title: The solubility-permeability interplay and oral drug formulation design: Two heads are better than one.
abstract: Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility-permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure. Overall, depending on the type of solubility-permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: arikd@bgu.ac.il.
authors.forename: Arik
authors.initials: A
authors.lastname: Dahan
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Beig
authors.affiliation: AbbVie Incorporation, North Chicago, IL 60064, United States.
authors.forename: David
authors.initials: D
authors.lastname: Lindley
authors.affiliation: AbbVie Incorporation, North Chicago, IL 60064, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Miller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics; D002463:Cell Membrane Permeability; D004339:Drug Compounding; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations
keywords: Biopharmaceutics Classification System (BCS); Drug solubility; Intestinal permeability; Solubility-enabling formulations; Solubility–permeability tradeoff