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

Abstract

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 lateappearing, 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.

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.…”

“…[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. Many of these difficult cases involve conformational polymorphs, in which different intramolecular conformations enable different intermolecular crystal packing motifs.…”

Crystal structures of two furazidin polymorphs revealed by a joint effort of crystal structure prediction and NMR crystallography

“…Crystal structure prediction (CSP) of fairly rigid, small chemicals with one molecule in an asymmetric part of a unit cell has recently become almost a routine task (Price, 2018;Price et al, 2016). This is mainly due to significant development of computational methods used in CSP in the last decades, leading to successful prediction of the most stable polymorphs of pharmaceutically relevant compounds (Bhardwaj et al, 2019) and functional materials with desired properties (Pulido et al, 2017), explanation of crystallization behavior and preferred supramolecular synthons formed in crystals of organic molecules , including formation of solvates and hydrates (Braun et al, 2016;Braun et al, 2019), enhancing our understanding of gelation performance of molecules (Piana et al, 2016), as well as crystal structure determination of active pharmaceutical ingredients, for which attempts to obtain appropriate crystal for single-crystal X-ray measurements have failed (Dudek et al, 2018;Baias et al, 2013b, Hofstetter et al, 2019. Still, some challenges remain, including for example handling flexible molecules (Day et al, 2017) and/or crystal structures with more than one molecule in an asymmetric part of a unit cell, as such CSP searches requires accounting for significantly more degrees of freedom, than the ones for Z'=1 and rigid molecules (Price, 2014;Reilly et al, 2016).…”

Crystal forms in pharmaceutical applications: olanzapine, a gift to crystal chemistry that keeps on giving

“…The crystal structure landscape of the OZPN anhydrates and hydrates, which was many years in the making, is shown in Fig. 7. OZPN, having been crystallized in 60+ forms, joins a distinguished group of highly crystallizable drug compounds, that among others, include sulfathiazole (Bingham et al, 2001), carbamazepine (Childs et al, 2009), axitinib (Chekal et al, 2009;Campeta et al, 2010) and galunisertib (Bhardwaj et al, 2019). It stands apart, however, for having one of the most thoroughly characterized structure landscapes, a testament to how well the compound crystallizes, the need in some cases for structure confirmation, and the general interest in exploring structure relationships underpinning form stability and transformation pathways.…”