Tuning Bottlebrush Polymer Architecture and Composition of Poly(acrylic acid) Improves GDC-0810 Drug Solubility...

Noncovalent interactions between a polymer excipient and an active pharmaceutical ingredient (API) are important for achieving the solubility of APIs as amorphous solid dispersion (ASD) formulations. Herein, we examined how polymer architecture, the placement of acrylic acid moieties in bottlebrush polymer architectures, and total carboxylic acid content affect the dissolution of GDC-0810, a class II breast cancer therapeutic. Four bottlebrush polymers and linear analogues were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and ring-opening metathesis polymerization (ROMP). The polymers were composed of poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) and poly(acrylic acid) (PAA) with carboxylic acid content of 0-1960 units. The ASDs containing 40 wt % GDC-0810 exhibited a linear performance trend, correlating improved performance to increased carboxylic acid content in bottlebrush polymers, indicating the importance of electrostatic repulsions with the weak acid API on dissolution efficacy. This work demonstrates the importance of architecture, placement, and amount of carboxylate groups in excipient performance.