43 JPP 2004, 56: 43–51 ß 2004 The Authors Received June 04, 2003 Accepted September 23, 2003 DOI 10.1211/0022357022511 ISSN 0022-3573 Department of Pharmaceutical Technology, J. W. Goethe University, Marie-Curie Str. 9, D-60439 Frankfurt am Main, Germany Edmund S. Kostewicz*, Martin Wunderlich, Jennifer B. Dressman Boehringer Ingelheim Pharma KG, Birkendorfer Str. 65, D-88397 Biberach an der Riss, Germany Ulrich Brauns, Robert Beckery, Thomas Bock Correspondence: J. B. Dressman, Department of Pharmaceutical Technology, J. W. Goethe University, Marie-Curie Str. 9, D-60439 Frankfurt am Main, Germany. E-mail: Dressman@em.uni-frankfurt.de Acknowledgement: The results have partly been presented at the AAPS Conference in New Orleans (1999), the APV Conference in Berlin Germany (2000) and the EUFEPS World Conference in Copenhagen Denmark (2001). Current address: *Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; yStresemannstr. 40, D-88400 Biberach, Germany. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine Edmund S. Kostewicz, Martin Wunderlich, Ulrich Brauns, Robert Becker, Thomas Bock, and Jennifer B. Dressman Abstract Solubility and dissolution relationships in the gastrointestinal tract can be critical for the oral bioavailability of poorly soluble drugs. In the case of poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may also affect the amount of drug available for uptake through the intestinal mucosa. To simulate the transfer out of the stomach into the intestine, a transfer model was devised, in which a solution of the drug in simulated gastric fluid is continuously pumped into a simulated intestinal fluid, and drug precipitation in the acceptor medium is examined via concentration–time measurements. The in-vitro precipitation of three poorly soluble weakly basic drugs, dipyridamole, BIBU 104 XX and BIMT 17 BS, was investigated. For all three, extensive supersaturation was achieved in the acceptor medium. Under simulated fasted-state conditions, precipitation occurred for all three compounds whereas under simulated fed-state conditions, the higher concentrations of bile components and the lower pH value in the acceptor medium inhibited precipitation at concentrations corresponding to usual doses in all cases. Comparison with pharmacokinetic data indicated that a combination of transfer model data with solubility and dissolution profiles should lead to better predictions of in-vivo behaviour of poorly soluble weak bases. Introduction The rate at which a drug goes into solution is an important determinant of drug absorption from the gastrointestinal tract. Factors that are important to the kinetics of drug dissolution, as identified by the Nernst-Brunner and Levich modifications of the Noyes-Whitney model (Noyes & Whitney 1897; Nernst & Brunner 1904; Levich 1962), are the physicochemical properties of the compound itself such as pK a , solu- bility, crystalline energy and specific surface area, as well as certain aspects of the prevailing conditions in the gastrointestinal tract. The physiological parameters that can play an important role include pH, surface tension, solubilisation, buffer capacity and the volume of the lumenal contents. These parameters not only vary widely with position in the gastrointestinal tract, but are also subject to change following the ingestion of food. The pH of the gastrointestinal fluids is of vital importance to the solubility of ionisable drugs. For weak acids and bases the solubility is dependent on the com- pound’s ionisation constant and the pH of the local environment. Reduction of the pH below the pK a value for weak bases, for example, leads to an increase in solubility due to the contribution of the more soluble, ionised form of the drug. As the pH in the gastrointestinal tract varies widely with location, one can expect significant changes in solubility during gastrointestinal passage. Bile components, including bile salts and lecithin, have also been shown to increase the in-vitro dissolution rate for numerous poorly soluble compounds (Bates et al 1966; Mithani et al 1996). Enhancement of the dissolution rate in the presence of bile salts and lecithin can occur by an increase in solubility via micellar solubilization (at concentrations above the critical micellar concentration) or by the enhancement of the wettability of the compound. The greater concentrations of bile components in the intestine following meal intake (Fausa 1974;