A PROCESS FOR CONTROLLED CRYSTALLIZATION OF AN ACTIVE PHARMACEUTICAL INGREDIENT FROM SUPERCOOLED LIQUID STATE BY HOT MELT EXTRUSION.

摘要

A process for controlling the crystallization of certain hydrophobic active pharmaceutical ingredients (APIs) from a supercooled liquid state by hot-melt extrusion processing is described. Also provided is a pharmaceutical composition comprising a solid crystalline dispersion of a cholesterol ester transfer protein inhibitor in a hydrophilic excipient matrix. By the claimed process, the API is fed to an extrusion system in a crystalline state contemporaneously with carrier excipients where it is first converted to a non-crystalline state by the application of heat and then subsequently recrystallized in-situ by the removal of heat and application of shear. Recrystallization of the API is controlled by carrier formulation design and the hot-melt extrusion process parameters; i.e. barrel temperature profile, feed rate, etc. The resultant product is a crystalline solid dispersion of the API in the excipient matrix where the mean particle diameter of the API after processing is reduced as compared to the API in the process feed. The resultant product exhibits a more rapid rate of dissolution as compared to the crystalline API formulated by conventional means; e.g. micronization or co- micronization. The carrier system is comprised of at least one thermoplastic, hydrophilic polymer and may also contain various functional excipients, such as: antioxidants, surfactants, wetting agents, disintegrants, stabilizing agents, acidifying agents, or similar functional excipients.