Skip to main content
SpringerLink
Log in

Study of the solubility, photostability and structure of inclusion complexes of carvedilol with β-cyclodextrin and (2-hydroxypropyl)-β-cyclodextrin

  • Original Article
  • Published:
Journal of Inclusion Phenomena and Macrocyclic Chemistry Aims and scope Submit manuscript

Abstract

Carvedilol is one of the most effective antihypertensive drugs used in the treatment of congestive heart failure. A major disadvantage of this pharmaceutical active substance is its limited solubility in water, gastric and intestinal fluids. One way to overcome this problem is the preparation of inclusion complexes. The aim of this study was to prepare the inclusion complexes of carvedilol with β-cyclodextrin (β-CD) and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and to investigate their physical properties. The formation of inclusion complexes with β-CD and HP-β-CD was confirmed using FTIR, 1H-NMR and XRD methods. Phase solubility studies indicate the formation of inclusion complexes in 1:2 molar ratio and the increase of carvedilol solubility. The stability constant (β 2) was found to be 3.4 × 104 and 5.1 × 104 M−2 for inclusion complexes of carvedilol:β-CD and carvedilol:HP-β-CD, respectively. Photostability of carvedilol was increased after preparation of inclusion complexes with β-CD and HP-β-CD. Based on the results of this study, it can be concluded that the prepared complexes of carvedilol improve the solubility and stability of carvedilol and give it an advantage to be applied for the design of new pharmaceutical formulations.

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
Fig. 8

Similar content being viewed by others

References

  1. Packer, M., Lukas, M., Tenero, D., Baidoo, C., Greenberg, B.: Pharmacokinetic profile of controlled-release carvedilol in patients with left ventricular dysfunction associated with chronic heart failure or after myocardial infarction. Am. J. Cardiol. 98, 39–45 (2006)

    Article  Google Scholar 

  2. Weber, A., Sica, A., Tarka, A., Iyengar, M., Fleck, R., Bakris, L.: Controlled-release carvedilol in the treatment of essential hypertension. Am. J. Cardiol. 98, 32–38 (2006)

    Article  Google Scholar 

  3. Palazzuoli, A., Calabria, P., Verzuri, M.S., Auteri, A.: Carvedilol: something else than a simple betablocker? Eur. Rev. Med. Pharmacol. Sci. 6, 115–126 (2002)

    CAS  Google Scholar 

  4. Ouyang, Y., Chen, Z., Tan, M., Liu, A., Chen, M., Liu, J., Fang, J.: Carvedilol, a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells. Biochem. Bioph. Res. Co. 441(4), 917–922 (2013)

    Article  CAS  Google Scholar 

  5. Lin, C.S., Lin, W.S., Lin, C.L., Kao, C.H.: Carvedilol use is associated with reduced cancer risk: a nationwide population-based cohort study. Int. J. Cardiol. 184, 9–13 (2015)

    Article  Google Scholar 

  6. Takekuma, Y., Yagisawa, K., Sugawara, M.: Mutual inhibition between carvedilol enantiomers during racemate glucuronidation mediated by human liver and intestinal microsomes. Biol. Pharm. Bull. 35(2), 151–163 (2012)

    Article  CAS  Google Scholar 

  7. Shete, A.S., Yadav, A.V., Murthy, S.M.: Chitosan and chitosan chlorhydrate based various approaches for enhancement of dissolution rate of carvedilol. DARU J. Pharm. Sci. 20(1), 93–97 (2012)

    Article  CAS  Google Scholar 

  8. Kasim, N., Whitehouse, M., Ramchandran, C., Bermejo, M., Lennernas, H., Hussain, A.S., Junginger, H.E., Stavchansky, S.A., Midha, K.K., Shah, V.P., Amidon, G.L.: Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol. Pharm. 1, 85–96 (2004)

    Article  CAS  Google Scholar 

  9. Khadra, I., Zhou, Z., Dunn, C., Wilson, C.G., Halbert, G.: Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. Eur. J. Pharm. Sci. 67, 65–75 (2015)

    Article  CAS  Google Scholar 

  10. Möllendorff, E.V., Reiff, K., Neugebauer, G.: Pharmacokinetics and bioavailability of carvedilol, a vasodilating beta-blocker. Eur. J. Clin. Pharmacol. 33(5), 511–513 (1987)

