(643c) Design of Additive Manufacturing for Crystalline Solid Dispersion with Solid State Control

Crystalline warfarin sodium isopropyl alcohol (WS-IPA), prescribed in a low solid oral dosage tablet (< 10 mg), is used for the treatment of blood clotting^1,2. Manufacturing such type of solid dosage formulation demands multiple unit operations and handling of powders for every stage of the formulation process, which is known to be more challenging compared to liquids. To circumvent these challenges, this study uses liquids and/or suspensions to manufacture crystalline solid dispersions (CSD) as solid dosage form. Specifically, a novel polymer-based solid dosage formulation strategy to obtain crystalline solid dispersion (CSD) for WS-IPA is presented³. The additive manufacturing process consists of dissolving WS-IPA in a binary saturated solution of IPA – polyethylene glycol (PEG) and dispensing it dropwise into a capsule for anti-solvent crystallization by adding heptane.

The drug loading was controlled by the number of drops added, which was validated offline via UV-vis spectrophotometry. By controlling the critical process parameters (e.g., temperature, concentration, anti-solvent composition) and kinetics⁴, the crystallization process can be tuned and controlled to ensure the stable crystalline form of WS-IPA while preventing the formation of the amorphous form. The CSDs were also characterized by PXRD, DSC, TGA and Raman spectroscopy. In addition, dissolution and thermal stability studies were conducted following US Pharmacopeia methods. Ultimately, this study demonstrates that thorough understanding of the thermodynamic and kinetic boundaries of an active pharmaceutical ingredient−polymer system leads to solid state control in CSDs.

References:

(1) Gao, D.; Maurin, M. B. Physical Chemical Stability of Warfarin Sodium. AAPS J. 2001, 3 (1).

(2) . Schroeder CH, L. K. Warfarin Sodium. 3 077 481., 1963.

(3) Sanabria Ortiz, K.; Hernández Espinell, J. R.; Ortiz Torres, D.; López-Mejías, V.; Stelzer, T. Polymorphism in Solid Dispersions. Cryst. Growth Des. 2020, 20 (2), 713–722.

(4) Evans, R. C.; Bochmann, E. S.; Kyeremateng, S. O.; Gryczke, A.; Wagner, K. G. Holistic QbD Approach for Hot-Melt Extrusion Process Design Space Evaluation: Linking Materials Science, Experimentation and Process Modeling. Eur. J. Pharm. Biopharm. 2019, 141, 149–160.