Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?

Abstract

The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level.

Is zeroth order crystal structure prediction (CSP_0) coming to maturity? What should we aim for in an ideal crystal structure prediction code?

“…2 is a limit on the energy differences between polymorphs obtained by solution crystallisation, which is comparable to the estimated range of polymorphic lattice energy differences of observed polymorphs, 29 and the cutoffs oen used for progressing CSP_0 to more demanding calculations. This can mean that polymorphs obtained by other methods, for example by desolvating solvates 11 or the solid state synthesis of the molecule, could be much more metastable than polymorphs obtained by solution crystallisation. The concept of a crystal energy landscape requires a cut-off of thermodynamic plausibility.…”

“…In addition, this study that started from a CSP on the pharmaceutical salt, was further complicated by the late appearance of a highly metastable polymorph. 11 This illustrates the issue of the level of atomic detail and energetic accuracy at which we want to predict crystal structures, in systems where there can be considerable stabilisation by solvents in a disordered form (DOI: 10.1039/c8fd00031j), or multiple similar ions can occupy the same position. The level of atomic detail required is intimately linked with the quality of the lattice energy model needed to accurately balance all the different types of intermolecular interactions present.…”

“…This is more possible for inorganic materials than pharmaceuticals. The pharmaceutical industrial scientists recognise that there is no such thing as a standard solid form screen; not only can the basic workow vary between companies, 11,29 but also between molecules from the same drug discovery program, e.g. if one is able to obtain an amorphous starting material for one, and not for the other 51 then there may be a difference in the extent to which the starting point of the crystallisation has lost the memory of the input material structure.…”

Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods

“…[18][19][20][21][22][23][24][25][26][27][28][29][30] Increasingly, DFT is being called on to explore pharmaceutical crystal energy landscapes as a complement to experimental solid form screening. [31][32][33][34][35][36][37][38][39] Computational prediction of a highly stable, unrealized polymorph of galunisertib played a key role in the extensive characterization of its solid form landscape, for example. 38 Despite many successes of DFT-driven crystal structure prediction, close inspection of the literature also nds polymorphic crystals for which widely-used DFT models fail dramatically.…”

Stacking Disorder by Design: Factors Governing the Polytypism of Silver Iodide upon Precipitation and Formation from the Superionic Phase

“…Countless other samples of stacking disorder exist ranging from complex inorganic materials 9,10 and openframework materials 11 to small-molecule pharmaceuticals. [12][13][14][15][16] At present, there is a growing realization that the presence of stacking disorder and the associated phenomenon of polytypism can have profound consequences for the physical and chemical properties of the material in question. For example, in case of ice I, the extent of stacking disorder has been shown to affect its vapour pressure, 17 crystal shapes, 18 spectroscopic 19 and light scattering properties 18 as well as potentially surface chemistry.…”