[en] 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.
Research Center/Unit :
MolSys - Molecular Systems - ULiège Center for Integrated Technology and Organic Synthesis
Mbodji, Aliou ; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, United States
Cruz, Kelitsha Mulero; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, United States, Department of Environmental Sciences, University of Puerto Rico, Rio Piedras Campus, San Juan, PR 00926, United States
Gómez, Andrea Arroyo; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, United States, Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, San Juan, PR 00926, United States
Vlaar, Cornelis P ; Department of Pharmaceutical Sciences, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, United States
Duconge, Jorge ; Department of Pharmaceutical Sciences, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, United States
Cersonsky, Rose K ; Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53705, United States
Yu, Lian; School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, Unites States, Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, United States
Zhang, Geoff Gz ; Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN 47907, United States, ProPhysPharm, Lincolnshire, IL 60069, United States
Coquerel, Gérard ; SMS Laboratory EA3233, University of Rouen Normandy, Mont Saint Aignan CEDEX, F-76821, France
Romañach, Rodolfo J ; Department of Chemistry, University of Puerto Rico, Mayaguez Campus, Mayaguez, PR 00681, United States
Stelzer, Torsten ; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, United States, Department of Pharmaceutical Sciences, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, United States. Electronic address: torsten.stelzer@upr.edu
Language :
English
Title :
Controlled API crystallization during additive manufacturing of solid dosage form for flexible integrated pharmaceutical manufacturing.
NASA - National Aeronautics and Space Administration NSF - National Science Foundation UPR - Universidad de Puerto Rico
Funding text :
This work was primarily supported by the National Aeronautics and Space Administration Experimental Program to Stimulate Competitive Research (80NSSC19M0148). Additional support was provided by the National Science Foundation (NSF) Wisconsin - Puerto Rico Partnership for Research and Education in Materials (DMR-1827894) as well as the UPR-UW PREM: Center for Advancing Research and Training for STEM Success (DMR-2425113). The Rigaku XtaLAB SuperNova X-ray micro diffractometer and TGA TA Q500 were acquired through the support of NSF under the Major Research Instrumentation Program (CHE-1626103) and the Puerto Rico Institute for Functional Nanomaterials (EPS-100241).The authors wish to thank Materials Characterization Center (MCC) at the University of Puerto Rico Molecular Sciences Research Center, particularly, Mildred Rivera-Isaac for her help with the GC analysis. We also gratefully acknowledge the support of all members of the Crystallization Design Institute (CDI) for their discussions and suggestions.
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