Evaporative Coupled with Antisolvent Crystallization for Additive Manufacturing of Personalized Solid Dosage Forms

Abstract

Flexible solid dosage manufacturing platform that enables customizing doses for personalized medicine, recognized as the future standard in pharmaceutical therapy. Using warfarin sodium isopropanol (WS-IPA) as a model drug substance with relevant personalized formulation needs, this study uses a solution-based additive manufacturing approach for the solid dosage formulation of individualized doses. A solution (drug substance, solvent, antisolvent, polymer) is dispensed into a capsule carrier (pullulan) based on model informed precision dosing algorithm to manufacture crystalline solid dispersion (CrySoD). Upon a controlled evaporative antisolvent-solvent crystallization (heptane/IPA), WS-IPA crystallizes inside the polymer matrix (polyethylene glycol, PEG). By controlling the critical process parameters (temperature, drug substance – PEG concentration, antisolvent composition) of the coupled crystallization and formulation process, the commercial crystalline solid form of WS-IPA can be obtained. The CrySoD capsules (commercial and individualized doses) matched key performance metrics (e.g., dissolution profile) of commercially formulated WS-IPA tablets (Coumadin®) following United State Pharmacopeia (USP) protocols. The workflow and insights provide a generalizable proof-of-concept for a model-informed solid dosage formulation platform enabled by process intensification. This study might be used as a rationale for further investigations, including other personalized medicine relevant drug substances, regulatory science, and technoeconomic analysis.

Keywords: Additive manufacturing, antisolvent-evaporative crystallization, solid dispersions, solid dosage form, warfarin sodium isopropanol, personalized medicine, process intensification