Precipitation Behavior of Highly Soluble Amphiphilic Drugs in Solution: Physical Instability of Drugs in Solution.

Physical instability of aqueous drug solutions, such as precipitation upon storage, has so far been difficult to predict or model. Understanding the molecular basis of such phenomena can help mitigate by influencing the product composition and by providing a mechanistic basis of experimental and in silico investigations. In this study, inconsistent precipitation of a model drug, GNE-01 in aqueous solutions was investigated. Chromatographic analyses of the drug solution that showed precipitation upon storage versus the one that did not indicate lack of covalent modification or degradation of the drug, suggesting that the precipitation was a physical phenomenon. Molecular level investigations were conducted using surface tension measurement and nuclear magnetic resonance (NMR) spectroscopy. The studies revealed self-association of the weakly basic drug in solution at slightly acidic pH values which was strengthened by the presence of polyionic excipients. The role of polyionic excipients in facilitating drug precipitation on storage was indicative of shifting solution equilibria in favor of a lower solubility drug-excipient complex. This study highlighted the importance of molecular understanding in mitigating difficult to predict physical instability of self-associating drugs in solution.