Chemical and in vitro enzymatic stability of newly synthesized celecoxib lipophilic and hydrophilic amides

Amjad Qandil, Farah El Mohtadi, Bassam Tashtoush

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP-HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were ≤13.6 and ≤40 ng/mL, respectively. The solubility and logPapp of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80 °C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY-CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53 h at 60, 70 and 80 °C, respectively, with extrapolated half-lives of 2060 and 443 h at 25 and 37 °C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79 h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis.
    Original languageEnglish
    Pages (from-to)85-96
    Number of pages12
    JournalInternational Journal of Pharmaceutics
    Volume416
    Issue number1
    Early online date15 Jun 2011
    DOIs
    Publication statusPublished - 15 Sept 2011

    Keywords

    • celecoxib
    • HPLC
    • hydrolysis
    • liver homogenate
    • hydrophobic interactions

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