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

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

Zoltán-István Szabó  1 , György Orbán  2 , Enikő Borbás  3 , Dóra Csicsák  2 , Szabina Kádár  3 , Béla Fiser  4   5 , Máté Dobó  2 , Péter Horváth  2 , Eszter Kiss  2 , Lívia Budai  6 , Judit Dobos  7 , Tamás Pálla  2 , László Őrfi  2   7 , Gergely Völgyi  2 , Gergő Tóth  2
Affiliations

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

Zoltán-István Szabó et al. Heliyon. .

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 AL-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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of pomalidomide.
Figure 2
Figure 2
2D structures of SBE-β-CD model isomers.
Figure 3
Figure 3
Some representative phase solubility diagrams of POM with different CDs.
Figure 4
Figure 4
Representative Job plot curves of POM with SBE-β-CD.
Figure 5
Figure 5
3D structures of S-POM-SBE-β-CD complexes with the calculated binding affinities (EA, kcal/mol).
Figure 6
Figure 6
X-ray powder diffraction pattern of POM, SBE-β-CD, PM, and LP.
Figure 7
Figure 7
Comparative FT-IR spectra of POM, SBE-β-CD, PM, and LP. Arrows show differences in the obtained FT-IR spectra.
Figure 8
Figure 8
The dissolution profile of POM and LP at pH = 1.6 (A) and pH = 7 (B).
Figure 9
Figure 9
Kinetic models of POM release from LP at pH = 1.6.
Figure 10
Figure 10
Kinetic models of POM release from LP at pH = 7.
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