Ritonavir and rotigotine are famous examples of disappearing polymorph events, with the late appearance of a new crystal form of a drug compound disrupting production or increasing time-to-market. Based on a thorough and critical analysis of the commercial crystal structure prediction studies of 41 pharmaceutical compounds with the GRACE software package, it can be concluded that for between 15 to 45% of all small-molecule drugs currently on the market the most stable experimentally observed polymorph is not the thermodynamically most stable crystal structure and the appearance of the latter is kinetically hindered. In recent years it has become possible to detect missing, substantially more stable and hence less soluble crystal forms by crystal structure prediction. A new energy calculation protocol, named PBE0+MBD+Fvib, now offers improved accuracy approaching 1 kJ/mol. It helps to remove false positives and confirms missing, more stable forms beyond doubt. The new method also allows for the prediction of the hydration state of a crystalline drug substance as a function of water activity and temperature, thus opening up a whole new range of applications. At given temperature, the relative humidity at which hydrate-anhydrate phase transitions occur is predicted to within a factor of two. The new method is typically accurate enough to distinguish monotropic from enantiotropic phase relationships, but error bars of about 100 K for predicting the phase transition temperature are not uncommon. To assess the risk of having missed a more stable crystal form, the experimental crystal structures need to be placed on the crystal energy landscape in the first place, i.e. their crystal structures need to be solved. For this purpose, a high-throughput method has been implemented in GRACE that screens experimental patterns against extensive lists of predicted crystal structures, allowing for the structure elucidation of disordered crystal structures and phase mixtures. When applied to entire portfolios, CSP helps to focus experimental screening efforts on high-risk compounds, provides opportunities for rational crystallization experiment design and makes it possible to avoid salts or co-crystals with risky crystal energy landscapes.

Detecting and avoiding disappearing polymorph cases by crystal structure prediction

ACS Spring Meeting 2021

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