Spectroscopic properties and interaction with model systems of two phenothiazine derivatives

Author(s)

Wilker Caetano

• Document type: Master's Dissertation
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT)
• Defense date: 1997-10-31

Examining board members

Marcel Tabak; Joao Baptista Sargi Bonilha; Mario Jose Politi

• Advisor: Marcel Tabak

Abstract

The spectroscopic properties and characteristics of binding of two phenothiazine antipsycothic drugs, namely, Chlorpromazine (CPZ) and Trifluoperazine (TFP), to cationic cetyltrimethylammonium chloride (CTAC), anionic sodium dodecylsulfate (SOS), zwitterionic N-hexadecyl-N,N-dimethyl-3-ammonio-1- propanesulfonate (HPS), neutral t-octylphenoxypolyethoxyeth anol (TRITON X-100) and polyoxyethylene dodecyl ether (Brij-35) micelles were investigated using optical absorption spectroscopy. Binding constants Kb and pKa values of drugs in micelles were estimated using the red shifts of the maximum absorption upon alkalinization or in the presence of detergents. The pKa of TFP shifts by 2.5 - 4.1 units to lower values in the presence of different surtactants suggesting a considerable change in the envinronment of the drug. The changes in pKa contributed by eletrostatic effects have all the sarne sign being small for CTAC (+0.2), grater for SOS (+1.7) and also significant for HPS (+0.9). For CPZ the pKa shift due to its interaction with micelles is in the range 0.7 - 2.3 units, 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 SOS (+2.2) being of opposite sign, and small for HPS (+0.2). This result suggests a more polar localization in the micelle of CPZ as compareci to TFP. The values of binding constants Kb(667 and 457M-1 to HPS, 140 e 400M-1 to Brij-35, 3.3 and 47M-1 to CTAC and 628 and 5021M-1 to SOS, for TFP and CPZ, respectively, in their fully protonated states) show that electrostatic interactions are essential in the affinity of protonated drugs to micelles bearing different charges on their headgroups. Data for Brij-35 evidentiate that the additional charge on TFP 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 pHs. 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 compareci to CPZ. The interaction of TFP with SOS deserves a special consideration since in this case a very strong binding takes place when the drug is fully protonated (pH 2.0) and a distinct binding takes place at stoichiometric detergent concentrations (probably interaction via detergent monomers) and at higher concentrations (in the presence of micelles). Our results suggest that in the presence of anionic detergent the binding constants can reach quite high values in the range of 2x104M-1. Finally it was observed that both drugs form stable Langmuir monolayers with the zwitterionic lipid dipalmitoylphosphatidyl choline (DPPC) at an air/aqueous solution interface. The incorporation of the drugs into the lipid monolayer changes the packing density and electrical properties of the monolayer during the process of compression, the effect depending on the drug location in the monolayer, on the state protonation of the drug and also on the charge state of the lipid. For both drugs a progressive expansion of the monolayer at their low reiative content (1-3 mal%) was observed with a further condensing of the film at higher drug concentrations. This effect of the drug is most pronounced at subphase pHs close to the drugs pKa. The presence of a fully protonated drug makes the monolayer more expanded due to electrostatic repulsion of positively charged species. This effect competes with the formation of aggregates of drug molecules at their higher relative concentrations within the monolayer, thus inducing the apparent compression of the latter. These results also suggest a more hidrophobic localization of TFP in the monolayer in comparison with CPZ. (AU)