Phase behavior of pharmaceutically relevant polymer/solvent mixtures

Abstract

In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.

Keywords: Amorphous solid dispersion; HPMCAS; Liquid-liquid phase separation; Miscibility gap; PC-SAFT; PVP; PVPVA64; Solvent selection.