Inclusion complexation of the anticancer drug pomalidomide with cyclodextrins: fast dissolution and improved solubility

Zoltán-István Szabó; György Orbán; Enikő Borbás; Dóra Csicsák; Szabina Kádár; Béla Fiser; Máté Dobó; Péter Horváth; Eszter Kiss; Lívia Budai; Judit Dobos; Tamás Pálla; László Őrfi; Gergely Völgyi; Gergő Tóth

doi:10.1016/j.heliyon.2021.e07581

Inclusion complexation of the anticancer drug pomalidomide with cyclodextrins: fast dissolution and improved solubility

Heliyon. 2021 Jul 15;7(7):e07581. doi: 10.1016/j.heliyon.2021.e07581. eCollection 2021 Jul.

Authors

Zoltán-István Szabó¹, György Orbán², Enikő Borbás³, Dóra Csicsák², Szabina Kádár³, Béla Fiser^{4

5}, Máté Dobó², Péter Horváth², Eszter Kiss², Lívia Budai⁶, Judit Dobos⁷, Tamás Pálla², László Őrfi^{2

7}, Gergely Völgyi², Gergő Tóth²

Affiliations

¹ Department of Pharmaceutical Industry and Management, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gh. Marinescu 38, RO-540139, Targu Mures, Romania.
² Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary.
³ Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rakpart 3., Budapest, H-1111, Hungary.
⁴ Computational Molecular Design Research Group, Institute of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, H-3515, Egyetemváros-Miskolc, Hungary.
⁵ Ferenc Rákóczi II. Transcarpathian Hungarian Institute, Beregszász, Transcarpathia, Ukraine.
⁶ Department of Pharmaceutics, Semmelweis University, Hőgyes Endre u. 7, Budapest, H-1092 Hungary.
⁷ Vichem Chemie Research Ltd, Hermann O. utca 15, H-1022, Budapest, Hungary.

Abstract

Pomalidomide (POM), a potent anticancer thalidomide analogue was characterized in terms of cyclodextrin complexation to improve its aqueous solubility and maintain its anti-angiogenic activity. The most promising cyclodextrin derivatives were selected by phase-solubility studies. From the investigated nine cyclodextrins - differing in cavity size, nature of substituents, degree of substitution and charge - the highest solubility increase was observed with sulfobutylether-β-cyclodextrin (SBE-β-CD). The inclusion complexation between POM and SBE-β-CD was further characterized with a wide variety of state-of-the-art analytical techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), circular dichroism spectroscopy, fluorescence spectroscopy as well as X-ray powder diffraction method (XRD). Job plot titration by NMR and the A_L-type phase-solubility diagram indicated 1:1 stoichiometry in a liquid state. Complementary analytical methods were employed for the determination of the stability constant of the complex; the advantages and disadvantages of the different approaches are also discussed. Inclusion complex formation was also assessed by molecular modelling study. Solid state complexation in a 1:1 M ratio was carried out by lyophilization and investigated by IR and XRD. The complex exhibited fast-dissolution with immediate release of POM, when compared to the pure drug at acidic and neutral pH. Kinetic analysis of POM release from lyophilized complex shows that Korsmeyer-Peppas and Weibull model described the best the dissolution kinetics. The cytotoxicity of the complex was tested against the LP-1 human myeloma cell line which revealed that supramolecular interactions did not significantly affect the anti-cancer activity of the drug. Overall, our results suggest that the inclusion complexation of POM with SBE-β-CD could be a promising approach for developing more effective POM formulations with increased solubility.

Keywords: Comparative dissolution; Cyclodextrin complexation; Inclusion complex; Pomalidomide; Pomalyst®; Solubility.