(63e) Computational Screening of Cellulosic Excipients for Drug Delivery

Solid dispersions of cellulosic polymers such as hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are widely used in the oral delivery of poorly soluble active pharmaceutical ingredients (APIs). The presence of three substitution positions on each monomeric unit of cellulosic polymers facilitates the chemical design of excipients with varying degrees of hydrophobicity. However, the large design space of cellulosic polymers also poses a technological challenge of designing polymers with optimal properties for a given API. We use atomistic molecular dynamics simulations to study excipient-API interactions and compare the efficiency of different excipients for representative APIs.  Simulations reveal formation of excipient-API complexes for some of the excipients and drugs, which results in a reduction of drug aggregation and crystallization. Beyond a certain excipient weight percent, the excipient forms a “gel”-like phase spanning the simulation box with API molecules encapsulated inside, which considerably slows API diffusion. Substantial differences are observed with variations in methyl, hydroxypropyl, acetate, and succinate substitution levels in the excipients. Further, the protonation state of succinate groups in HPMCAS substantially influence the complexation behavior, signaling possible excipient response to pH changes in the stomach and GI tract. Simulations are also performed with seed drug crystals to understand excipient effect on crystal nucleation and growth. Quantitative measures developed in this study are expected to prove useful as computational screening tools in excipient design.