The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of PVP were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.
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