The composite solubility versus pH profile and its role in intestinal absorption prediction.
The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile.
Hendriksen
Barry A
BA
Eli Lilly and Co, Lilly Research Centre, Windlesham, Surrey, GU20 6PH, UK. b.a.hendriksen@tesco.net
Felix
Manuel V Sanchez
MV
Bolger
Michael B
MB
D019985:Benchmarking; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004064:Digestive System / Q000737:chemistry*; D004068:Digestive System Physiological Phenomena; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D012986:Software Validation; D012995:Solubility
D004364:Pharmaceutical Preparations