Skip to main content
SpringerLink
Log in

Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation

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

Abstract

The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.

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. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J. 2009;11:740–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Fu Q, Kou LF, Gong C, Sun J, He ZG, et al. Relationship between dissolution and bioavailability for nimodipine colloidal dispersions: the critical size in improving bioavailability. Int J Pharm. 2012;427:358–64.

    Article  CAS  PubMed  Google Scholar 

  3. Plakkot S, de Matas M, York P, Saunders M, Sulaiman B. Comminution of ibuprofen to produce nano-particles for rapid dissolution. Int J Pharm. 2011;415:307–14.

    Article  CAS  PubMed  Google Scholar 

  4. Pokharkar VB, Malhi T, Mandpe L. Bicalutamide nanocrystals with improved oral bioavailability: in vitro and in vivo evaluation. Pharm Dev Technol. 2013;18:660–6.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang JJ, Huang YT, Liu DP, Gao Y, Qian S. Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement. Eur J Pharm Biopharm. 2013;48:740–7.

    CAS  Google Scholar 

  6. Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a Class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS PharmSciTech. 2011;12:799–810.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Ribeiro ME, de Moura CL, Vieira MG, Gramosa NV, Ricardo NM, et al. Solubilisation capacity of Brij surfactants. Int J Pharm. 2012;436:631–5.

    Article  CAS  PubMed  Google Scholar 

  8. Machatha SG, Bustamante P, Yalkowsky SH. Deviation from linearity of drug solubility in ethanol/water mixtures. Int J Pharm. 2004;283:83–8.

    Article  CAS  PubMed  Google Scholar 

  9. Seedher N, Kanojia M. Co-solvent solubilization of some poorly-soluble antidiabetic drugs. Pharm Dev Technol. 2009;14:185–92.

    Article  CAS  PubMed  Google Scholar 

  10. Forster A, Hempenstall J, Tucker I, Rades T. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm. 2001;226:147–61.

    Article  CAS  PubMed  Google Scholar 

  11. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.

    Article  CAS  PubMed  Google Scholar 

  12. Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59:645–66.

    Article  CAS  PubMed  Google Scholar 

  13. Holvoet C, Heyden YV, Plaizier-Vercammen J. Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use. Drug Dev Ind Pharm. 2005;31:567–75.

    Article  CAS  PubMed  Google Scholar 

  14. Loftsson T, Hereinsdottir D, Masson M. Evaluation of cyclodextrin solubilization of drugs. Int J Pharm. 2005;302:18–28.

    Article  CAS  PubMed  Google Scholar 

  15. Saetern AM, Nguyen NB, Bauer-Brandl A, Brandl M. Effect of hydroxypropyl-B-cyclodextrin complexation and pH on solubility of camptothecin. Int J Pharm. 2004;284:61–8.

    Article  CAS  PubMed  Google Scholar 

  16. Mallick S, Mondal A, Sannigrahi S. Kinetic measurements of the hydrolytic degradation of cefixime: effect of Captisol complexation and water-soluble polymers. J Pharm Pharmacol. 2008;60:833–41.

    Article  CAS  PubMed  Google Scholar 

  17. Ozdemir N, Erkin J. Enhancement of dissolution rate and bioavailability of sulfamethoxazole by complexation with beta-cyclodextrin. Drug Dev Ind Pharm. 2012;38:331–40.

    Article  PubMed  Google Scholar 

  18. Trapani A, Lopedota A, Denora N, Trapani G, Liso G, et al. A rapid screening tool for estimating the potential of 2-hydroxypropyl-beta-cyclodextrin complexation for solubilization purposes. Int J Pharm. 2005;295:163–75.

    Article  CAS  PubMed  Google Scholar 

  19. Yang J, Wiley CJ, Godwin DA, Felton LA. Influence of hydroxypropyl-beta-cyclodextrin on transdermal penetration and photostability of avobenzone. Eur J Pharm Biopharm. 2008;69:605–12.

