Developing multi-component solid formulation strategies for PROTAC dissolution enhancement [dataset]

PROTACs are an emerging class of beyond-rule-of-5 molecular drugs currently under clinical investigation for the treatment of malignant diseases and are capable of degrading previously “undruggable” protein targets. They are poorly crystallizable due to their structure, consisting of two ligands joined chemically by a flexible linker, and yet the inherent insolubility of their amorphous phases hinders their development into sufficiently bioavailable medicines. Formulation approaches to improve the dissolution properties of PROTACs are required as a result, but research in this area is made even more challenging by the scarcity of available samples. In this work, amorphous solid dispersion (ASD) formulations of four cereblon-recruiting PROTACs ‘AZ1-4’ using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a polymer excipient are described. ASDs of AZ1 showed up to a 2-fold increase in drug supersaturation compared to the pure amorphous API, observed up to a drug loading of 20 % w/w. Preparing the ASDs by slurry conversion offers greater solubility enhancement over those prepared by solvent evaporation and maintains the dissolution advantage up to a higher drug load. Positive deviations from theoretical Tg values coupled with a lack of spectral evidence of drug-polymer hydrogen-bond interactions suggest that the ASDs may differ from ideal mixtures via predominantly dispersive drug-polymer interactions. ASDs that provided a dissolution enhancement were stored at elevated temperature and humidity for one month and showed no sign of plasticization or loss of physical stability. Co-amorphous formulations using low molecular weight excipients, by contrast, showed no dissolution advantage despite evidence of drug-coformer hydrogen-bonding interactions, proving the need for a greater understanding of how to develop successful formulation approaches to bRo5 compounds.