    Article  Google Scholar 

  11. Savic, I., Marinkovc, V., Savic, I., Sibinovic, P., Cekic, N.: Application of the experimental design method to photostability studies of Karvileks tablet. Ind. J. Pharm. Edu. Res. 46(3), 275–282 (2012)

    Google Scholar 

  12. Yuvaraja, K., Khanam, J.: Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins, water soluble polymers and hydroxyl acid. J. Pharm. Biomed. 96, 10–20 (2014)

    Article  CAS  Google Scholar 

  13. Lee, S.N., Poudel, B.K., Tran, T.H., Marasini, N., Pradhan, R., Im Lee, Y., Kim, J.O.: A novel surface-attached carvedilol solid dispersion with enhanced solubility and dissolution. Arch. Pharm. Res. 36(1), 79–85 (2013)

    Article  CAS  Google Scholar 

  14. Planinšek, O., Kovačič, B., Vrečer, F.: Carvedilol dissolution improvement by preparation of solid dispersions with porous silica. Int. J. Pharma. 406(1), 41–48 (2011)

    Article  Google Scholar 

  15. Tapas, A., Kawtikwar, P., Sakarkar, D.: An improvement in physicochemical properties of carvedilol through spherically agglomerated solid dispersions with PVP K30. Acta Pol. Pharm. 69(2), 299–308 (2012)

    CAS  Google Scholar 

  16. Sanjula, B., Shah, F.M., Javed, A., Alka, A.: Effect of poloxamer 188 on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles for bioavailability enhancement. J. Drug Target. 17(3), 249–256 (2009)

    Article  CAS  Google Scholar 

  17. Wei, L., Sun, P., Nie, S., Pan, W.: Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev. Ind. Pharm. 31(8), 785–794 (2005)

    Article  CAS  Google Scholar 

  18. Salimi, A., Zadeh, B.S.M., Hemati, A., Birgani, S.A.: Design and evaluation of self-emulsifying drug delivery system (SEDDS) of carvedilol to improve the oral absorption. Jundishapur J. Nat. Pharm. Prod. 9(3), e16125 (2014)

    Article  Google Scholar 

  19. Zhang, Y., Zhi, Z., Li, X., Gao, J., Song, Y.: Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol. Int. J. Pharm. 454(1), 403–411 (2013)

    Article  CAS  Google Scholar 

  20. Nikolic, V., Kapor, A.J., Nikolic, L.B., Savic, I.M., Savic-Gajic, I.M.: The importance of inclusion complexes with cyclodextrins in pharmacy. In: Ramirez, F.G. (ed.) Cyclodextrins: Synthesis, Chemical Applications and Role in Drug Delivery, pp. 225–240. Nova Science Publishers Inc, New York (2015)

    Google Scholar 

  21. Savic, I.M., Nikolic, V.D., Savic-Gajic, I., Nikolic, L.B., Radovanovic, B.C., Mladenovic, J.D.: Investigation of properties and structural characterization of the quercetin inclusion complex with (2-hydroxypropyl)-β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 82(3), 383–394 (2015)

    Article  CAS  Google Scholar 

  22. Tačić, A., Savić, I., Nikolić, V., Savić, I., Ilić-Stojanović, S., Ilić, D., Petrović, S., Popsavin, M., Kapor, A.: Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 80(1–2), 113–124 (2014)

    Google Scholar 

  23. Dawoud, A.A., Al-Rawashdeh, N.: Spectrofluorometric, thermal, and molecular mechanics studies of the inclusion complexation of selected imidazoline-derived drugs with β-cyclodextrin in aqueous media. J. Incl. Phenom. Macrocycl. Chem. 60(3–4), 293–301 (2008)

    Article  CAS  Google Scholar 

  24. Al-Rawashdeh, N.A., Al-Sadeh, K.S., Al-Bitar, M.B.: Physicochemical study on microencapsulation of hydroxypropyl-β-cyclodextrin in dermal preparations. Drug Dev. Ind. Pharm. 36(6), 688–697 (2010)

    Article  CAS  Google Scholar 

  25. Bani-Yaseen, A.D., Al-Rawashdeh, N.F., Al-Momani, I.: Influence of inclusion complexation with β-cyclodextrin on the photostability of selected imidazoline-derived drugs. J. Incl. Phenom. Macrocycl. Chem. 63(1–2), 109–115 (2009)

