Interaction of chlorpromazine and trifluoperazine with ionic micelles: electronic absorption spectroscopy studies

Abstract

The characteristics of binding of two phenothiazine antipsychotic drugs, namely, chlorpromazine (CPZ) and trifluoperazine (TFP), to cationic cetyltrimethylammonium chloride (CTAC), zwitterionic N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (HPS), neutral t-octylphenoxypolyethoxyethanol (TRITON X-100) and polyoxyethylene dodecyl ether (Brij-35) micelles were investigated using electronic absorption spectroscopy. Binding constants Kb and pKa values of drugs in micelles were estimated using the red shifts of the maximum absorption upon alkalization or in the presence of detergents. The pKa of TFP seems to be shifted by 2.5–4.1 units to lower values in the presence of different surfactants as compared to the experimental value of pKa obtained in buffer which is around 7.0. Consideration of the second pKa around 4.0 reported in the literature for TFP leads to a better rationalization of pKa changes for this compound. The changes in pKa contributed by electrostatic effects are all positive, small for CTAC (+0.2), and greater for HPS (+0.9). For CPZ the pKa shift due to its interaction with micelles is in the 0.7–2.3 range, the direction of the shift depending on the charge of the polar head. The electrostatic contribution for the shift is great for CTAC (−0.8) and smaller for HPS (+0.2). This result suggests a more polar localization in the micelle of CPZ as compared to TFP. The values of binding constants Kb for TFP and CPZ in different protonation states show that electrostatic interactions are essential in the affinity of the drugs to micelles bearing different charges on their headgroups (CTAC, HPS). Data for Brij-35 demonstrate that the additional charge on the TFP ring at pH 2.0 leads to a decrease of binding constant probably due to the repulsion of the phenothiazine ring from the protons accumulated at the polar head of the micelle at acidic pH values. For this micelle at pH 5.0 TFP has a Kb 3-fold greater than that for CPZ while at pH 2.0 Kb for TFP is 3-fold less than that for CPZ. So, for more hydrophobic TFP electrostatic interactions due to protonation of the ring are quite important even considering its deeper penetration into the micelle interior as compared to CPZ.