    Article  CAS  PubMed  Google Scholar 

  20. Felton LA, Wiley CJ, Godwin DA. Influence of hydroxypropyl-B-cyclodextrin on the transdermal permeation and skin accumulation of oxybenzone. Drug Dev Ind Pharm. 2002;28:1117–24.

    Article  CAS  PubMed  Google Scholar 

  21. Godwin DA, Wiley CJ, Felton LA. Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen. Eur J Pharm Biopharm. 2006;2:85–93.

    Article  Google Scholar 

  22. Kear CL, Yang J, Godwin DA, Felton LA. Investigation into the mechanism by which cyclodextrins influence transdermal drug delivery. Drug Dev Ind Pharm. 2008;34:692–7.

    Article  CAS  PubMed  Google Scholar 

  23. Loftsson T, Brewster ME. Cyclodextrins as functional excipients: methods to enhance complexation efficiency. J Pharm Sci. 2012;101:3019–32.

    Article  CAS  PubMed  Google Scholar 

  24. Tongiani S, Ozeki T, Stella VJ. Sulfobutyl ether-alkyl ether mixed cyclodextrin derivatives with enhanced inclusion ability. J Pharm Sci. 2009;98:4769–80.

    Article  CAS  PubMed  Google Scholar 

  25. Kou W, Cai CF, Xu SY, Wang H, Zhang TH, et al. In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: complexation with hydroxypropyl-beta-cyclodextrin in the presence of HPMC. Int J Pharm. 2011;409:75–80.

    Article  CAS  PubMed  Google Scholar 

  26. Lee YH, Sathigari S, Lin YJ, Ravis WR, Babu RJ, et al. Gefitinib-cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies. Drug Dev Ind Pharm. 2009;35:1113–20.

    Article  Google Scholar 

  27. Sinha VR, Anitha R, Ghosh S, Nanda A, Kumria R. Complexation of celecoxib with beta-cyclodextrin: characterization of the interaction in solution and in solid state. J Pharm Sci. 2005;94:676–87.

    Article  CAS  PubMed  Google Scholar 

  28. Uzqueda M, Martin C, Zornoza A, Sanchez M, Velaz I, et al. Characterization of complexes between naftifine and cyclodextrins in solution and in the solid state. Pharm Res. 2006;23:980–8.

    Article  CAS  PubMed  Google Scholar 

  29. Kratz JM, Teixeira MR, Ferronato K, Teixeira HF, Simoes CM, et al. Preparation, characterization, and in vitro intestinal permeability evaluation of thalidomide-hydroxypropyl-beta-cyclodextrin complexes. AAPS PharmSciTech. 2011;13:118–24.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Palem CR, Battu SK, Gannu R, Yamsani VV, Yamsani MR, et al. Role of cyclodextrin complexation in felodipine-sustained release matrix tablets intended for oral transmucosal delivery: in vitro and ex vivo characterization. Pharm Dev Technol. 2011;17:321–32.

    Article  PubMed  Google Scholar 

  31. Chari R, Qureshi F, Moschera J, Tarantino R, Kalonia D. Development of improved empirical models for estimating the binding constant of a beta-cyclodextrin inclusion complex. Pharm Res. 2009;26:161–71.

    Article  CAS  PubMed  Google Scholar 

  32. Li H, Sun J, Wang Y, Sui X, Sun L, Zhang JJ, et al. Structure-based in silico model profiles the binding constant of poorly soluble drugs with B-cyclodextrin. Eur J Pharm Sci. 2011;42:55–64.

    Article  CAS  PubMed  Google Scholar 

  33. Higuchi T, Connors KA. Phase-solubility techniques. In: Reilley CN, editor. Advances in analytical chemistry and instrumentation. New York: John Wiley & Sons, Inc; 1965. p. 117–212.

    Google Scholar 

  34. Omile CI, Tebbett IR, Danesh B. Determination of ten anti-inflammatory drugs in serum by isocratic liquid chromatography. Chromatographia. 1986;22:187–8.

