title: Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.
abstract: OBJECTIVE
  To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).
  
  
  METHODS
  Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.
  
  
  RESULTS
  Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.
  
  
  CONCLUSIONS
  Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.
authors.affiliation: Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23, Uppsala, Sweden.
authors.forename: Jonas H
authors.initials: JH
authors.lastname: Fagerberg
authors.forename: Eva
authors.initials: E
authors.lastname: Karlsson
authors.forename: Johan
authors.initials: J
authors.lastname: Ulander
authors.forename: Gunilla
authors.initials: G
authors.lastname: Hanisch
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D005215:Fasting / Q000378:metabolism*; D005544:Forecasting; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007419:Intestinal Secretions / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations