on multiple-point H-bond connections should typically lead to more packing alternatives and ultimately to a larger number of viable low-energy structures than a competing one-point HBS (i.e. dimer vs. catemer). Coulombic interaction energies associated with typical short intermolecular C–H···O contact geometries are small in comparison with dispersion effects associated with the packing complementary molecular shapes.Graphical abstractCompeting H-bond motifs can differ markedly in their energy contributions
Electronic supplementary material
The online version of this article (doi:10.1186/s13065-016-0152-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13065-016-0152-5
PMCID: PMC4763432  PMID: 26909105
3.  Creatine: Polymorphs Predicted and Found 
Crystal growth & design  2014;14(10):4895-4900.
Graphical Abstract
Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, badly water soluble, zwitterionic compound, has enabled the finding and characterization of its anhydrate polymorphs, including the thermodynamic room temperature form. Crystal structures of the novel forms were determined by combining laboratory powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all experimental forms but predicted the correct stability order, which was experimentally confirmed by measurements of the heat of hydration.
doi:10.1021/cg501159c
PMCID: PMC4693963  PMID: 26722225
4.  Insights into Hydrate Formation and Stability of Morphinanes from a Combination of Experimental and Computational Approaches 
Molecular pharmaceutics  2014;11(9):3145-3163.
Morphine, codeine and ethylmorphine, are important drug compounds, whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules and the Cl− counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modelling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All twelve structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compounds except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to estimate the heat of the hydrate ↔ anhydrate phase transformations, indicating an enthalpic stabilization of the respective hydrate of 5.7 to 25.6 kJ mol−1 relative to the most stable anhydrate. These results are in qualitative agreement with static 0 K lattice energy calculations for all systems except morphine hydrochloride, showing the need for further improvements in quantitative thermodynamic prediction of hydrates having water⋯water interactions. Thus, the combination of a variety of experimental techniques, covering temperature and moisture dependent stability, and computational modelling allowed us to generate sufficient kinetic, thermodynamic and structural information to understand the principles of hydrate formation of the model compounds. This approach also led to the detection of several new crystal forms of the investigated morphinanes.
Graphical Abstract
doi:10.1021/mp500334z
PMCID: PMC4685752  PMID: 25036525
morphine; codeine; ethylmorphine; dionine; hydrate; crystal polymorphism; crystal structure; lattice energy calculations; thermal analysis; differential scanning calorimetry; isothermal calorimetry; moisture sorption/desorption; X-ray diffraction; IR spectroscopy
5.  Solid state forms of 4-aminoquinaldine - From void structures with and without solvent inclusion to close packing 
CrystEngComm / RSC  2015;17(12):2504-2516.
Polymorphs of 4-aminoquinaldine (4-AQ) have been predicted in silico and experimentally identified and characterised. The two metastable forms, AH (anhydrate) II and AH III, crystallise in the trigonal space group R3¯ and are less densely packed than the thermodynamically most stable phase AH I° (P21/c). AH II can crystallise and exist both, as a solvent inclusion compound and as an unsolvated phase. The third polymorph, AH III, is exclusively obtained by desolvation of a carbon tetrachloride solvate. Theoretical calculations correctly estimated the experimental 0K stability order, confirmed that AH II can exist without solvents, gave access to the AH III structure, and identified that there exists a subtle balance between close packing and number of hydrogen bonding interactions in the solid state of anhydrous 4-AQ. Furthermore, the prevalence of void space and solvent inclusion in R3¯ structures is discussed.
doi:10.1039/C5CE00118H
PMCID: PMC4693969  PMID: 26726294
6.  Structural Properties, Order–Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms 
Molecular Pharmaceutics  2016;13(3):1012-1029.
Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order–disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.
doi:10.1021/acs.molpharmaceut.5b00856
PMCID: PMC4783786  PMID: 26741914
crystal structure prediction; thermal analysis; gravimetric moisture sorption/desorption; water activity; powder X-ray diffraction; vibrational spectroscopy; solid-state NMR; dehydration
7.  Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate 
Crystal Growth & Design  2013;13(9):4071-4083.
