Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular <i>ab initio</i> calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles

Is the Fenamate Group a Polymorphophore? Contrasting the Crystal Energy Landscapes of Fenamic and Tolfenamic Acids

The concept of a polymorphophore was investigated by contrasting the crystal energy landscapes of monomorphic fenamic acid (2-(phenylamino)-benzoic acid, FA) and one of its highly polymorphic derivatives, tolfenamic acid (2-[(3-chloro-2-methylphenyl)­amino]-benzoic acid, TA). The crystal energy landscapes of both molecules show that the benzoic acid <i>R</i>₂²(8) dimer motif is found in all low energy crystal structures, but conformational flexibility of the phenyl rings leads to a wide range of crystal structures with different packings of this dimer. Many of the observed fenamate crystal structures can overlay a significant proportion of the coordination environment with other observed or calculated structures, but the substituents of the phenyl group affect the ordering of the related low energy crystal structures. The crystal energy landscape of tolfenamic acid has several crystal structures, including the observed polymorphs, tightly clustered around the global minimum, whereas the corresponding cluster contains only the observed and a closely related structure for fenamic acid. Hence, the fenamate fragment is potentially permissive of a large number of structures because of the conformational flexibility, but the substituents determine whether a specific fenamate will be polymorphic. Thus, a polymorphophore promotes but does not guarantee polymorphism

Evaluating a Crystal Energy Landscape in the Context of Industrial Polymorph Screening

To evaluate how the calculation of a crystal energy landscape can be used in the solid-form screening of pharmaceuticals, a Knowledge Transfer Secondment between GlaxoSmithKline (GSK) and University College London was established to carry out computational crystal structure prediction (CSP) and further guided experimentation on a molecule from GSK’s compound collection. The molecule chosen was 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)­methyl]­oxy)­phenyl)­methyl]-2-pyridinecarboxylic acid (GSK269984B) since the preliminary thermodynamic form screening had only identified one anhydrate, Form I. The calculations confirmed that Form I is the most thermodynamically stable form. The thermodynamically competitive computed structures all had very different conformations of GSK269984B, and further experiments were designed to attempt to generate these conformations in solution and hence the crystalline solid. The experimental screening generated four novel solvates which all eventually transformed to Form I, two of which could also be structurally characterized by single crystal X-ray diffraction. The molecular conformation (apart from the position of the polar proton) in all three crystal structures was, however, very similar. GSK269984B appears to have an unusually small number of solid forms because there is no kinetic barrier to crystallizing in the most stable conformation which corresponds to the most thermodynamically stable and densely packed structure

The Complexity of Hydration of Phloroglucinol: A Comprehensive Structural and Thermodynamic Characterization

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

The Complexity of Hydration of Phloroglucinol: A Comprehensive Structural and Thermodynamic Characterization

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

Navigating the Waters of Unconventional Crystalline Hydrates

Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo­[<i>b</i>,<i>f</i>]­[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 (DB7^z). 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

Complex Polymorphic System of Gallic AcidFive Monohydrates, Three Anhydrates, and over 20 Solvates

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

Contrasting Polymorphism of Related Small Molecule Drugs Correlated and Guided by the Computed Crystal Energy Landscape

Solid form screening and crystal structure prediction (CSP) calculations were carried out on two related molecules, 3-(4-(benzo­[d]­isoxazole-3-yl)­piperazin-1-yl)-2,2-dimethylpropanoic acid (B5) and 3-(4-dibenzo­[b,f]­[1,4]­oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7). Only one anhydrate form was crystallized for B5, whereas multiple solid forms, including three neat polymorphs, were found for DB7. The crystal structure of B5 is <i>P</i>2₁/<i>n</i> Z′ = 1 with intramolecular hydrogen bonding, whereas Forms I and II of DB7 are conformational polymorphs with distinct <i>Z</i>′ = 1 <i>P</i>1̅ structures and intermolecular hydrogen bonds. A disordered structure for Form III of DB7 is proposed, based on CSP-generated structures which gave a promising match to the X-ray powder diffraction and solid state NMR data for this metastable form. The differences in the hydrogen bonding and experimental solid form landscapes of the two molecules appear to arise from the dominance of the self-assembly of the benzoisoxazolepiperazinyl and dibenzoxepinylpiperazinyl fragments and the consequent inability to produce amorphous or solvate forms as intermediates for B5. There is a subtle balance between the intramolecular conformational energy and the intermolecular dispersion, electrostatic and polarization interactions apparent in the analysis of the computationally generated thermodynamically competitive structures, which makes their relative stability quite sensitive to the computational method used. The value of simultaneously exploring the computationally and experimentally generated solid form landscapes of molecules in pharmaceutical development is discussed

Are Oxygen and Sulfur Atoms Structurally Equivalent in Organic Crystals?

New guidelines for the design of structurally equivalent molecular crystals were derived from structural analyses of new cocrystals and polymorphs of saccharin and thiosaccharin, aided by a computational study. The study shows that isostructural crystals may be obtained through an exchange of >CO with >CS in the molecular components of the solids, but only if the exchanged atom is not involved in hydrogen bonding

Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine

An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization