Impurities Assisted with Control of Polymorphs during Seeded Crystallization

In the process of pharmaceutical crystallization, it is important to control polymorphic forms of active pharmaceutical ingredients (APIs) and sometimes their intermediate compounds, because such polymorphs may affect physical properties such as bioavailability and bulk powder behavior. Seeding is a typical approach to control polymorphs, and seed quality such as particle size is very important in seeded crystallization. Impurities in the crystallization mixture are known to make it difficult to control polymorphs, because impurities can inhibit nucleation and crystal growth. Herein, we show the effects that particle size of seeds and impurities included in the mixture had on the control of polymorphs in the seeded crystallization of Compound X, an intermediate compound of a drug candidate. We found that not only did ground seeds with a large surface area play a key role, but also did the presence of impurities in the mixture by inhibiting nucleation of the undesired crystal form, Form II. As a result, we were able to successfully control polymorphs to the desired crystal form, Form III, which had good filterability. Interestingly, those impurities were incorporated into Form II crystals; whereas, they were purged from Form III crystals during the process of crystallization. Furthermore, we found that the morphology of Form II crystals, which were originally needle-like, was changed by the impurities to a plate-like morphology with poor filterability. Our findings in this practical study remind us of the importance of seed quality and impurities included in crystallization mixture.