title: Accurate potentiometric determination of lipid membrane-water partition coefficients and apparent dissociation constants of ionizable drugs: electrostatic corrections.
abstract: OBJECTIVE
  Potentiometric lipid membrane-water partition coefficient studies neglect electrostatic interactions to date; this leads to incorrect results. We herein show how to account properly for such interactions in potentiometric data analysis.
  
  
  METHODS
  We conducted potentiometric titration experiments to determine lipid membrane-water partition coefficients of four illustrative drugs, bupivacaine, diclofenac, ketoprofen and terbinafine. We then analyzed the results conventionally and with an improved analytical approach that considers Coulombic electrostatic interactions.
  
  
  RESULTS
  The new analytical approach delivers robust partition coefficient values. In contrast, the conventional data analysis yields apparent partition coefficients of the ionized drug forms that depend on experimental conditions (mainly the lipid-drug ratio and the bulk ionic strength). This is due to changing electrostatic effects originating either from bound drug and/or lipid charges. A membrane comprising 10 mol-% mono-charged molecules in a 150 mM (monovalent) electrolyte solution yields results that differ by a factor of 4 from uncharged membranes results.
  
  
  CONCLUSIONS
  Allowance for the Coulombic electrostatic interactions is a prerequisite for accurate and reliable determination of lipid membrane-water partition coefficients of ionizable drugs from potentiometric titration data. The same conclusion applies to all analytical methods involving drug binding to a surface.
authors.affiliation: IDEA AG, Frankfurter Ring 193a, Munich, Germany. mmaelsayed@gmail.com
authors.forename: Mustafa M A
authors.initials: MM
authors.lastname: Elsayed
authors.forename: Ulrich
authors.initials: U
authors.lastname: Vierl
authors.forename: Gregor
authors.initials: G
authors.lastname: Cevc
mesh_terms: D002045:Bupivacaine / Q000737:chemistry; D004008:Diclofenac / Q000737:chemistry; D007477:Ions / Q000737:chemistry; D007660:Ketoprofen / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry*; D009281:Naphthalenes / Q000737:chemistry; D009994:Osmolar Concentration; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011199:Potentiometry / Q000379:methods*; D012680:Sensitivity and Specificity; D012995:Solubility; D055672:Static Electricity; D000077291:Terbinafine; D017186:Titrimetry; D014867:Water / Q000737:chemistry*
chemical_list: D007477:Ions; D008563:Membrane Lipids; D009281:Naphthalenes; D004364:Pharmaceutical Preparations; D014867:Water; D004008:Diclofenac; D007660:Ketoprofen; D000077291:Terbinafine; D002045:Bupivacaine