2025 AIChE Annual Meeting

(576a) Additive Manufacturing for Personalized Solid Dosage Formulation of Warfarin Sodium

Authors

Andrea Arroyo Gomez, University of Puerto Rico
Kelitsha Mulero Cruz, Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico
Gianelle Bigio Silva, University of Puerto Rico
Gianelle Bigio Silva, University of Puerto Rico
Cornelis Vlaar, University of Puerto Rico
Jean-Christophe Monbaliu, University of Liege
Rodolfo Romañach, University of Puerto Rico, Mayaguez
Jorge Duconge, University of Puerto Rico
Torsten Stelzer, Crystallization Design Institute
Precision Medicine is poised to become the standard of care in pharmaceutical therapy, necessitating a fundamental transformation in the design and development of innovative custom-made drug products. Warfarin sodium, a cardiovascular drug, is the poster child of model-informed tailoring dose strength by combining different doses of tablets or splitting these tablets. Both approaches represent known challenges. Thus, to achieve the full potential of precision medicine, innovative formulation technologies are needed to tailor solid dosage forms.1

The presented study uses crystallization process to manufacture crystalline solid dispersions (CSD) as solid dosage forms for warfarin sodium with model informed precision dosing. This additive manufacturing processes dispenses a solution of the drug dissolved in a binary solution of solvent and polymer into a carrier followed by an antisolvent addition to trigger an antisolvent crystallization. Upon evaporation of the solvent a CSD is formed. Paramount for the crystallization process design is the determination of the thermodynamic design space within the ternary system to control the solid form (crystalline versus amorphous) within the forming polymer matrix. Critical process parameters, e.g., temperature, concentration, and antisolvent composition, were evaluated to map the design space for the crystallization process. The obtained CSD formulations with individualized dosage strength were characterized by PXRD, Raman, DSC and TGA. Drug loading, content uniformity, and dissolution studies followed US Pharmacopeia methods and are compared to commercial tablets of warfarin sodium.

The presented workflow and insight provides a generalizable approach applicable to other drugs while enhancing the understanding of a for small-scale solid-dosage manufacturing via a combination of crystallization and process intensification.2

(1) Martínez-Jiménez, J. E.; Sathisaran, I.; Reyes-Figueroa, F.; Reyes, S.; López-Nieves, M.; Vlaar, C. P.; Monbaliu, J.-C. M.; Romañach, R.; Ruaño, G.; Stelzer, T.; et al. A Review of Precision Medicine in Developing Pharmaceutical Products: Perspectives and Opportunities. Int. J. Pharm. 2025, 125070. https://doi.org/https://doi.org/10.1016/j.ijpharm.2024.125070.

(2) Stelzer, T.; Lakerveld, R.; Myerson, A. S. Process Intensification in Continuous Crystallization. In The Handbook of Continuous Crystallization; Yazdanpanah, N., Nagy, Z. K., Eds.; The Royal Society of Chemistry, 2020; pp 266–320. https://doi.org/10.1039/9781788013581-00266.