Polymorphic transformation as a result of atovaquone incompatibility with selected excipients

Abstract

Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, and hot-stage microscopy were employed to evaluate the drug–excipient compatibility of atovaquone with commonly used tablet excipients. The DSC curves of pure drug and excipients were compared with their physical mixtures. Microcrystalline cellulose, titanium dioxide, colloidal silica, ferric oxide, lactose monohydrate, and sodium starch glycolate were compatible, while magnesium stearate, polyethylene glycol (PEG) 8000, Poloxamer 188, and hydroxypropyl methyl cellulose (HPMC) E15 showed incompatibility with the drug. Heat–cool–heat analysis of the physical and the ground mixture of later three excipients showed polymorphic transformation of atovaquone form III to form I, which occurred via amorphization with HPMC E15 and through solubilization mechanism with remaining two excipients. These outcomes were further supported by hot-stage microscopy. Results of milling experiments revealed a milling time-dependent polymorphic transformation and solubilization with HPMC E15 and PEG 8000, respectively. This study highlights the importance of compatibility assessment for selection of excipients in specific unit operations such as milling and grinding.