Impact of Polymer Colloids and Protein Degrader Flexibility on the Speciation of Spray-Dried Dispersions in Biorelevant Media

Impact of Polymer Colloids and Protein Degrader Flexibility on the Speciation of Spray-Dried Dispersions in Biorelevant Media

Wesley K. Tatum,  Gursirat S. Grewal, Sorfina Suzali, Parker Borne, James Maxwell Frisbie, Erica Schlesinger ​

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Introduction:

• Amorphous solid dispersions (ASDs) enhance absorption via supersaturation of free drug and the formation of drug-polymer colloids

• Drug-polymer colloids increase diffusion through the unstirred water layer to rapidly resupply free drug as it is absorbed

• Recent publications^{1, 2} highlight the need to understand how speciation impacts dissolution, supersaturation, and permeability

• Protein degraders are large, flexible, and poorly soluble molecules that demonstrate complex conformational behaviors. This flexibility enables chameleonicity, that satisfies hydrophobic/hydrophilic interactions of the API molecules ³

• Anecdotally, some protein degraders exhibit self-association in aqueous solutions – forming amorphous nano-aggregates. We hypothesize that this phenomena for self-association is related to chameleonicity and linker flexibility and is important for understanding speciation in a protein degrader ASD

• This study evaluates the speciation of three chemically similar protein degraders with different linker lengths in biorelevant media both on their own and in the presence of HPMCAS-M colloids

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Conclusions:

• Centrifugation has minimal effect on separating empty polymer colloids by size, however a more significant effect in separating species through centrifugation is observed in the presence of API and polymer

• The larger count rate of samples with polymer represents the presence of polymer colloids which the API can partition into. This correlates with the higher assay values observed when HPMCAS-M is present

• Despite differences in API solubilities, similar assay values were observed for all APIs in the presence of HPMCAS-M and evidence of self-association as a function of linker length was reduced suggesting that partitioning into HPMCAS colloids may not be heavily influenced by linker length and chameleonicity