Quasi-Emulsion Precipitation of Pharmaceuticals. 2. Application to Control of Polymorphism

Abstract

Under a number of mixing conditions, a quasi-emulsion is formed during solute precipitation in which the solvent [e.g., 60 mass % polyethylene glycol 300 (PEG300) in water] is more viscous than the antisolvent (e.g., water).8 This microscopically segregated dispersion typically results in an increase in nucleation induction time, and this behavior can be exploited to control the polymorphic form produced during antisolvent precipitation. For three pharmaceutical solutes that form polymorphs (methylparaben, p-aminobenzoic acid, and sulfanilamide), it is demonstrated that quasi-emulsion precipitation results in the formation of the stable polymorphic form. On the other hand, when the fluid is rapidly mixed to homogeneity, a metastable polymorph form is first produced. Thus, polymorph formation can be highly mixing sensitive. When a solute is dissolved in a solvent less viscous than the antisolvent as is the case for the precipitation of glycine from water with aqueous PEG300, quasi-emulsions are not formed, and the metastable polymorph is first formed unless extreme fluid segregation (no agitation) is employed.