    Article  CAS  Google Scholar 

  26. Al-Rawashdeh, N.A., Al-Sadeh, K.S., Al-Bitar, M.B.: Inclusion complexes of sunscreen agents with β-cyclodextrin: spectroscopic and molecular modeling studies. J. Spectrosc. 2013, 11 (2013)

    Google Scholar 

  27. Al-Rawashdeh, N.A.: Interactions of nabumetone with γ-cyclodextrin studied by fluorescence measurements. J. Incl. Phenom. Macrocycl. Chem. 51(1–2), 27–32 (2005)

    Article  CAS  Google Scholar 

  28. Szejtli, J.: Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98(5), 1743–1754 (1998)

    Article  CAS  Google Scholar 

  29. Lombardo, D., Longo, A., Darcy, R., Mazzaglia, A.: Structural properties of nonionic cyclodextrin colloids in water. Langmuir 20(4), 1057–1064 (2004)

    Article  CAS  Google Scholar 

  30. Del Valle, E.M.: Cyclodextrins and their uses: a review. Process Biochem. 39(9), 1033–1046 (2004)

    Article  Google Scholar 

  31. Zoghbi, A., Wang, B.: Carvedilol solubility enhancement by inclusion complexation and solid dispersion: review. J. Drug Deliv. Ther. 5(2), 1–8 (2015)

    CAS  Google Scholar 

  32. Yuvaraja, K., Das, S.K., Khanam, J.: Process optimization and characterization of carvedilol solid dispersion with hydroxypropyl-β-cyclodextrin and tartaric acid. Korean J. Chem. Eng. 32, 1–9 (2015)

    Article  Google Scholar 

  33. Sharma, A., Jain, C.P.: Carvedilol-β-cyclodextrin systems: preparation, characterization and in vitro evaluation. Dhaka Univ. J. Pharm. Sci. 12(1), 51–58 (2013)

    Article  CAS  Google Scholar 

  34. Pamudji, J.S., Mauludin, R., Lestari, V.A.: Improvement of carvedilol dissolution rate through formation of inclusion complex with β-cyclodextrin. Int. J. Pharm. Pharm. Sci. 6(4), 228–233 (2014)

    CAS  Google Scholar 

  35. Loftsson, T., Vogensen, S.B., Desbos, C., Jansook, P.: Carvedilol: solubilization and cyclodextrin complexation: a technical note. AAPs Pharm. Sci. Tech. 9(2), 425–430 (2008)

    Article  CAS  Google Scholar 

  36. Soleymanpour, A., Ghasemian, M.: Chemically modified carbon paste sensor for the potentiometric determination of carvedilol in pharmaceutical and biological media. Measurement 59, 14–20 (2015)

    Article  Google Scholar 

  37. Cappello, B., De Rosa, G., Giannini, L., La Rotonda, M.I., Mensitieri, G., Miro, A., Russo, R.: Cyclodextrin-containing poly (ethyleneoxide) tablets for the delivery of poorly soluble drugs: potential as buccal delivery system. Int. J. Pharm. 319(1), 63–70 (2006)

    Article  CAS  Google Scholar 

  38. Hirlekar, R., Kadam, V.: Preparation and characterization of inclusion complexes of carvedilol with methyl-β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 63(3–4), 219–224 (2009)

    Article  CAS  Google Scholar 

  39. Talvani, A., Bahia, M.T., de Sá-Barreto, L.C.L., Lima, E.M., da Cunha-Filho, M.S.S.: Carvedilol: decomposition kinetics and compatibility with pharmaceutical excipients. J. Therm. Anal. Calorim. 115(3), 2501–2506 (2014)

    Article  CAS  Google Scholar 

  40. Wen, X., Tan, F., Jing, Z., Liu, Z.: Preparation and study the 1:2 inclusion complex of carvedilol with β-cyclodextrin. J. Pharm. Biomed. 34(3), 517–523 (2004)

    Article  CAS  Google Scholar 

  41. Pokharkar, V., Khanna, A., Venkatpurwar, V., Dhar, S., Mandpe, L.: Ternary complexation of carvedilol, β-cyclodextrin and citric acid for mouth-dissolving tablet formulation. Acta Pharm. 59(2), 121–132 (2009)

