Karen Kleberg1, Jette Jacobsen, Anette Müllertz. 1. Department of Pharmaceutics and Analytical Chemistry Bioneer:FARMA, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark.
Abstract
OBJECTIVES: Based on the knowledge of human intestinal fluids, compositions of biorelevant media and their impact on solubility, dissolution and permeability studies of poorly soluble drug compounds are discussed. KEY FINDINGS: Human intestinal fluids show large variations with regard to composition and pH, which complicate the selection of biorelevant media. The influence of concentration and ratio of bile salts, phospholipids and hydrolysis products, such as monoglycerides and free fatty acids, in well characterised media, on the solubility, dissolution and permeability of a given drug provides valuable information on the behaviour of the drug in the intestine, thus enabling the prediction of the in-vivo absorption. SUMMARY: This review discusses the implications of biorelevant media composition on the solubility, dissolution and permeability of poorly soluble drug compounds. Biorelevant media contain bile salts and phospholipids and when simulating the fed state also monoglycerides and free fatty acids. Solubility of some poorly soluble drugs increase independently of the type of surfactants included in the biorelevant media, while others have a higher solubility in monoglyceride- and fatty acid-containing media. This is independent of the log P (the octanol-water partition coefficient) of the drug. The use of biorelevant dissolution media improves the correlation to in-vivo data, compared with compendial media, and although the field of permeability studies is complex the use of biorelevant media in this setting shows promise with respect to a better prediction of absorption.
OBJECTIVES: Based on the knowledge of human intestinal fluids, compositions of biorelevant media and their impact on solubility, dissolution and permeability studies of poorly soluble drug compounds are discussed. KEY FINDINGS:Human intestinal fluids show large variations with regard to composition and pH, which complicate the selection of biorelevant media. The influence of concentration and ratio of bile salts, phospholipids and hydrolysis products, such as monoglycerides and free fatty acids, in well characterised media, on the solubility, dissolution and permeability of a given drug provides valuable information on the behaviour of the drug in the intestine, thus enabling the prediction of the in-vivo absorption. SUMMARY: This review discusses the implications of biorelevant media composition on the solubility, dissolution and permeability of poorly soluble drug compounds. Biorelevant media contain bile salts and phospholipids and when simulating the fed state also monoglycerides and free fatty acids. Solubility of some poorly soluble drugs increase independently of the type of surfactants included in the biorelevant media, while others have a higher solubility in monoglyceride- and fatty acid-containing media. This is independent of the log P (the octanol-water partition coefficient) of the drug. The use of biorelevant dissolution media improves the correlation to in-vivo data, compared with compendial media, and although the field of permeability studies is complex the use of biorelevant media in this setting shows promise with respect to a better prediction of absorption.