Polymer mediated drug supersaturation controlled by drug-polymer interactions persisting in aqueous environment.

Research paper by Yuejie Y Chen, Yipshu Y Pui, Huijun H Chen, Shan S Wang, Peter P Serno, Wouter W Tonnis, Linc L Chen, Feng F Qian

Indexed on: 20 Nov '18Published on: 20 Nov '18Published in: Molecular Pharmaceutics


We investigated the drug-polymer interactions in non-aqueous and aqueous environments between a poorly water-soluble drug, BAY1161909 (909), and two commonly used polymers in amorphous solid dispersions, i.e., PVP and HPMC-AS. In non-aqueous state, drug-polymer Flory-Huggins interaction parameter, solution NMR and FT-IR results revealed that strong specific interactions existed between 909 and PVP, while not between 909 and HPMC-AS. After prolonged moisture exposure under 95% RH, 909/PVP intermolecular interaction no longer existed, while hydrophobic interaction between 909 and HPMC-AS occurred and persisted. In aqueous supersaturation study of 909, co-dissolved PVP significantly outperformed pre-dissolved PVP in maintaining 909 supersaturation. We hypothesized that the co-dissolved PVP formed specific interaction with 909 thus was able to prolong 909 supersaturation before disruption of the interaction in aqueous medium, while pre-dissolved PVP formed hydrogen bonds with water thus was no longer able to form specific interactions with 909 to prolong its supersaturation. In contrast, HPMC-AS effectively mediated 909 supersaturation through hydrophobic interaction, which became pronounced in aqueous environment and was independent of how HPMC-AS was added. This hypothesis was supported by dynamic light scattering analysis, wherein the formation of nano-sized drug/polymer aggregations was found to be correlating with the supersaturation of 909. In summary, we concluded that polymer mediated drug supersaturation was controlled by drug-polymer interactions persisting in aqueous environment. Therefore, the physical nature of drug-polymer interaction, as well as the dissolution kinetic of the drug and polymer, are all critically important to achieve an optimal ASD formulation design.