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Dissociation constants (pKa) determination for the drugcandidates in the early stage of drug discovery anddevelopment
Update time: 2014-08-13
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Most of the drugs have acidic and/or basic functionalities and theionization state is controlled by both solution pH and dissociation constants (i.e. pKavalues). The ionized form is usually watersoluble, while the neutral form is more lipophilic with higher membrane permeability. Thus the properties of solubility, lipophilicityand peameability are pKa-dependent, which further affect thephysiological properties of absorption, distribution, metabolismand elimination (ADME). Hence,the knowledge of pKavalueis a key parameter for understanding the interaction of theinterest compound with its pharmacological targetsand is helpful for thefurther salt formation selection and the optimization ofthe pharmaceutics technology.

Potentiometric titration and spectrophotometry are traditionalpKadetermination methods. Both methods suffer from the samedifficulties in dealing with impure samples which are frequentlyencountered nowadays during early stage of drug discovery anddevelopment.Capillary electrophoresis (CE) has evolved considerably over thelast decade and is particularly effective in separating ionic species. Ithas therefore, been investigated for the determination of pKavalues.

In our group pressure-assisted capillary electrophoresis was recently developed to determine the pKavalues of atriptolide derivative (LLDT-246) and its impurities.During the electrophoretic runs at lower buffer pH(<4), thefused-silica capillary surface is neutralized and EOF is diminished which may cause long separation time for the analytes.Therefore external pressure-assisted CE has been developed for its generic screening purpose.The values of pKaof LLDT-246 and two impurities were calculated based on thepH dependence of effective mobilities. This method was convenient for the fast screening purpose of pKavalues with the impuresample available at its early discovery stage.

This work has been published on the Journal of Pharmaceutical and Biomedical Analysis (WangJL, XuXJ, ChenDY. Determination of pKavalues of a triptolidederivative and itsimpurities by pressure-assisted capillary electrophoresis [J].J. Pharm. Biomed. Anal., 2014, 88: 22-26.)

 Fig. 1 Dependence of the effective mobilities of compound (LLDT-246)and itsimpuritison pH
(Image by SIMM)

 
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