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Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins.
J Pharm Biomed Anal. 2014 Feb; 89:142-9.JP

Abstract

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.

Authors+Show Affiliations

Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy.Department of Chemistry, School of Human Health Sciences, University of Florence, Via Schiff 6, Sesto Fiorentino I-50019, Florence, Italy. Electronic address: paola.mura@unifi.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24291109

Citation

Mennini, Natascia, et al. "Physico-chemical Characterization in Solution and in the Solid State of Clonazepam Complexes With Native and Chemically-modified Cyclodextrins." Journal of Pharmaceutical and Biomedical Analysis, vol. 89, 2014, pp. 142-9.
Mennini N, Bragagni M, Maestrelli F, et al. Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins. J Pharm Biomed Anal. 2014;89:142-9.
Mennini, N., Bragagni, M., Maestrelli, F., & Mura, P. (2014). Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins. Journal of Pharmaceutical and Biomedical Analysis, 89, 142-9. https://doi.org/10.1016/j.jpba.2013.11.009
Mennini N, et al. Physico-chemical Characterization in Solution and in the Solid State of Clonazepam Complexes With Native and Chemically-modified Cyclodextrins. J Pharm Biomed Anal. 2014;89:142-9. PubMed PMID: 24291109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins. AU - Mennini,Natascia, AU - Bragagni,Marco, AU - Maestrelli,Francesca, AU - Mura,Paola, Y1 - 2013/11/15/ PY - 2013/09/22/received PY - 2013/10/30/revised PY - 2013/11/01/accepted PY - 2013/12/3/entrez PY - 2013/12/3/pubmed PY - 2014/8/6/medline KW - Clonazepam KW - Cyclodextrin complexation KW - Differential scanning calorimetry KW - Dissolution rate KW - Phase-solubility analysis SP - 142 EP - 9 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 89 N2 - 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. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/24291109/Physico_chemical_characterization_in_solution_and_in_the_solid_state_of_clonazepam_complexes_with_native_and_chemically_modified_cyclodextrins_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(13)00515-3 DB - PRIME DP - Unbound Medicine ER -