    Article  CAS  Google Scholar 

  35. Loftsson T, Hereinsdottir D, Masson M. The complexation efficiency. J Incl Phenom Macrocycl Chem. 2007;57:545–52.

    Article  CAS  Google Scholar 

  36. Gundogdu E, Koksal C, Karasulu E. Comparison of cefpodoxime proxetil release and antimicrobial activity from tablet formulations: complexation with hydroxypropyl-beta-cyclodextrin in the presence of water soluble polymer. Drug Dev Ind Pharm. 2012;38:689–96.

    Article  CAS  PubMed  Google Scholar 

  37. Mihajlovic T, Kachrimanis K, Graovac A, Djuric Z, Ibric S. Improvement of aripiprazole solubility by complexation with (2-hydroxy)propyl-beta-cyclodextrin using spray drying technique. AAPS PharmSciTech. 2012;13:623–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Wojciechowski ML, Lesyng B. Generalized born model: analysis, refinement, and applications to proteins. J Phys Chem B. 2004;108:18368–76.

    Article  CAS  Google Scholar 

  39. Lin A. QuaSAR-descriptor. 2012.

  40. Wildman SA, Crippen GM. Prediction of physiochemical parameters by atomic contributions. J Chem Inf Comput Sci. 1999;39:868–73.

    Article  CAS  Google Scholar 

  41. Pedraza A, Sicilia MD, Rubio S, Perez-Bendito D. Pharmaceutical quality control of acid and neutral drugs based on competitive self-assemply in amphiphilic systems. Analyst. 2006;131:81–9.

    Article  CAS  PubMed  Google Scholar 

  42. Drugbank.ca. June 6, 2013.

  43. Salustio PJ, Feio G, Figueirinhas JL, Pinto JF, Marques HM. The influence of the preparation methods on the inclusion of model drugs in a beta-cyclodextrin cavity. Eur J Pharm Biopharm. 2009;71:377–86.

    Article  CAS  PubMed  Google Scholar 

  44. Loftsson T, Magnusdottir A, Masson M, Sigurjonsdottir JF. Self-association and cyclodextrin solubilization of drugs. J Pharm Sci. 2002;91:2307–16.

    Article  CAS  PubMed  Google Scholar 

  45. Hopfinger AJ, Yang L, Liu J. The binding of drugs and small biological molecules to carbon naotubes as a possible source of nanotoxicity. Mol Pharm. 2009;6:873–82.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Perlovich GL, Skar M, Bauer-Brandl A. Driving forces and the influence of the buffer composition on the complexation reaction between ibuprofen and HPCD. Eur J Pharm Sci. 2003;20:197–200.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding for this work was supported in part by Roquette Freres. Computational facilities from both Exe Research LLC and The Chem21 Group, Inc. were made available in order to perform the modeling and molecular dynamics simulation studies reported in this paper.

Author information

Authors and Affiliations

  1. College of Pharmacy, Department of Pharmaceutical Sciences, University of New Mexico, MSC09 5360, 1 University of New Mexico, Albuquerque, New Mexico, 87131, USA

    Linda A. Felton, Cody Wiley & Anton J. Hopfinger

  2. Roquette America, Inc., Geneva, Illinois, USA

    Carmen Popescu

  3. The Chem21 Group, Inc., Lake Forest, Illinois, USA

    Emilio Xavier Esposito & Anton J. Hopfinger

  4. Exe Research LLC, East Lansing, Michigan, USA

    Emilio Xavier Esposito

  5. Roquette Freres, Lestrem, France

    Philippe Lefevre

Authors
  1. Linda A. Felton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmen Popescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cody Wiley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emilio Xavier Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philippe Lefevre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anton J. Hopfinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda A. Felton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Felton, L.A., Popescu, C., Wiley, C. et al. Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation. AAPS PharmSciTech 15, 872–881 (2014). https://doi.org/10.1208/s12249-014-0110-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-014-0110-2

KEY WORDS

Search

Navigation