Determination of dissociation constants of labile drug compounds by capillary electrophoresis

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 33; no. 3; pp. 379 - 391
• Main Authors: Örnskov, Eivor, Linusson, Anna, Folestad, Staffan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15-10-2003; Elsevier Science
• Subjects: Analysis; Analytical, structural and metabolic biochemistry; Benzenesulfonic acid phenethyloxy–phenyl esters; Benzimidazoles - analysis; Benzimidazoles - chemistry; Benzimidazoles - pharmacokinetics; Biological and medical sciences; Capillary electrophoresis; Dissociation constant; Electrophoresis, Capillary - methods; Fundamental and applied biological sciences. Psychology; General pharmacology; Medical sciences; Pharmacology. Drug treatments; Pyridinyl–methyl–sulfinyl–benzimidazoles; Technology, Pharmaceutical - methods; Dissociation constant; Benzenesulfonic acid phenethyloxy–phenyl esters; Capillary electrophoresis; Pyridinyl–methyl–sulfinyl–benzimidazoles; Drug; Quantitative analysis
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/S0731-7085(03)00238-3

The utility of capillary electrophoresis (CE) for determination of the negative logarithm of dissociation constants (p
K
a) of labile compounds was investigated. In this study pyridinyl–methyl–sulfinyl–benzimidazoles (PMSB's), which have both an acidic and a basic p
K
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 p
K
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 p
K
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 p
K
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.