Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin
Hongbo Chen, Hongyun Xu, Chenguang Wang, Hyunho Kang, Christy L. Haynes, Mahesh K. Mahanthappa, Changquan Calvin Sun
Abstract
The successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution characteristics. Here, we report a novel quasi-emulsion solvent diffusion cocrystallization (QESD-CC) method as an integrated crystal and particle engineering approach for successful generation of spherical cocrystal agglomerates of the poorly soluble drug indomethacin (IMC) and the sweet cocrystallization agent saccharin (SAC). The QESD-CC process consists of two distinct steps: (1) formation of a transient emulsion containing solvated IMC and SAC and (2) subsequent precipitation of IMC–SAC cocrystals from the emulsion as hollow spherical particles. Solution 1H NMR analyses and computational modeling studies indicated that hydroxypropyl methylcellulose (HPMC) preferentially interacts with the SAC molecules through hydrogen bonds, thus driving the polymer to form a shell that stabilizes the transient emulsion droplets and coats the resulting particles. Spherical QESD-CC particles exhibited excellent flowability, while the HPMC coating and microsize primary crystals led to excellent tabletability. Outstanding manufacturability and high cocrystal solubility thus enabled the successful development of a high-drug-loading tablet formulation comprising 46.3 wt % IMC.