Toltrazuril Polymorphs and the Effect on Hygroscopicity and Dissolution Rate

Abstract

The different arrangement and/or conformation polymorphs frequently generate a pivotal difference in hygroscopicity, stability, and dissolvability. For the purpose of screening the preponderant polymorphs of toltrazuril (Tol) with the desired physicochemical property, two polymorphs (Forms I and II) are screened out, and structure−property relationships are meticulously explored. Interaction energy analyses show that Form II is not stronger than Form I in packing due to the lower intermolecular lattice energy. And the dissolution rate of Form II is higher than that of Form I because the loosened packing in Form II would facilitate diffusion and dissolution. The percentage of mass change of Forms I and II in hygroscopicity at 95% RH is less than 0.2%, and they are both nonhygroscopic crystalline forms. Interestingly, the weight increase of Form II at 95% RH is about twice that of Form I, which might be due to plentiful −CF 3 groups exposed on the facet (001) (about 72% area ratio) of Form II possessed a weakly negatively charged region to capture a few H 2 O molecules in surroundings. Overall, Form II not only exhibits higher solubility and dissolution rate relative to Form I, but also possesses good stability (high temperature, humidity, and light); hence, Form II might be an advantageous candidate crystalline form. This work may provide inspirational thinking for predicting the trends in hygroscopicity and dissolvability of polymorphic APIs and avoiding compromising upcoming pharmaceuticals.