Sacubitril-valsartan cocrystal revisited: role of polymer excipients in the formulation

Objectives: This study investigated the impact of polymer excipients on a typical cocrystal for sacubitril (SAC) and valsartan (VAL), aiming to guide optional formulation design and maximize oral bioavailability.Methods: Poly vinyl pyrrolidone (PVP) and hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) were selected. The dissolution/permeation system was used to predict both the kinetics of drug supersaturation and the simple permeation. The intermolecular interaction was analyzed by ¹H NMR spectroscopy and molecular dynamics simulation. Pharmacokinetic study was performed to assess the impact of polymer excipients in vivo.Results: Our study found that unappreciated excipients in the formulation, especially some polymers, might compete with the intermolecular hydrogen bonding among the cocrystals components and provide unexpected affinity, and thus leverage the therapeutic benefits. HPMC as a coating excipient used in the Entresto® tablet hampered the supersaturation of API, which led to the poor oral absorption of cocrystals. Conversely, PVP appeared to promote and maintain drug supersaturation, resulting in improved bioavailability of API.Conclusion: In conclusion, understanding the interplay between the cocrystal components and polymers is the key to optimizing the excipients to maximize the performance of cocrystal based oral drug formulation.