Skip to main content
SpringerLink
Log in

Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The objectives of this research were to prepare and characterize inclusion complexes of clonazepam with β-cyclodextrin and hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of clonazepam, a water-insoluble lipid-lowering drug. The phase-solubility profiles with both cyclodextrins were classified as AP-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy \( \left( {\Delta {G_{tr}}^o} \right) \) values were all negative, indicating the spontaneous nature of clonazepam solubilization, and they decreased with increase in the cyclodextrins concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of clonazepam were prepared with cyclodextrins by various methods such as kneading, coevaporation, and physical mixing. The complexes were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. These studies indicated that complex prepared kneading and coevaporation methods showed successful inclusion of the clonazepam molecule into the cyclodextrins cavity. The complexation resulted in a marked improvement in the solubility and wettability of clonazepam. Among all the samples, complex prepared with hydroxypropyl-β-cyclodextrin by kneading method showed highest improvement in in vitro dissolution rate of clonazepam. Mean dissolution time of clonazepam decreased significantly after preparation of complexes and physical mixture of clonazepam with cyclodextrins. Similarity factor indicated significant difference between the release profiles of clonazepam from complexes and physical mixture and from plain clonazepam. Tablets containing complexes prepared with cyclodextrins showed significant improvement in the release profile of clonazepam as compared to tablet containing clonazepam without cyclodextrins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Skerritt JH, Johnston GA. Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983;89(3–4):193–8.

    Article  CAS  PubMed  Google Scholar 

  2. Lehoullier PF, Ticku MK. Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons. Eur J Pharmacol. 1987;135(2):235–8.

    Article  CAS  PubMed  Google Scholar 

  3. Proudfoot S. Factors affecting bioavailability: factors influencing drug absorption from the gastrointestinal tract. In: Aulton ME, editor. Pharmaceutics: the science of dosage from design. Edinburgh: Churchill Livingstone; 1991. p. 135–73.

    Google Scholar 

  4. Pitha J, Milecki J, Fales H, Pannell L, Uekama K. Hydroxypropyl-β-cyclodextrin: preparation and characterization; effects on solubility of drugs. Int J Pharm. 1986;29:73–82.

    Article  CAS  Google Scholar 

  5. Duchêne D. Cyclodextrins and their industrial uses. Editions de Santé Paris, 1987; SS. 447–460.

  6. Baboota S, Agarwal SP. Rofecoxib complexation with β-cyclodextrin: influence on the anti-inflammatory and ulcerogenic activity. Die Pharmazie. 2003;58:73–4.

    CAS  PubMed  Google Scholar 

  7. Fernandes CM, Teresa VM, Veiga FJ. Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds. Eur J Pharm Sci. 2002;15:79–88.

    Article  CAS  PubMed  Google Scholar 

  8. Kamada M, Hirayama F, Udo K, Yano H, Arima H, Uekama K. Cyclodextrin conjugate-based controlled release system: repeated- and prolonged-releases of ketoprofen after oral administration in rats. J Control Release. 2002;82:407–16.

    Article  CAS  PubMed  Google Scholar 

  9. Mukne AP, Nagarsenker MS. Triamterene-β-cyclodextrin systems: preparation, characterization and in vivo evaluation. AAPS PharmSci Tech. 2004;5:article 19.

  10. Uekama K, Otagiri M. Cyclodextrins in drug carrier systems. Crit Rev Ther Drug Carrier Syst. 1987;3:1–40.

    CAS  PubMed  Google Scholar 

  11. Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev. 1994;14:353–86.

    Article  CAS  PubMed  Google Scholar 

  12. Xianhong W, Ziyang L, Tianqiang Z. Mass spectrometry and molecular modeling studies on the inclusion complexes between α β-cyclodextrins and simvastatin. Chem Phys Lett. 2005;405:114–7.

    Article  Google Scholar 

  13. Baboota S, Dhaliwal M, Kohli K. Physicochemical characterization, in vitro dissolution behavior, and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. AAPS PharmSciTech. 2005;6:E83–90.

    Article  PubMed  Google Scholar 

  14. Ghorab MK, Adeyeye MC. Elucidation of solution state complexation in wet-granulated oven-dried ibuprofen and β-cyclodextrin: FT-IR and 1H-NMR studies. Pharm Dev Technol. 2001;6:315–24.

    Article  CAS  PubMed  Google Scholar 

  15. Veiga FJ, Fernandes C, Carvalho RA, Geraldes CF. Molecular modeling and 1H-NMR: ultimate tools for the investigation of tolbutamide: β-cyclodextrin and tolbutamide: hydroxypropyl-β-cyclodextrin complexes. Chem Pharm Bull. 2001;49:1251–6.

    Article  CAS  PubMed  Google Scholar 

  16. Tirucherai GS, Mitra AK. Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. AAPS PharmSciTech. 2003;4:E45.

    Article  PubMed  Google Scholar 

  17. Nalluri BN, Chowdary KPR, Murthy KVR, Hayman AR, Becket G. Physicochemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems. AAPS Pharm Sci Tech. 2003;4:E2.

    Article  Google Scholar 

  18. Peeters J, Neeskens P, Tollenaere JP, Van Remoortere P, Brewster ME. Characterization of the interaction of 2-hydroxypropyl-betacyclodextrin with itraconazole at pH 2, 4, and 7. J Pharm Sci. 2002;91:1414–22.

