Controlled API crystallization during additive manufacturing of solid dosage form for flexible integrated pharmaceutical manufacturing.

Conventional manufacturing of solid dosage forms (e.g., tablets, capsules) demands multiple unit operations and handling of solids, known to be more challenging than handling liquids. To circumvent these challenges, this study explored liquid dispensing to manufacture an oral solid dosage form. The presented additive manufacturing process dispenses a solution (drug substance, solvent, polymer) into a carrier (capsule). Upon controlled solvent evaporation, the model active pharmaceutical ingredient, racemic modafinil (MOD), crystallizes inside a polymer matrix (polyethylene glycol) generating a crystalline solid dispersion. The critical process parameters (e.g., temperature, concentration, evaporation rate, choice of solvent) and key performance metrics were evaluated to ensure robust crystalline solid dispersion manufacturing. The coupled crystallization and formulation process delivers the desired polymorph form I of MOD inside a crystalline solid dispersion that matches the quality attributes of commercially formulated MOD tablets (Provigil®) following US Pharmacopeia methods. Moreover, the developed workflow and insights presented provide a generalizable approach applicable to other drug substance - polymer - solvent systems, independent if crystalline or amorphous solid dispersion is needed. Ultimately, this study demonstrates the flexible (additive) formulation of solid dosage forms, needed for, e.g., point-of-use manufacturing in remote areas or personalized medicine via a process intensification approach.