Prediction of Solvent Penetration Rate-Limited Release of Drug from Amorphous Solid Dispersion Discs of Various...

Studies have frequently shown that successful drug release from amorphous solid dispersions (ASDs) is highly dependent on polymer dissolution. Underpinning drug release from ASDs is a series of complex steps involving solvent penetration into the glassy core, gel formation and swelling, and colloid formation and release. The objective of this study was to predict ritonavir (RTV) and polymer release from ASDs of RTV and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) from discs with varying geometries based solely on solvent penetration. Using vacuum compression molding, ASD discs containing RTV/PVPVA were fabricated with drug load ranging from 0 to 50%. Three disc geometries were 8 mm thin disc, 20 mm thin discs, and 8 mm thick discs, where 8 and 20 mm denoted disc diameter. Hence, ASDs varied in drug load and geometry. ASDs were subjected to microscope-enabled disc dissolution system (MeDDiS) testing (i.e., simultaneous imaging and dissolution from disc side) as well as USP II dissolution testing, which allowed release from additional surfaces. Five disc models were derived based on solvent penetration and varied in releasing surface areas [i.e., disc side model, disc top and bottom (T&B) model, disc top model, sunken disc model, and total disc model]. Solvent penetration rate was visually observed to be rate-limiting and was quantitatively measured from MeDDiS imaging, where the solvent penetration rate was approximately the same across drug loads from 0 to 25% and across disc geometries. Predicted drug and polymer release was obtained from each of the five disc dissolution models for each of the three disc geometries, including base-case models that reflected visual observations of disc dissolution (i.e., disc side model for MeDDiS and either sunken disc model or total disc model for USP II). There was excellent agreement between predicted and observed ASD drug (and polymer) release. In particular, the observed drug and polymer release from MeDDiS closely matched the disc side model, reflecting the base-case of only release from the disc side. Meanwhile, release from USP II testing closely matched the base-cases of the sunken disc model (for 8 mm thin and 8 mm thick discs) and the total disc model (for 20 mm discs). However, predicted profiles were slightly faster than the observed profiles, indicating solvent penetration was rate-dominating, although not the only barrier to drug and polymer release. Results here indicate successful model predictions of drug release from a well-studied ASD drug/polymer pair, which has promise to aid the understanding of less well-studied ASDs.