Evaporative coupled with antisolvent crystallization for additive manufacturing of personalized solid dosage forms.

Flexible solid dosage manufacturing platforms that enable customizing doses for personalized medicine, are recognized as the future standard in pharmaceutical therapy. This study uses a solution-based additive manufacturing approach for the solid dosage formulation of individualized doses, precisely controlled in increments as little as 0.2 mg. The drug substance warfarin sodium isopropanol (WS-IPA) has relevant personalized formulation needs and was used as the highly potent model compound. A solution (drug substance, solvent, antisolvent, polymer) is dispensed into a capsule carrier (pullulan) based on a 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) met key performance metrics (e.g., dissolution profile) of commercially formulated WS-IPA tablets (Coumadin®) following United States 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.