The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher energy structure on a computationally generated crystal energy landscape, which has the anhydrate crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated crystal energy landscape and lattice energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two monotropically related dimethyl sulfoxide monosolvates were found in the accompanying solid form screen.
The structural transformation between anhydrous and hydrated pyrogallol, the only two practically relevant forms emerging from a solid form screen, has been unraveled with complementary experimental techniques (moisture sorption analysis, thermal analysis, X-ray diffraction, and water activity measurements) and crystal energy landscape calculations.
doi:10.1021/cg4009015
PMCID: PMC3767201  PMID: 24027438
8.  Creatine: Polymorphs Predicted and Found 
Crystal Growth & Design  2014;14(10):4895-4900.
Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-soluble, zwitterionic compound, has enabled the finding and characterization of its anhydrate polymorphs, including the thermodynamic room temperature form. Crystal structures of the novel forms were determined by combining laboratory powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all experimental forms but also predicted the correct stability order, which was experimentally confirmed by measurements of the heat of hydration.
A computationally driven experimental search for anhydrate and hydrate solid forms of creatine enabled the finding and characterization (structure and stability) of its three polymorphs and the monohydrate. The computational method not only found the experimental forms but also correctly predicted the stability order, which was experimentally confirmed by measurements of the heat of hydration.
doi:10.1021/cg501159c
PMCID: PMC4693963  PMID: 26722225
9.  Navigating the Waters of Unconventional Crystalline Hydrates 
Molecular Pharmaceutics  2015;12(8):3069-3088.
Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.
doi:10.1021/acs.molpharmaceut.5b00357
PMCID: PMC4525282  PMID: 26075319
hydrate; crystal polymorphism; proton transfer; crystal structure; electronic structure calculations; NMR prediction; thermal analysis; gravimetric moisture sorption/desorption; Raman spectroscopy; solid state NMR spectroscopy; hydrogen/deuterium exchange
10.  Four Polymorphs of Methyl Paraben: Structural Relationships and Relative Energy Differences 
Crystal Growth & Design  2013;13(3):1206-1217.
Four polymorphic forms of methyl paraben (methyl 4-hydroxybenzoate, 1), denoted 1-I (melting point 126 °C), 1-III (109 °C), 1-107 (107 °C), and 1-112 (112 °C), have been investigated by thermomicroscopy, infrared spectroscopy, and X-ray crystallography. The crystal structures of the metastable forms 1-III, 1-107, and 1-112 have been determined. All polymorphs contain the same O–H···O=C connected catemer motif, but the geometry of the resulting H-bonded chain is different in each form. The Z′ = 3 structure of 1-I (stable form; space group Cc) contains local symmetry elements. The crystal packing of each of the four known crystal structures of 1 was compared with the crystal structures of 12 chemical analogues. Close two-dimensional relationships exist between 1-112 and a form of methyl 4-aminobenzoate and between 1-107 and dimethyl terephthalate. The lattice energies of the four methyl paraben structures have been calculated with a range of methods based on ab initio electronic calculations on either the crystal or single molecule. This shows that the differences in the induction energy of the different hydrogen-bonded chain geometries have a significant effect on relative lattice energies, but that conformational energy, repulsion, dispersion, and electrostatic also contribute.
A single O−H···O=C connected catemer motif results in four fundamentally different chain geometries. This study highlights the challenges associated with the computation of polymorphic energy differences.
doi:10.1021/cg301639r
PMCID: PMC3594894  PMID: 23505337
11.  Complex Polymorphic System of Gallic Acid—Five Monohydrates, Three Anhydrates, and over 20 Solvates 
Crystal Growth & Design  2012;13(1):19-23.
We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.
