Dual drug nanocrystals loaded microparticles for fixed dose combination of simvastatin and ezetimibe

Dual drug nanocrystals loaded nano embedded microparticles (DNEMs) were prepared for fixed dose combination of simvastatin (SIM) and ezetimibe (EZE) using NanoCrySP technology. The purpose was to generate nanonized SIM and EZE dispersed in matrix of single crystallization inducing excipient and investigate their in vitro performance. DNEM were prepared using mannitol (MAN) as crystallization inducer (active pharmaceutical ingredients (APIs)/MAN = 3:7 w/w) using spray drying. TPGS (0.1% w/v) was used as surfactant for stabilization of nanocrystals. Crystallinity of DNEM was confirmed by solid-state characterization using DSC and PXRD. Particle size analysis was carried out using Zetasizer^® and the Scherrer equation as primary techniques and SEM and TEM as orthogonal techniques. Size of both SIM and EZE in DNEM was close to 600 nm. In vitro performance was assessed using USP apparatus II in 0.025% SLS containing sodium phosphate buffer. Powder dissolution of DNEM increased 1.45 times for SIM and 1.65 times for EZE as compared to their physical mixture in discriminatory medium. MAN did not plasticize SIM or EZE by virtue of its immiscibility with the two drugs. However, MAN helped in inducing crystallization via heterogeneous nucleation. The generated DNEM were stable in terms of assay, polymorphic form and dissolution for 90 days of accelerated storage at 40 °C/75% RH.