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Pharmaceutical Research

, Volume 11, Issue 4, pp 522–527 | Cite as

The Effect of Temperature and pH on the Solubility of Quinolone Compounds: Estimation of Heat of Fusion

  • Xuanqiang Yu
  • Gail L. Zipp
  • G. W. Ray Davidson III
Article

Abstract

Although many reports involving fluoroquinolone agents have been published in the past decades, only a few address preformulation studies. In this paper, we describe the effect of temperature and pH on the aqueous solubility of two typically used quinolones, ciprofloxacin and norfloxacin. We measured the aqueous solubilities over the pH range of 5.5 to 9.5 at temperature of 6, 25, 30, and 40°C. The intrinsic solubilities and the thermodynamic dissociation constants were determined from solubility data and the temperature dependence of the intrinsic solubility was evaluated using van’t Hoff and Hildebrand plots. The heat effusion was determined from these two plots. When the heat effusion was compared to that measured from differential scanning calorimetry (DSC) studies, we found that the Hildebrand method overestimated, and the van’t Hoff equation underestimated, the heat of fusion. From the absolute values of the relative errors, the Hildebrand plot produced the better results. DSC results show that the heat effusion is 15.41 kcal/mol for ciprofloxacin and 7.88 kcal/mol for norfloxacin.

ciprofloxacin norfloxacin solubility dissociation constants heat of fusion 

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REFERENCES

  1. 1.
    J. S. Wolfson and D. C. Hooper. Fluoroquinolone antimicrobial agents. Clin. Microbiol. Rev. 2:237–424 (1989).Google Scholar
  2. 2.
    J. M. Domagala, C. L. Heifetz, M. P. Hutt, T. F. Mich, J. B. Nichols, M. Solomon, and D. F. Worth. 1-Substituted-7-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolonecarboxylicacids. New quantitative structure activity relationships at N1 for the quinolone antibacterials. J. Med. Chem. 31:991–1001 (1988).Google Scholar
  3. 3.
    D. Bouzard, P. Di Cesare, M. Essiz, J. P. Jacquet, P. Remuzon, A. Weber, T. Oki, and M. Masuyoshi. Fluoronaphthyridines and quinolones as antibacterial agents. 1. Synthesis and structure-activity relationships of new 1-substitutes derivatives. J. Med. Chem. 32:537–542 (1989).Google Scholar
  4. 4.
    D. L. Ross and C. M. Riley. Aqueous solubilities of some variously substituted quinolone antimicrobials. Int. J. Pharm. 63:237–250 (1990).Google Scholar
  5. 5.
    D. L. Ross and C. M. Riley. Physicochemical properties of the fluoroquinolone antimicrobials. II. Acid ionization constants and their relationship to structure. Int. J. Pharm. 83:267–272 (1992).Google Scholar
  6. 6.
    D. L. Ross and C. M. Riley. Physicochemical properties of the fluoroquinolone antimicrobials. III. Complexation of lomefloxacin with various metal ions and the effect of metal ion complexation on aqueous solubility. Int. J. Pharm. 87:203–213 (1992).Google Scholar
  7. 7.
    R. Kitzes-Cohen. Quinolone in CNS infections/pharmacokinetics. Quinolones Bull. 3:7–14 (1987).Google Scholar
  8. 8.
    Takacs-Novak, B. Noszal, I. Hermecz, G. Kereszturi, B. Podanyi, and G. Szasz. Protonation equilibria of quinolone antibacterials. J. Pharm. Sci. 79:1023–1028 (1990).Google Scholar
  9. 9.
    I. Zimmermann. Determination of overlapping pKa values from solubility data. Int. J. Pharm. 31:69–74 (1986).Google Scholar
  10. 10.
    J. Blanchard, J. O. Boyle, and S. V. Van. Determination of the partition coefficients, and dissociation constants, and intrinsic solubility of carbenoxolone. J. Pharm. Sci. 77:548–552 (1988).Google Scholar
  11. 11.
    C. C. Peck and L. Z. Benet. General method for determination macrodissociation constants of polyprotic, amphoteric compounds from solubility measurements. J. Pharm. Sci. 67:12–16 (1978).Google Scholar
  12. 12.
    J. N. Butler. Ionic Equilibrium: A Mathematical Approach, Addison-Wesley, Reading, MA, 1964.Google Scholar
  13. 13.
    K. C. James. Solubility and Related Properties, Marcel Dekker, New York and Basel, 1986.Google Scholar
  14. 14.
    S. H. Neau and G. L. Flynn. Solid and liquid heat capacities of n-alkyl para-aminobenzoates near the melting point. Pharm. Res. 7:1157–1162 (1990).Google Scholar
  15. 15.
    J. H. Hildebrand. The temperature dependence of the solubility of solid nonelectrolytes. J. Chem. Phys. 20:190–191 (1952).Google Scholar
  16. 16.
    J. H. Hildebrand and R. L. Scott. Regular Solutions, Prentice-Hall, Englewood Cliffs, NJ, 1962.Google Scholar
  17. 17.
    J. H. Hildebrand, J. M. Prausnitz, and R. L. Scott. Regular and Related Solutions, Van Nostrand Reinhold, New York, 1970.Google Scholar
  18. 18.
    S. H. Yalkowsky, G. L. Flynn, and G. T. Slunick. Importance of chain length of physicochemical and crystalline properties of organic homologs. J. Pharm. Sci. 61:852–857 (1972).Google Scholar
  19. 19.
    S. H. Yalkowsky and S. C. Valvani. Solubility and partitioning. I. Solubility of nonelectrolytes in water. J. Pharm. Sci. 69:912–922 (1980).Google Scholar
  20. 20.
    S. H. Yalkowsky. Solubility and partitioning. V. Dependence of solubility on melting point. J. Pharm. Sci. 70:971–973 (1981).Google Scholar
  21. 21.
    T. A. Hagen and G. L. Flynn. Solubility of hydrocortisone in organic and aqueous media: Evidence for regular solution behavior in apolar solvents. J. Pharm. Sci. 72:409–414 (1983).Google Scholar
  22. 22.
    D. J. W. Grant, M. Mendizadeh, A. H.-L. Chow, and J. E. Fairbrother. Non-linear van't Hoff solubility-temperature plots and their pharmaceutical interpretation. Int. J. Pharm. 18:25–38 (1984).Google Scholar
  23. 23.
    R. J. Prankerd and R. H. McKeown. Physio-chemical properties of barbituric acid derivatives. I. Solubility-temperature dependence for 5,5-disubstituted barbituric acids in aqueous solutions. Int. J. Pharm. 62:37–62 (1990).Google Scholar
  24. 24.
    R. J. Prankerd. Solid-state properties of drugs. I. Estimation of heat capacities for fusion and thermodynamic function for solution from aqueous solubility-temperature dependence measurements. Int. J. Pharm. 84:233–244 (1992).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Xuanqiang Yu
    • 1
  • Gail L. Zipp
    • 1
  • G. W. Ray Davidson III
    • 1
  1. 1.The Upjohn Company, DDR&DKalamazoo

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