    Article  CAS  PubMed  Google Scholar 

  19. Moore JW, Flanner H. Mathematical comparison of dissolution profiles. Pharm Tech. 1996;20:64–74.

    Google Scholar 

  20. Guidance for Industry SUPAC-MR: modified release solid oral dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls; in vitro dissolution testing and in vivo bioequivalence documentation. US Food and Drug Administration, Rockville, MD, USA, 1997. www.fda.gov/cder/guidance/index.html.

  21. Human Medicines Evaluation Unit, EMEA. Notes for Guidance on Quality of Modified-Release Products; A Oral Dosage Forms; B Transdermal Dosage Forms, Section 1 (Quality) 1999.

  22. Reppas C, Nicolaides E. Analysis of drug dissolution data. In: Dressman JB, Lennernäs H, editors. Oral drug absorption prediction and assessment. New York: Marcel Dekker; 2000. p. 229–54.

    Google Scholar 

  23. Vueba ML, Batista de Carvalho LAE, Veiga F, Sousa JJ, Pina ME. Influence of cellulose ether polymers on ketoprofen release from hydrophilic matrix tablets. Eur J Pharm Biopharm. 2004;58:51–9.

    Article  CAS  PubMed  Google Scholar 

  24. Higuchi T, Connors K. Phase solubility techniques. Adv Anal Chem Instru. 1965;4:17–123.

    Google Scholar 

  25. Szejtli J. Cyclodextrin inclusion complexes. In Cyclodextrin Technology. Dordrecht: Kluwer Academic Publishers; 1988. p. 101–2.

    Google Scholar 

  26. Peri D, Wyandt CM, Cleary RW, Hickal AH, Jones AB. Inclusion complexes of tolnaftate with β-Cyclodextrin and hydroxy-β-cyclodextrin. Drug Dev Ind Pharm. 1994;20:1401–10.

    Article  CAS  Google Scholar 

  27. Labenderia JJT, Lopez ME, Penin LS, Jato JLV. Glibornuride-β-cyclodextrin inclusion complexes: preparation, structural characterization, and in vitro dissolution behavior. J Pharm Biopharm. 1993;39:255–9.

    Google Scholar 

  28. Chengsheng L, Chenguang L, Kashappa HD. Enhancement of dissolution rate of valdecoxib using solid dispersions with polyethylene glycol 4000. Drug Dev Ind Pharm. 2005;1:1–10.

    Google Scholar 

  29. Bloch DW, Elegakey MA, Speiser PP. Solid dispersions of chlorthalidone in urea. Pharm Acta Helv. 1982;57(8):231–5.

    CAS  PubMed  Google Scholar 

  30. Loftsson T, Brewster EM. Pharmaceutical application of cyclodextrins. 1. drug solubilization and stabilization. J Pharm Sci. 1996;85:1017–25.

    Article  CAS  PubMed  Google Scholar 

  31. Uekama K, Hirayama F, Otagiri M, Ikeda K. Inclusion complexation of cyclodextrin with some sulfonamides in aqueous solution. Chem Pharm Bull. 1978;26(4):1162–7.

    CAS  Google Scholar 

  32. Moyano JR, Arias-Blanco MJ, Gine’s JM, Giordano F. Study of the complexation behaviour of gliclazide with partially methylated b-cyclodextrin in solution and solid state. Int J of Pharm. 1997;157:239–43.

    Article  CAS  Google Scholar 

  33. Hedges AR. Industrial applications of cyclodextrins. Chem Rev. 1998;98:2035–44.

    Article  CAS  PubMed  Google Scholar 

  34. Serajuddin ATM, Sheen PC, Augustine MA. Improved dissolution of poorly water soluble drug from solid dispersions in polyethylene: polysorbate 80 mixture. J Pharm Sci. 1990;79:463–4.

    Article  CAS  PubMed  Google Scholar 

  35. Barzegar-Jalali M, Maleki N, Garjani A, Khandar AA, Haji-Hosseinloo M, Jabbari RC, et al. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev Ind Pharm. 2002;28:681–6.

    Article  CAS  PubMed  Google Scholar 

  36. Tang L, Khan SU, Muhmmad NA. Evaluation and selection of bio-relevant dissolution media for a poorly water soluble new chemical entity. Pharm Dev Technol. 2001;6:531–40.

    Article  CAS  PubMed  Google Scholar 

  37. Aulton ME. Pharmaceutical technology. In: Pharmaceutics: The Science of Dosage Form Design. London: Churchill Livingstone. 1988; 600–616.

Download references

Acknowledgment

We are thankful to Roquette Frères, France for the generous gift of HPβ-CD and β-CD. We would like to thank Centaur Chemicals Pvt. Ltd., Mumbai, India for donating Clonazepam. We would also like to thank Maan Pharmaceuticals Ltd. for providing formulation excipients. We are grateful to the Department of Pharmacy, M. S. University, India for conducting DSC studies of the samples.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, Mehsana-Gozaria Highway, PIN-382711, Mehsana, Gujarat, India

    Rakesh Patel & Nirav Purohit

Authors
  1. Rakesh Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nirav Purohit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rakesh Patel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patel, R., Purohit, N. Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds. AAPS PharmSciTech 10, 1301–1312 (2009). https://doi.org/10.1208/s12249-009-9321-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-009-9321-3

Key words

Search

Navigation