Determination of dissociation constants of labile drug compounds by capillary electrophoresis.
The utility of capillary electrophoresis (CE) for determination of the negative logarithm of dissociation constants (pK(a)) of labile compounds was investigated. In this study pyridinyl-methyl-sulfinyl-benzimidazoles (PMSB's), which have both an acidic and a basic pK(a), were selected as a first set of model drug compounds. This is a group of compounds that are known to degrade in aqueous solutions under neutral and acidic conditions which thus may impair their pK(a) determination when using common batch techniques based on spectrophotometry or potentiometry. An additional set of model drug compounds, benzenesulfonic acid phenethyloxy-phenyl esters (BSAP's), which are labile at high pH, were also studied. It is demonstrated that pK(a) values can be determined with high precision and accuracy by CE for both these sets of model compounds because decomposition products and impurities can be sufficiently separated from the main component. Based on the results in this study, a general strategy is proposed and discussed for determination of pK(a) for labile compounds. Key steps comprise use of a stabilizing sample diluent, injection by electromigration, short analysis time, and characterization of the main component by UV-Vis spectra.
Ornskov
Eivor
E
Pharmaceutical and Analytical R&D, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
Linusson
Anna
A
Folestad
Staffan
S
D001562:Benzimidazoles / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics*; D019075:Electrophoresis, Capillary / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods*
D001562:Benzimidazoles