Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins

• The complexing and solubilizing properties of various cyclodextrins towards clonazepam were evaluated.
• The role of host cavity size, presence and type of substituents on carrier performance was studied.
• Phase-solubility analyses were performed to assess and compare host–guest interactions in solution.
• DSC was used to select the best carrier and preparation method to obtain host–guest solid systems.
• MethylβCD proved the best carrier and cogrinding the best preparation method of binary solid systems.

Clonazepam (CLZ) is a benzodiazepine derivative, whose bioavailability, limited by its very poor water-solubility, could be improved by cyclodextrin complexation. However, the choice of the most proper cyclodextrin to use to fully exploit its potential favourable effects on the drug, is a critical step. Therefore, in the present work, the performance of some amorphous cyclodextrin (CD) derivatives in terms of complexing, solubilizing and amorphizing power towards CLZ was carefully evaluated and compared with that of natural CDs. The role of CD cavity size, amorphous or crystalline nature, and presence and type of substituents on its ability in producing effective interactions with the drug has been investigated. Equimolar CLZ–CD solid systems were obtained by blending, kneading, co-grinding and coevaporation. Drug–CD interactions were investigated by phase-solubility analysis, differential scanning calorimetry and X-ray powder diffractometry. Among the natural CDs, β-CD showed the highest complexing ability, suggesting that its cavity size is the most proper to host the drug molecule. The presence of substituents had a negative effect on the performance of α-CD and γ-CD, while it improved the complexing and solubilizing power of β-CD, and the methylated derivative was more effective than the hydroxypropylated one. Solid-state studies revealed that amorphous CDs had highest amorphizing power than the corresponding natural crystalline ones, and methylated-β-CD (Me-β-CD) was the best carrier. As for the preparation method, co-grinding was the most powerful in promoting the formation of efficacious drug–CD solid-state interactions. Dissolution rate studies confirmed Me-β-CD as the best partner for CLZ and co-grinding as the best method for maximizing the drug dissolution properties. Therefore, co-ground products with Me-β-CD could be selected as the best system for future development of CLZ formulations with improved therapeutic efficacy.

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