Discovery of a new polymorph of clotrimazole through melt crystallization: Understanding nucleation and growth kinetics

Clotrimaz ole (CMZ) is a classical antifungal drug for studying crystallization. In this study, a new CMZ polymorph (Form 2) was discovered during the process of nucleation and growth rate determination in the melt. High-quality single crystals were grown from melt micro droplets to determine the crystal structure by X-ray diffraction. Form 2 is metastable and exhibits a weathercock-type disordered structure. The crystal nucleation and growth kinetics of the two CMZ polymorphs were systematically measured. The maximum nucleation rate of Form 1 and 2 was observed at 50 ℃ (1.07 Tg). Form 2 nucleates and grows faster than the existing form (Form 1). The polymorphic composition can be switched by changing the relative kinetics of crystal nucleation and growth through varying the temperature. This study is relevant for the discovering new drug polymorphs through an understanding of nucleation and growth kinetics during melt crystallization.