The potential of computed crystal energy landscapes to aid solid-form development

Solid-form screening to identify all solid forms of an active pharmaceutical ingredient (API) has become increasingly important in ensuring the quality by design of pharmaceutical products and their manufacturing processes. However; despite considerable enlargement of the range of techniques that have been shown capable of producing novel solid forms; it is possible that practically important forms might not be found in the short timescales currently allowed for solid-form screening. Here; we report on the state-of-the-art use of computed crystal energy landscapes to complement pharmaceutical solid-form screening. We illustrate how crystal energy landscapes can help establish molecular-level understanding of the crystallization behavior of APIs and enhance the ability of solid-form screening to facilitate pharmaceutical development

Can computed crystal energy landscapes help understand pharmaceutical solids?

Computational crystal structure prediction (CSP) methods can now be applied to the smaller pharmaceutical molecules currently in drug development. We review the recent uses of computed crystal energy landscapes for pharmaceuticals, concentrating on examples where they have been used in collaboration with industrial-style experimental solid form screening. There is a strong complementarity in aiding experiment to find and characterise practically important solid forms and understanding the nature of the solid form landscape

Diabat method for polymorph free energies: Extension to molecular crystals

Lattice-switch Monte Carlo and the related diabat methods have emerged as efficient and accurate ways to compute free energy differences between polymorphs. In this work, we introduce a one-to-one mapping from the reference positions and displacements in one molecular crystal to the positions and displacements in another. Two features of the mapping facilitate lattice-switch Monte Carlo and related diabat methods for computing polymorph free energy differences. First, the mapping is unitary so that its Jacobian does not complicate the free energy calculations. Second, the mapping is easily implemented for molecular crystals of arbitrary complexity. We demonstrate the mapping by computing free energy differences between polymorphs of benzene and carbamazepine. Free energy calculations for thermodynamic cycles, each involving three independently computed polymorph free energy differences, all return to the starting free energy with a high degree of precision. The calculations thus provide a force field independent validation of the method and allow us to estimate the precision of the individual free energy differences

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 P21/n Z′ = 1 with intramolecular hydrogen bonding, whereas Forms I and II of DB7 are conformational polymorphs with distinct Z′ = 1 P1̅ 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

A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs

The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of late-appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes

A molecular picture of the problems in ensuring structural purity of tazofelone

Almost twenty years after the crystal polymorphism of tazofelone was first studied at Lilly, the compound was revisited by calculating the crystal energy landscape and complementing the calculations with experimental work for calibration purposes. The crystal structure prediction study confirmed the stability of racemic form II (RCII) and showed that the racemic compound had greater potential for polymorphism than the single enantiomer. The seeding experiment that has previously been shown to produce a racemic solid solution (SS) correlates with the isostructurality between some low energy racemic structures and the enantiopure form. Other low energy structures have the same layer structure as both racemic polymorphs and the newly-discovered, but closely related, polymorph RCIII, which accounts for the difficulty in obtaining phase pure samples of the metastable RCI and RCIII and the problems of structural purity evidenced by streaked diffraction spots for RCI–III in the single crystal diffraction. This molecular picture of the problems in ensuring structural purity in the layer structure polymorphs of tazofelone not only explains the crystal dependent thermochemistry measurements of tazofelone, but also shows the value of combining a range of experimental and computational techniques to investigate the organic solid state

Structure searching methods: general discussion.

This is the published record of a Faraday Discussion, not a peer-reviewed journal article