(774a) Understanding the Role of Hpmcas in Phenytoin Solid Dispersion Formulation Using Coarse Grained Molecular Dynamics Simulations

Many orally administrated drug candidates currently being developed are highly lipophilic, which necessitates the use of an excipient to stabilize and increase their solubility in the gastrointestinal tract. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been identified to be a very effective excipient; however, to date very little understanding has been established on how HPMCAS interacts with drug molecules at a molecular level, and how different structural variables such as molecular weight and substitution pattern affect the performance of HPMCAS as an excipient. In this study, we employed coarse-grained (CG) molecular dynamics (MD) simulations to model HPMCAS and a drug candidate, phenytoin, in an implicit water environment. We parameterized our CG model using the radial distribution functions (RDFs) from atomistic simulations of short HPMCAS oligomers and applied the model to simulate long chains. We studied the effect of individual substitution type (e.g. methyl, hydroxypropyl, acetate etc.) by simulating homogenous polymer chains with drug molecules. We found the conformation and the structural details of the polymer-drug complex are affected by monomer substitution type, the amount of polymer loading, and polymer length. Specifically, bulky hydroxypropyl group results in a more loosely packed polymer matrix, thus allowing drug molecules to diffuse through the matrix more easily. The use of high polymer concentration (>80 wt%) can significantly reduce the size of the drug aggregates in the complex. We determined the drug release rate for different polymer-drug complex by running simulations for over 50μs. We also modeled the heterogeneous copolymer and investigated the effect of deprotonated succinate substitution on the release behavior. We found that the polymer-drug complex swells when succinate groups switch from protonated to deprotonated state, thus facilitates the release of the drug molecules. Our simulation box size is comparable to the size of polymer-drug complex identified from the experiment. This study provides insights to help optimizing the composition of HPMCAS (e.g. ratio of acetate to succinate group) for any given drug.