Matrix-Assisted Cocrystallization: The simulataneous production and formulation of pharmaceutical cocrystals using melt extrusion
Abstract
Matrix-Assisted Cocrystallization (MAC) is introduced herein as a novel method of manufacturing pharmaceutical cocrystals, by extruding a drug and coformer in the presence of a functional matrix material made liquid by the temperature of the extruder. MAC is a solvent-free, scalable, and potentially continuous process that minimizes degradation of the drug and coformer by reducing thermal and mechanical stresses during production compared to other solid-state cocrystallization methods. The development of MAC presented in this work focuses on the ability of MAC to produce cocrystals that are equivalent to solution-made cocrystals, the effects of extrusion processing parameters on MAC products and efficiency of cocrystal conversion, and the pharmaceutically relevant performance of the resulting MAC products. Using carbamazepine and sulfamethazine as model drugs, and nicotinamide and saccharin as model coformers, MAC was demonstrated to produce cocrystals that were near-equivalent to reference materials in solid-state analysis. A predictive model based on partial least squares regression was used to determine MAC product composition, which confirmed the qualitative analytical findings, and also identified differences in MAC products that were made using extrusion conditions of varying temperature, screw speed, and residence time. Using elevated shear stress (low temperature, high screw speed, high residence time) in the extrusion process produced the highest cocrystal conversion from starting components. MAC products showed to be superior to pure cocrystal in the ability to form and maintain supersaturated drug solutions upon dissolution, as a result of drug solubilization and inhibition of lower solubility drug forms. The cocrystal phase of MAC products exhibited no dissociation during storage, meaning that MAC can produce stable cocrystals that are simultaneously formulated for enhanced dissolution behavior.
Degree
Ph.D.
Advisors
Pinal, Purdue University.
Subject Area
Pharmacy sciences
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