Deconstructing HPMCAS: Excipient Design to Tailor Polymer-Drug Interactions for Oral Drug Delivery

Abstract

Spray-dried dispersions (SDDs) are fascinating polymer-drug mixtures that exploit the amorphous state of a drug to dramatically elevate its apparent aqueous solubility above equilibrium. For practical usage in oral delivery, understanding how polymers mechanistically provide physical stability during storage and prevent supersaturated drugs from succumbing to precipitation during dissolution remains a formidable challenge. To this end, we developed a versatile polymeric platform with functional groups analogous to hydroxypropyl methyl cellulose acetate succinate (HPMCAS, a heterogeneous leading excipient candidate for SDDs) and studied its interactions with Biopharmaceutical Classification System Class II drug models probucol, danazol, and phenytoin at various dosages. By conducting reversible addition-fragmentation chain transfer polymerizations with monomeric components chemically analogous to HPMCAS, we synthetically dismantled the highly polydisperse architecture of HPMCAS into well-defined polymer systems (i.e., targetable M_n, Đ < 1.3, tunable T_g). In the powdered SDD form, by wide-angle X-ray diffraction all HPMCAS analogs yielded amorphous danazol and phenytoin up to 50 wt % loading, whereas for probucol, hydrophobic methoxy functionality and high polymeric T_g were key to inhibit immediate partitioning into crystalline domains. Nonsink in vitro dissolution tests revealed distinct release profiles. The polymer containing only acetyl and succinoyl substituents spray-dried with probucol increased the area under the dissolution curve by a factor of 180, 112, and 26 over pure drug at 10, 25, and 50 wt % loading, respectively. For crystallization-prone danazol and phenytoin, we observed that the water-soluble polymer with hydroxyl groups inhibited crystal growth and enabled high burst release and supersaturation maintenance. Our findings provide fundamental insight into how excipient microstructures can complex with drugs for excipient formulation applications.

Keywords: HPMCAS; amorphous solid dispersions; oral drug delivery; polymer-drug interactions; precipitation inhibition.