Binary isobaric phase diagrams of stearyl alcohol-poloxamer 407 formulations in the molten and solid state

Abstract

Multiparticulate formulations allow for the design of specialized pharmaceutical dosage forms that cater to the needs of a wide range of patient demographics, such as pediatric and geriatric populations, by affording control over the release rate and facilitating the formulation of fixed-dose combination drugs. Melt spray-congealing (MSC) is a method for preparing multiparticulate dosage forms from a suspension or solid solution of active pharamaceutical ingredients (API) and a molten carrier matrix. Stearyl alcohol and poloxamer 407 mixtures are widely used as carrier matrices in MSC microsphere formulations. In this report, the phase equilibria of stearyl alcohol-poloxamer 407 mixtures were investigated by generating binary phase diagrams of composition, i.e. weight/weight percent of poloxamer 407 in stearyl alcohol, and temperature in the molten form and the solid state. The phase equilibria of the molten state were characterized by ¹H NMR measurements. The miscibility curves of stearyl alcohol-poloxamer 407 molten mixtures revealed that stearyl alcohol and poloxamer 407 are not miscible in all proportions and that miscibility substantially increases with temperature. The phase equilibria of the solid state were characterized by DSC and PXRD experiments. The phase diagrams of the solid state indicate that stearyl alcohol and poloxamer 407 crystallize and melt separately and, thus, do not form a eutectic or a single phase. The phases equilibria of the bulk mixtures were compared to the phases observed in placebo MSC microspheres and it was determined that the microspheres consist of a mixture of thermodynamically stable and metastable stearyl alcohol crystals immediately after manufacture.

Keywords: Melt-spray-congeal; Miscibility; Multiparticulates; Phase equilibria; Poloxamer 407; Stearyl alcohol.