title: Cocrystal Transition Points: Role of Cocrystal Solubility, Drug Solubility, and Solubilizing Agents.
abstract: In this manuscript we bring together concepts that are relevant to the solubilization and thermodynamic stability of cocrystals in the presence of drug solubilizing agents. Simple equations are derived that allow calculation of cocrystal solubilization and transition point solubility. Analysis of 10 cocrystals in 6 different solubilizing agents shows that cocrystal solubilization is quantitatively predicted from drug solubilization. Drug solubilizing agents such as surfactants and lipid-based media are also shown to induce cocrystal transition points, where drug and cocrystal solubilities are equal, and above which the cocrystal solubility advantage over drug is eliminated. We have discovered that cocrystal solubility at the transition point (S*) is independent of solubilizing agent, and can be predicted from knowledge of only the aqueous solubilities of drug and cocrystal. For 1:1 cocrystals, S* = (Scocrystal,aq)(2)/Sdrug,aq. S* is a key indicator of cocrystal thermodynamic stability and establishes the upper solubility limit below which cocrystal is more soluble than the constituent drug. These findings have important implications to tailor cocrystal solubility and stability in pharmaceutical formulations from commonly available drug solubility descriptors.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Maya P
authors.initials: MP
authors.lastname: Lipert
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Naír
authors.initials: N
authors.lastname: Rodríguez-Hornedo
mesh_terms: D003460:Crystallization; D004355:Drug Stability; D008055:Lipids / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D008055:Lipids; D004364:Pharmaceutical Preparations; D013501:Surface-Active Agents
keywords: biorelevant media; co-crystal; cocrystal; enhancing solubility; formulation; lipids; micelles; solubilization; solubilizing agent; stability; surfactant; transition point