Physico-Chemical Profiling of Antidepressive Sertraline: Solubility,Ionisation, Lipophilicity

Karoly      Tihanyi; Bela      Noszal; Krisztina      Takacs-Novak; Katalin      Deak

doi:10.2174/157340606777723997

Abstract

The fundamental physico-chemical parameters of sertraline, a potent selective serotonin reuptake inhibitor and reference compound in the development of new antidepressive agents, were determined. The thermodynamic solubility of the hydrochloride salt (S = 4.24 ± 0.02 mg/ml) and the free base form (S ≉ 0.002 mg/ml) was measured by the saturation shake-flask method. The co-solvent technique in methanol/water mixtures and the Yasuda-Shedlovsky extrapolation were applied for the determination of the dissociation constant (pKa = 9.16 ± 0.02). The partition of sertraline was studied in octanol/water and alkane/water systems determining the logPoct and logPch values by potentiometric and shake-flask methods, respectively. These experimental data were used to interpret the excellent pharmacokinetic properties of the molecule. The high lipophilicity value (logPoct =4.30 ± 0.01) of the nonionised form confirms the good absorption and distribution in the body. However, the good brain penetration can better be explained with the lack of polar interactions evidenced here by the zero ΔlogP (logPoct - logPch) value of sertraline.

Keywords: logP, pKa, logS, pharmacokinetics, physico-chemical profiling, Sertraline

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