High-Throughput Microarray Approaches for Predicting the Stability of Drug-Polymer Solid Dispersions.

Abstract

Amorphous solid dispersions (ASDs) offer a well-recognized strategy to improve the effective solubility and, hence, bioavailability of poorly soluble drugs. In this study, we developed an extensive library of a significant number of solid dispersion formulations using a library of chemically diverse drugs combined with a water-soluble polymer (polyvinylpyrrolidone vinyl acetate, PVPVA) at different loadings. These formulations were printed as microarrays of solid dispersion formulations, utilizing minimal material amounts (nanograms). They were subjected to a six-month stability study under accelerated conditions (40 °C and 75% relative humidity). Physical stability outcomes varied significantly among the different drug-polymer combinations, with stability ranging from immediate drug crystallization to several days of stability. The comprehensive data set obtained from this high-throughput screening was used to construct multiple linear regression models to correlate the stability of ASDs with the physicochemical properties of the used Active Pharmaceutical Ingredients (APIs). Our findings reveal that increased stability of ASDs is associated with a lower number of hydrogen bond acceptors alongside a higher overall count of heteroatoms and oxygen atoms in the drug molecules. This suggests that, while heteroatoms and oxygen are abundant, their role as hydrogen bond acceptors is limited due to their specific chemical environments, contributing to overall stability. Additionally, drugs with lower melting points formed more stable ASDs within the polymer matrix. This study, hence, highlights the importance of minimizing repulsive drug-polymer interactions to yield a physically stable ASD. The developed models, validated through Leave-One-Out Cross-Validation, demonstrated good predictability of stability trends. Hence, the high-throughput 2D inkjet printing technique that was used to manufacture the microarrays proved valuable for assessing drug-polymer crystallization onset risks and predicting stability outcomes. In conclusion, this study demonstrates a novel approach to solid dispersion formulation physical stability screening, enhancing efficiency, minimizing material requirements, and expanding the range of samples evaluated. Our findings provide insights into the critical physicochemical properties influencing ASD stability, offering a significant advancement in developing stable ASDs.