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
Szejtli J. (1998). Chem. Rev. 98: 1743
Tinwalla A.Y., Hoesterey B.L., Xiang T., Lim K. and Anderson B.D. (1993). Pharm. Res. 10: 1136
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
Kim Y., Oksanen D.A., Massefski W., Blake J.F., Duffy E.M. and Chrunyk B. (1998). J. Pharm. Sci. 87: 1560
Ping G., Tabibi S.E. and Yalkowsky S.H. (1998). J. Pharm. Sci. 87: 1535
McCandless R. and Yalkowsky S.H. (1998). J. Pharm. Sci. 87: 1639
Piel G., Evrard B., Fillet M., Llabres G. and Delattre L. (1998). Int. J. Pharm. 169: 15
Piel G., Evrard B., Llabres G. and Delattre L. (1999). STP Pharm. Sci. 9: 257
Evard B., Chiap P., DeTullio P., Ghalmi F., Piel G., Crommen J., Losson B. and Delattre L. (2002). J. Control. Release 85: 45
Garcia J.J., Bolas F. and Torrado J.J. (2003). Int. Pharm J. 250: 351
Casella R., Williams D.A. and Jambhekar S.S. (1998). Int. J. Pharm. 165: 15
Redenti E., Szente L. and Szejtli J. (2001). J. Pharm. Sci. 90: 979
Mura P., Maestrelli F. and Cirri M. (2003). Int. J. Pharm. 260: 293
A.A. Badwan, A. Abu-Malooh, M. Haddadin, and H. Ibrahim: US Patent No. 5646131 A 19970708 (1997)
Cabral H.M., Hadgraft M.J. and Kellawy I.W. (1990). Int. J. Pharm. 63: 259
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
Ventura P. Ventura, P. Chiesi, M. Pasini, E. Redenti, J. Szejtli, and M. Vikmon: US Patent No. US5855916 (1995)
Piel G., Pirotte B., Delneuville I., Neven P., Llabres G., Delarge J. and Delattre L. (1997). J. Pharm. Sci. 86: 475
Redenti E., Szente L. and Szejtli J. (2000). J. Pharm. Sci. 89: 1
BP (British Pharmacopoeia). Volume IV, Appendix V F p A181–A182. British Pharmacopoeia Commission, London (2003)
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
Zughul M.B. and Badwan A.A. (1998). J. Incl. Phenom. 31: 243
Zughul M.B. and Badwan A.A. (1997). Int. J. Pharm. 151: 109
Zughul M.B., Al-Omari M. and Badwan A.A. (1998). Pharm. Dev. Technol. 3: 43
Fenyvesi E., Vikmon M., Szeman J., Redenti E., Delcanale M., Ventura P. and Szejtli J. (1999). J. Incl. Phenom. 33: 339
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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