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.