An extensive experimental screen for solid forms, driven by computationally generated anhydrate and monohydrate crystal energy landscapes, revealed the fifth (!) monohydrate structure of gallic acid, structures of two additional anhydrate polymorphs, and evidence of at least 22 solvates. The application of computational studies in combination with other analytical techniques helps unravel the complex polymorphic system of gallic acid.
doi:10.1021/cg301506x
PMCID: PMC3557919  PMID: 23378823
12.  Stable polymorph of morphine1  
In the stable polymorph of the title compound, C17H19NO3 [systematic name: (5α,6α)-7,8-didehydro-4,5-ep­oxy-17-methyl­morphinan-3,6-diol], the mol­ecular conformation is in agreement with the characteristics of previously reported morphine forms. The molecule displays the typical T-shape and its piperidine ring adopts a slightly distorted chair conformation. Inter­molecular O—H⋯O hydrogen bonds link the mol­ecules into helical chains parallel to the b axis. Intra­molecular O—H⋯O hydrogen bonds are also observed.
doi:10.1107/S1600536812048945
PMCID: PMC3588323  PMID: 23476407
13.  Morphine hydro­chloride anhydrate1  
In the title mol­ecular salt [systematic name: (5α,6α)-7,8-didehydro-4,5-ep­oxy-17-methyl­morphinan-3,6-diol hydro­chloride], C17H20NO3 +·Cl−, the conformation of the morphinium ion is in agreement with the characteristics of the previously reported morphine forms [for example, Gylbert (1973 ▶). Acta Cryst. B29, 1630–1635]. In the crystal, the cations and chloride anions are linked into a helical chain propagating parallel to the b-axis direction by N—H⋯Cl and O—H⋯Cl hydrogen bonds. The title salt and the morphine monohydrate [Bye (1976 ▶) Acta Chem. Scand. 30, 549–554] display very similar one-dimensional packing modes of their morphine components.
doi:10.1107/S1600536812046405
PMCID: PMC3588957  PMID: 23476193
14.  Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test 
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
doi:10.1107/S0108768111042868
PMCID: PMC3222142  PMID: 22101543
15.  Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test 
The results of the fifth blind test of crystal structure prediction, which show important success with more challenging large and flexible molecules, are presented and discussed.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
doi:10.1107/S0108768111042868
PMCID: PMC3222142  PMID: 22101543
prediction; blind test; polymorph; crystal structure prediction
16.  Which, if any, hydrates will crystallise? Predicting hydrate formation of two dihydroxybenzoic acids† 
A study of two dihydroxybenzoic acid isomers shows that computational methods can be used to predict hydrate formation, the compound : water ratio and hydrate crystal structures. The calculations also help identify a novel hydrate found in the solid form screening that validates this study.
doi:10.1039/c1cc10762c
PMCID: PMC3175531  PMID: 21475750
17.  Solid-State Forms of β-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be? 
Crystal Growth & Design  2010;11(1):210-220.
A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found.
An extensive experimental screen, coupled with a computational study, revealed seven new solid-state forms of β-resorcylic acid. The known, stable polymorph II° shows a reversible phase transformation to the new, kinetically stable, probably disordered high temperature form I. The study provides a consistent picture of the solid-state of β-resorcylic acid.
doi:10.1021/cg101162a
PMCID: PMC3015459  PMID: 21218174
18.  The Complexity of Hydration of Phloroglucinol: A Comprehensive Structural and Thermodynamic Characterization 
The Journal of Physical Chemistry. B  2012;116(13):3961-3972.
Hydrate formation is of great importance as the inclusion of water molecules affects many solid state properties and hence determines the required chemical processing, handling, and storage. Phloroglucinol is industrially important, and the observed differences in the morphology and diffuse scattering effects with growth conditions have been scientifically controversial. We have studied the anhydrate and dihydrate of phloroglucinol and their transformations by a unique combination of complementary experimental and computational techniques, namely, moisture sorption analysis, hot-stage microscopy, differential scanning calorimetry, thermogravimetry, isothermal calorimetry, single crystal and powder X-ray diffractometry, and crystal energy landscape calculations. The enthalpically stable dihydrate phase is unstable below 16% relative humidity (25 °C) and above 50 °C (ambient humidity), and the kinetics of hydration/dehydration are relatively rapid with a small hysteresis. A consistent atomistic picture of the thermodynamics of the hydrate/anhydrate transition was derived, consistent with the disordered single X-ray crystal structure and crystal energy landscape showing closely related low energy hydrate structures. These structures provide models for proton disorder and show stacking faults as intergrowth of different layers are possible. This indicates that the consequent variability in crystal surface features and diffuse scattering with growth conditions is not a practical concern.
doi:10.1021/jp211948q
PMCID: PMC3320094  PMID: 22390190

Results 1-18 (18)