    Article  CAS  Google Scholar 

  42. Shewale, B.D., Sapkal, N.P., Raut, N.A., Gaikwad, N.J., Fursule, R.A.: Effect of hydroxylpropyl-β-cyclodextrin on solubility of carvedilol. Indian J. Pharm. Sci. 70(2), 255–257 (2008)

    Article  CAS  Google Scholar 

  43. Bhutani, S., Hiremath, S.N., Swamy, P.V., Raju, S.A.: Preparation and evaluation of inclusion complexes of carvedilol. J. Sci. Ind. Res. 66(10), 830–834 (2007)

    CAS  Google Scholar 

  44. Higuchi, T., Connors, K.: Phase-solubility techniques. Adv. Anal. Chem. Instrum. 7, 117–122 (1965)

    Google Scholar 

  45. Hamidi, H., Abderrahim, R., Meganem, F.: Spectroscopic studies of inclusion complex of β-cyclodextrin and benzidine diammonium dipicrate. Spectrochim. Acta A. 75, 32–36 (2010)

    Article  Google Scholar 

  46. Wen, X., Tan, F., Jing, Z., Liu, Z.: Preparation and study the 1:2 inclusion complex of carvedilol with β-cyclodextrin. J. Pharm. Biomed. 34(3), 517–523 (2004)

    Article  CAS  Google Scholar 

  47. Sambasevam, K.P., Mohamad, S., Sarih, N.M., Ismail, N.A.: Synthesis and characterization of the inclusion complex of β-cyclodextrin and azomethine. Int. J. Mol. Sci. 14(2), 3671–3682 (2013)

    Article  CAS  Google Scholar 

  48. Bocanegra-Diaz, A., Mohallem, N.D., Sinisterra, R.D.: Preparation of a ferrofluid using cyclodextrin and magnetite. J. Braz. Chem. Soc. 14(6), 936–941 (2003)

    Article  CAS  Google Scholar 

  49. Loftsson, T., Magnusdottir, A., Masson, M., Sigurjonsdottir, J.F.: Self-association and cyclodextrin solubilization of drugs. J. Pharm. Sci. 91, 2307–2316 (2002)

    Article  CAS  Google Scholar 

  50. Loftsson, T., Masson, M., Brewster, M.E.: Self-association of cyclodextrins and cyclodextrin complexes. J. Pharm. Sci. 93(5), 1091–1099 (2004)

    Article  CAS  Google Scholar 

  51. Guideline, ICH Harmonised Tripartite.: Stability testing of new drug substances and products. Q1A (R2). Curr. Step 4, 1–22 (2003)

    Google Scholar 

  52. Jouyban, A., Hasanzadeh, M., Shadjou, N.: Non-aqueous electromigration analysis of some degradation products of carvedilol. Iran. J. Pharm. Res. 13(2), 471–486 (2014)

    CAS  Google Scholar 

  53. http://www.drugfuture.com/pharmacopoeia/usp35/data/v35300/usp35nf30s0_m2730.html

Download references

Acknowledgments

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia under the Project TRp-34012.

Author information

Authors and Affiliations

  1. Faculty of Technology, University of Nis, Bulevar oslobodjenja 124, 16000, Leskovac, Serbia

    Ivana Savic-Gajic, Ivan M. Savic, Vesna D. Nikolic & Ljubisa B. Nikolic

  2. Institute of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica, 21000, Novi Sad, Serbia

    Mirjana M. Popsavin

  3. Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica, 21000, Novi Sad, Serbia

    Agnes J. Kapor

Authors
  1. Ivana Savic-Gajic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivan M. Savic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vesna D. Nikolic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ljubisa B. Nikolic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mirjana M. Popsavin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Agnes J. Kapor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ivana Savic-Gajic.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal informed consent

This article does not contain any studies with human or animals subjects.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Savic-Gajic, I., Savic, I.M., Nikolic, V.D. et al. Study of the solubility, photostability and structure of inclusion complexes of carvedilol with β-cyclodextrin and (2-hydroxypropyl)-β-cyclodextrin. J Incl Phenom Macrocycl Chem 86, 7–17 (2016). https://doi.org/10.1007/s10847-016-0635-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10847-016-0635-y

Keywords

Search

Navigation