Molecular dynamics simulation of amorphous hydroxypropyl-methylcellulose acetate succinate (HPMCAS): polymer model development, water distribution, and plasticization.

Molecular models for HPMCAS polymer have been developed for molecular dynamics (MD) simulation that attempt to mimic the complex substitution patterns in HPMCAS observed experimentally. These molecular models were utilized to create amorphous HPMCAS solids by cooling of the polymeric melts at different water contents to explore the influence of water on molecular mobility, which plays a critical role in stability and drug release from HPMCAS-based solid matrices. The densities found for the simulated amorphous HPMCAS were 1.295, 1.287, and 1.276 g/cm(3) at 0.7, 5.7, and 13.2% w/w water, indicating swelling of the polymer with increasing water content. These densities compare favorably with the experimental density of 1.285 g/cm(3) for commercial HPMCAS-(AQOAT AS-MF) supporting the present HPMCAS models as a realistic representation of amorphous HPMCAS solids. Water molecules were observed to be mostly isolated from each other at a low water content (0.7% w/w), while clusters or strands of water were pervasive and broadly distributed in size at 13.2% w/w water. The average number of first-shell water molecules (n(w)) increased from 0.17 to 3.5, though the latter is still far below that (8.9) expected for the onset of a separate water phase. Increasing water content from 0.7 to 13.2% w/w was found to reduce the T(g) by ~81 K, similar to experimental observations. Plasticization with increasing water content resulted in increasing polymer mobility and water diffusivity. From 0.7 to 13.2% w/w water, the apparent water diffusivity increased from 1.1 × 10(-9) to 7.0 × 10(-8) cm(2)/s, though non-Einsteinian behavior persisted at all water contents explored. This and the water trajectories in the polymers suggest that water diffusion at 0.7% w/w water follows a "hopping" mechanism. At a higher water content (13.2% w/w) water diffusion follows dual diffusive processes: (1) fast water motions within water clusters; and (2) slower diffusion through the more rigid polymer matrix.