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Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes

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Abstract

Ternary complexes exploiting solubility synergism (SSn) between basic drugs and β-cyclodextrin (β-CD) in the presence of an organic hydoxy acid have been reported to provide the pharmaceutical technology with highly soluble ternary complexes, even with the least soluble β-CD. In this work, phase solubility techniques were used to study factors affecting SSn in aqueous solution, which may help in understanding the mechanism involved in ternary complex formation in solution, under equilibrium conditions. The equilibrium solubility of both β-CD and each of 8 structurally unrelated drugs were measured in tandem in the presence of different acid types at low and high pHs, and at different time intervals over a period of 1–40 days. The results indicate that SSn is evident regardless of acid type (organic and inorganic) at low pH, but the extent of SSn is acid type dependant and is limited by the drug salt solubility product constant (pK sp). Among different drugs, no apparent trend exists between drug salt solubility and the extent of SSn, but lowering drug salt solubility by increasing pH depresses SSn. The results also reveal no apparent trend between the magnitude of the complex formation constant (K ij) and SSn. For example, drugs of low K ij values such as astemizole, cisapride and sildenafil do not show any SSn, yet ketotifen and pizotifen, which also have low K ij values, exhibit substantial SSn. However, the solublizing power of β-CD represented by the slope of phase solubility diagram can be used as a marker for SSn (slopes exceeding 0.4 induce SSn).

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References

  1. Szejtli J. (1998). Chem. Rev. 98: 1743

    Article  CAS  Google Scholar 

  2. Tinwalla A.Y., Hoesterey B.L., Xiang T., Lim K. and Anderson B.D. (1993). Pharm. Res. 10: 1136

    Article  CAS  Google Scholar 

  3. Esclusa-Diaz M.T., Gayo-Otero M., Perez-Marcos M.B., Vila-Jato J.K. and Torres-Labandeira J.J. (1996). Int. J. Pharm. 142: 183

    Article  CAS  Google Scholar 

  4. Kim Y., Oksanen D.A., Massefski W., Blake J.F., Duffy E.M. and Chrunyk B. (1998). J. Pharm. Sci. 87: 1560

    Article  CAS  Google Scholar 

  5. Ping G., Tabibi S.E. and Yalkowsky S.H. (1998). J. Pharm. Sci. 87: 1535

    Article  Google Scholar 

  6. McCandless R. and Yalkowsky S.H. (1998). J. Pharm. Sci. 87: 1639

    Article  CAS  Google Scholar 

  7. Piel G., Evrard B., Fillet M., Llabres G. and Delattre L. (1998). Int. J. Pharm. 169: 15

    Article  CAS  Google Scholar 

  8. Piel G., Evrard B., Llabres G. and Delattre L. (1999). STP Pharm. Sci. 9: 257

    CAS  Google Scholar 

  9. Evard B., Chiap P., DeTullio P., Ghalmi F., Piel G., Crommen J., Losson B. and Delattre L. (2002). J. Control. Release 85: 45

    Article  Google Scholar 

  10. Garcia J.J., Bolas F. and Torrado J.J. (2003). Int. Pharm J. 250: 351

    Article  CAS  Google Scholar 

  11. Casella R., Williams D.A. and Jambhekar S.S. (1998). Int. J. Pharm. 165: 15

    Article  CAS  Google Scholar 

  12. Redenti E., Szente L. and Szejtli J. (2001). J. Pharm. Sci. 90: 979

    Article  CAS  Google Scholar 

  13. Mura P., Maestrelli F. and Cirri M. (2003). Int. J. Pharm. 260: 293

    Article  CAS  Google Scholar 

  14. A.A. Badwan, A. Abu-Malooh, M. Haddadin, and H. Ibrahim: US Patent No. 5646131 A 19970708 (1997)

  15. Cabral H.M., Hadgraft M.J. and Kellawy I.W. (1990). Int. J. Pharm. 63: 259

    Article  Google Scholar 

  16. Szente L., Szejtli J., Vikmon M., Szeman J., Fenyvesy E., Pasini M., Redenti E. and Ventura P. (1995). Proceedings of the 1st World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology. APGI, Chatenary Malabry (France), 579–580

    Google Scholar 

  17. Ventura P. Ventura, P. Chiesi, M. Pasini, E. Redenti, J. Szejtli, and M. Vikmon: US Patent No. US5855916 (1995)

  18. Piel G., Pirotte B., Delneuville I., Neven P., Llabres G., Delarge J. and Delattre L. (1997). J. Pharm. Sci. 86: 475

    Article  CAS  Google Scholar 

  19. Redenti E., Szente L. and Szejtli J. (2000). J. Pharm. Sci. 89: 1

    Article  CAS  Google Scholar 

  20. BP (British Pharmacopoeia). Volume IV, Appendix V F p A181–A182. British Pharmacopoeia Commission, London (2003)

  21. T. Higuchi and K.A. Connors: In C.N. Reilley (1965). (eds) Advances in Analytical Chemistry and Instrumentation, pp 117–212. Wiley-Interscience, New York

    Google Scholar 

  22. Zughul M.B. and Badwan A.A. (1998). J. Incl. Phenom. 31: 243

    Article  CAS  Google Scholar 

  23. Zughul M.B. and Badwan A.A. (1997). Int. J. Pharm. 151: 109

    Article  CAS  Google Scholar 

  24. Zughul M.B., Al-Omari M. and Badwan A.A. (1998). Pharm. Dev. Technol. 3: 43

    Article  CAS  Google Scholar 

  25. Fenyvesi E., Vikmon M., Szeman J., Redenti E., Delcanale M., Ventura P. and Szejtli J. (1999). J. Incl. Phenom. 33: 339

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. The Jordanian Pharmaceutical Manufacturing Company, Naor, Jordan

    Mahmoud M. Al Omari & Adnan A. Badwan

  2. Department of Chemistry, University of Jordan, Amman, Jordan

    Mohammad B. Zughul

  3. Department of Environmental Science, Lancaster University, Lancaster, England

    J. Eric D. Davies

Authors
  1. Mahmoud M. Al Omari
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  2. Mohammad B. Zughul
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  3. J. Eric D. Davies
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  4. Adnan A. Badwan
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Correspondence to Adnan A. Badwan.

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Omari, M.M.A., Zughul, M.B., Davies, J.E.D. et al. Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes. J Incl Phenom Macrocycl Chem 54, 159–164 (2006). https://doi.org/10.1007/s10847-005-6287-y

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  • DOI: https://doi.org/10.1007/s10847-005-6287-y

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