High-Throughput Microarray Approaches for Predicting\nthe Stability of Drug–Polymer Solid Dispersions

Amorphous solid dispersions\n(ASDs) offer a well-recognized strategy\nto improve the effective solubility and, hence, bioavailability of\npoorly soluble drugs. In this study, we developed an extensive library\nof a significant number of solid dispersion formulations using a library\nof chemically diverse drugs combined with a water-soluble polymer\n(polyvinylpyrrolidone vinyl acetate, PVPVA) at different loadings.\nThese formulations were printed as microarrays of solid dispersion\nformulations, utilizing minimal material amounts (nanograms). They\nwere subjected to a six-month stability study under accelerated conditions\n(40 °C and 75% relative humidity). Physical stability outcomes\nvaried significantly among the different drug–polymer combinations,\nwith stability ranging from immediate drug crystallization to several\ndays of stability. The comprehensive data set obtained from this high-throughput\nscreening was used to construct multiple linear regression models\nto correlate the stability of ASDs with the physicochemical properties\nof the used Active Pharmaceutical Ingredients (APIs). Our findings\nreveal that increased stability of ASDs is associated with a lower\nnumber of hydrogen bond acceptors alongside a higher overall count\nof heteroatoms and oxygen atoms in the drug molecules. This suggests\nthat, while heteroatoms and oxygen are abundant, their role as hydrogen\nbond acceptors is limited due to their specific chemical environments,\ncontributing to overall stability. Additionally, drugs with lower\nmelting points formed more stable ASDs within the polymer matrix.\nThis study, hence, highlights the importance of minimizing repulsive\ndrug–polymer interactions to yield a physically stable ASD.\nThe developed models, validated through Leave-One-Out Cross-Validation,\ndemonstrated good predictability of stability trends. Hence, the high-throughput\n2D inkjet printing technique that was used to manufacture the microarrays\nproved valuable for assessing drug–polymer crystallization\nonset risks and predicting stability outcomes. In conclusion, this\nstudy demonstrates a novel approach to solid dispersion formulation\nphysical stability screening, enhancing efficiency, minimizing material\nrequirements, and expanding the range of samples evaluated. Our findings\nprovide insights into the critical physicochemical properties influencing\nASD stability, offering a significant advancement in developing stable\nASDs.