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Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives

Abstract : The stability of N-substituted derivatives of thalidomide was studied and compared to that of thalidomide itself. Nitrogen atom included in glutarimide ring was successively substituted by a hydroxy group, a methyl acetate group, and an ethyl group. Lipophilicities of these compounds were determined using the method based on experimental determinations of partition coefficients developed by Hansch. Hydroxy group led to a decrease of lipophilicity. Substitution of the nitrogen atom by an ethyl group or a methyl acetate group allowed an increase of lipophilicity. Relative stabilities of each compound were determined under physiological conditions: pH (7.4) and temperature (37 °C) using high performance liquid chromatography procedure. The program Sigma Plot was used to fit experimental data in order to obtain the half-lifes of thalidomide and its analogs. In the case of substitution by an ethyl group, the increase of lipophilicity (Δlog P = 0.36) was in agreement with a higher stability in aqueous medium. In the case of methyl acetate group, hydrolysis of the cycle was chemically favoured despite a higher lipophilicity compared to those of thalidomide. In the case of N-hydroxy compound, the decrease in lipophilicity was not sufficient to affect the stability.
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Submitted on : Friday, November 22, 2019 - 11:14:09 AM
Last modification on : Saturday, June 25, 2022 - 9:54:36 AM

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François Estour, Vincent Ferranti, Christiane Chabenat, Emilie Toussaint, Hervé Galons, et al.. Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives. Journal of Pharmaceutical and Biomedical Analysis, 2007, 45 (2), pp.237-242. ⟨10.1016/j.jpba.2007.06.010⟩. ⟨hal-02375835⟩



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