Dissociation Constant of Chlorpromazine Incorporated in Lecithin Vesicles Determined by ^1H Nuclear Magnetic Resonance Titration

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The pK_a value of chlorpromazine incorporated in lecithin vesicles, denoted by pK__<av>, was determined by proton nuclear magnetic resonance (^1H-NMR) spectrometric titration in D_2O containing 50 mM NaCl and 2.5 mM Na_2B_4O_7・10H_2O at 25℃ for the drug and lipid concentrations of 1.76-3.5 mM and 20-67 mM, respectively. The pK_<av> value was calculated from the relation between the chemical shift of the N-dimethyl signal of the incorporated chlorpromazine and the bulk pH value using a nonlinear least-squares method. Six experiments gave the mean value of pK_<av> 8.48±0.07 (S.D.). The value was significantly lower than pK_a 9.8 in D_2O, which was determined by extrapolating the pK_a's obtained in mixtures of methanol-d_4 and D_2O by the same ^1H-NMR titration method. The results indicated that about 10% of chlorpromazine incorporated in lecithin vesicles was in a deprotonated free base state at physiological pH 7.5,although it was considered to be mostly in a protonated cationic state in aqueous solution of the same pH.
社団法人日本薬学会の論文
1989-05-25