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

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.

Nanocrystals as an effective strategy to improve Pomalidomide bioavailability in rodent

“…On the contrary, total dissolution of POM as a coarse suspension (POM-CMCS) was reached only after 6 h. The dissolution rate of the raw drug was even slower than that of POM-CMCS, as after 8 h only 38% of raw POM dissolved into the buffer solution. This slow dissolution of POM, whether as the raw drug or as a coarse suspension, is in line with the recent studies of Szabó et al (Szabó et al 2021), who similarly demonstrated slow dissolution into both Britton-Robinson buffer at pH 7.0 and simulated gastric fluid at pH 1.6. The substantial increase in the the solubility of POM formulated as nanosuspension and its immediate dissolution clearly indicates that nanosizing may increase the POM absorption rate and, therefore, the bioavailability after i.p.…”

“…The POM endotherm is slightly shifted towards a lower temperature, possibly due to the drug's small particle size in the nanocrystalline suspension, dissolution of the drug in the stabilizer during the DSC run, or strong interaction between the drug and the stabilizer, as also suggested by the decreased enthalpy of POM in the formulation. (Szabó et al, 2021) the sharp diffraction peaks of bulk POM powder at 12.3, 14.1, 16.9, 17.3, 18.3, 24.3, 24.7, 25.6, and 28.0 2ϑ indicate its crystalline nature. Also in the POM-NS diffractogram the characteristic peaks of POM are clearly evident, thus suggesting that its crystal pattern is not affected by the formulation process.…”

Development of an LC-MS/MS Method for ARV-110, a PROTAC Molecule, and Applications to Pharmacokinetic Studies

“…No. P2074, logP = 0.01, pKa = 1.89 [ 20 ]) was provided by Tokyo Chemical Industry (Tokyo, Japan). HPLC-grade water (Cat.…”

Co-crystallization: a green approach for the solubility enhancement of poorly soluble drugs

“…Cyclodextrins are cyclic oligosaccharides with a polar moiety and a hydrophilic external surface that are structurally linked. 15 The inclusion complexation approach has been employed for various drugs for improving their solubility and dissolution rate, like pomalidomide (), 16 docetaxel, 17 etodolac, 18 and econazole nitrate. 19…”