Acid-base cosolvent method for determining aqueous permeability of amiodarone, itraconazole, tamoxifen, terfenadine and other very insoluble molecules

Chem Pharm Bull (Tokyo). 2004 May;52(5):561-5. doi: 10.1248/cpb.52.561.


A high-throughput, UV-detection PAMPA (parallel artificial membrane permeability assay) cosolvent procedure is described, based on the use of 20% v/v acetonitrile in aqueous buffer. A training set of 32 drugs (17 bases, 13 acids, 2 ampholytes) was studied both in aqueous buffer and in cosolvent-buffer solutions. A procedure was devised, where intrinsic permeability values, log P(o)(COS), measured in cosolvent solution, are converted to values expected under cosolvent-free conditions, using an in silico model based on Abraham H-bond acidity (alpha) and basicity (beta) descriptors, developed with the Algorithm Builder computer program, to obtain aqueous intrinsic permeability values: log P(o)=0.738+0.885 log P(o)(COS)-1.262alpha+0.436beta, r(2)=0.97, q(2)=0.96, s=0.38, n=32, F=279. Five sparingly-soluble weak bases (solubility <1 microg/ml), which could not be characterized without cosolvent, had their aqueous intrinsic permeability, P(o), estimated: miconazole 0.32 cm/s; itraconazole 3.2 cm/s; amiodarone 13 cm/s; tamoxifen 28 cm/s; terfenadine 162 cm/s.

MeSH terms

  • Acids / chemistry
  • Amiodarone / chemistry
  • Amiodarone / pharmacokinetics*
  • Hydrogen-Ion Concentration / drug effects
  • Itraconazole / chemistry
  • Itraconazole / pharmacokinetics*
  • Permeability / drug effects
  • Solubility / drug effects
  • Solvents / chemistry
  • Tamoxifen / chemistry
  • Tamoxifen / pharmacokinetics*
  • Terfenadine / chemistry
  • Terfenadine / pharmacokinetics*
  • Water / chemistry


  • Acids
  • Solvents
  • Water
  • Tamoxifen
  • Itraconazole
  • Terfenadine
  • Amiodarone