Excipient variability critically impacts crystallization propensity of spray-dried amorphous solid dispersions.

Abstract

Polymeric amorphous solid dispersions (ASDs) are frequently used to improve solubility and oral bioavailability of poorly water-soluble drugs. The goal of the current investigation was to correlate the variability in the presence of polymeric stabilizer, from different sources and batches, with the stability of the spray-dried ASDs. Polyvinylpyrrolidone-vinyl acetate (PVPVA) and griseofulvin (GSV) were selected as model stabilizer and drug, respectively. Powder X-ray diffraction (pXRD), Differential Scanning Calorimetry (DSC), and Polarized Light Microscopy (PLM) confirmed the amorphous form and phase homogeneity of the spray-dried ASDs. pXRD and modulated DSC were used to determine the functionality (% crystallization) and intermediate functionality (enthalpy relaxation) of PVPVA, respectively, in spray-dried ASDs. The variability in different physicochemical properties of PVPVA, viz. glass transition temperature, viscosity of PVPVA solution in acetone, K-value, residue on ignition, true density, increase in water activity after storage, surface free energy, solvent evaporation kinetics, and diffusion coefficient of GSV in acetone in presence of PVPVA, were measured. Later, these properties were correlated with functionality and intermediate functionality using Pearson's correlation coefficient. Strong correlation (r ≥ 0.6) was observed with solvent evaporation kinetics, diffusion coefficient of GSV in acetone, in presence of PVPVA (indicates interaction of drug with polymer in feed solution of spray drying), K-value (indicates polymer molecular weight and chain length), and increase in water activity after storage (indicates interaction of polymer with water). Functionality-related characteristics (FRCs), and their corresponding functionality-related tests (FRTs), that can affect the functionality of PVPVA, as a stabilizer in GSV-PVPVA spray-dried ASD have been proposed. The learnings of this study will be beneficial to ensure robust performance of spray-dried ASDs containing other poorly soluble drug(s) and water soluble polymer(s). Due attention should be paid to ensure compliance to the proposed FRCs of the stabilizer from different batches and sources, during the manufacturing of spray-dried ASD, to ensure consistent quality and performance.