title: Cocrystal Solubilization in Biorelevant Media and its Prediction from Drug Solubilization.
abstract: This work examines cocrystal solubility in biorelevant media (FeSSIF, fed-state simulated intestinal fluid), and develops a theoretical framework that allows for the simple and quantitative prediction of cocrystal solubilization from drug solubilization. The solubilities of four hydrophobic drugs and seven cocrystals containing these drugs were measured in FeSSIF and in acetate buffer at pH 5.00. In all cases, the cocrystal solubility (Scocrystal ) was higher than the drug solubility (Sdrug ) in both buffer and FeSSIF; however, the solubilization ratio of drug, SRdrug = (SFeSSIF /Sbuffer )drug , was not the same as the solubilization ratio of cocrystal, SRcocrystal = (SFeSSIF /Sbuffer )cocrystal , meaning drug and cocrystal were not solubilized to the same extent in FeSSIF. This highlights the potential risk of anticipating cocrystal behavior in biorelevant media based on solubility studies in water. Predictions of SRcocrystal from simple equations based only on SRdrug were in excellent agreement with measured values. For 1:1 cocrystals, the cocrystal solubilization ratio (SR) can be obtained from the square root of the drug SR. For 2:1 cocrystals, SRcocrystal is found from (SRdrug )(2/3) . The findings in FeSSIF can be generalized to describe cocrystal behavior in other systems involving preferential solubilization of a drug such as surfactants, lipids, and other drug solubilizing media.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065.
authors.forename: Maya P
authors.initials: MP
authors.lastname: Lipert
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065.
authors.forename: Lilly
authors.initials: L
authors.lastname: Roy
authors.affiliation: Renovo Research, Atlanta, Georgia 30316.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Childs
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065. Electronic address: nrh@umich.edu.
authors.forename: Naír
authors.initials: N
authors.lastname: Rodríguez-Hornedo
mesh_terms: D003460:Crystallization; D006863:Hydrogen-Ion Concentration; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D004364:Pharmaceutical Preparations; D014867:Water
keywords: cocrystals; food effects; mathematical model; oral absorption; physicochemical properties; poorly water-soluble drugs; preformulation; solubility; supersaturation; surfactants