Estimation and Correlation of Solubility of Practically Insoluble Drug Itraconazole in 1,4-Butanediol + Water Mixtures Using Extended Hildebrand Solubility Approach

  • Sachin K. Jagdale
  • Rajesh B. NawaleEmail author
Original Article



Extended Hildebrand solubility approach (EHSA) was applied to estimate and correlate the solubilities of itraconazole in 1,4-butanediol + water mixtures at 298.15 K.


Experimental solubilities and properties like entropy of fusion and ideal mole fraction solubilities were determined. EHSA was applied to estimate interaction parameter W to understand the solute solvent interaction. Theoretical solubilities were calculated by using W as a function of solubility parameter of solvent blend (δ1) and by direct method using logarithmic experimental solubilities (logX2) against solubility parameter of solvent mixture (δ1). Prediction capacities of EHSA and direct method were compared using mean percent deviations obtained while comparing theoretical solubilities with experimental ones.


Itraconazole solubility was increased in all the proportions of solvent mixtures and was found to be highest at 0.9 mass fraction of 1,4-butanediol where solubility parameter of drug matched with solvent mixture. Prediction capacity of EHSA was found to be better with regular polynomial equation of order 5 with mean deviation of − 1.69%.


Using EHSA, the solubility of any solute can be adequately predicted with the knowledge of few physicochemical properties.


Itraconazole 1,4-Butanediol + water solvent mixture Solute solvent interactions Extended Hildebrand solubility approach Solubility parameter 



The authors are grateful to Marathwada Mitramandal’s College of Pharmacy, Kalewadi – Pune, India, and Y B Chavan College of Pharmacy, Aurangabad – India, for providing the necessary facilities to carry out the study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ceesay MM, Couchman L, Smith M, Wade J, Flanagan RJ, Pagliuca A. Triazole antifungals used for prophylaxis and treatment of invasive fungal disease in adult haematology patients: trough serum concentrations in relation to outcome. Med Mycol. 2016;54:691–8.CrossRefGoogle Scholar
  2. 2.
    Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–60.CrossRefGoogle Scholar
  3. 3.
    Hardin TC, Graybill JR, Fetchick R. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother. 1988;32:1310–3.CrossRefGoogle Scholar
  4. 4.
    Gupta AK, Adam P, Hofstader SL. Itraconazole oral solution for the treatment of onychomycosis. Pediatr Dermatol. 1998;15:472–4.CrossRefGoogle Scholar
  5. 5.
    Korting HC, Schöllmann C. The significance of itraconazole for treatment of fungal infections of skin, nails and mucous membranes. J Dtsch Dermatol Ges. 2009;7:11–9 11-20.Google Scholar
  6. 6.
    Boogaerts MA, Maertens JR, Van Der Geest, Bosly A, Michaux JM, Van Hoof A, et al. Pharmacokinetics and safety of a 7-day administration of intravenous itraconazole followed by a 14-day administration of itraconazole oral solution in patients with hematologic malignancy. Antimicrob Agents Chemother. 2001;45:981–5.CrossRefGoogle Scholar
  7. 7.
    Goktas S, Sakarya R, Erdogan E, Sakarya Y, Ozcimen M, Dursunoglu D, et al. Antiangiogenic effect of itraconazole on corneal neovascularization: a pilot experimental investigation. Ophthalmic Res. 2014;52:170–4.CrossRefGoogle Scholar
  8. 8.
    Davis MT, Potter CB, Mohammadpour M, Albadarin AB, Walker GM. Design of spray dried ternary solid dispersions comprising itraconazole, soluplus and HPMCP: effect of constituent compositions. Int J Pharm. 2017;519:365–72.CrossRefGoogle Scholar
  9. 9.
    Chen X, Fadda HM, Aburub A, Mishra D, Pinal R. Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone). Int J Pharm. 2015;494:346–56.CrossRefGoogle Scholar
  10. 10.
    Peng H, Li H, Wang C, Zhang D, Pan B, Xing B. Sorption and solubility of ofloxacin and norfloxacin in water–methanol cosolvent. Chemosphere. 2014;103:322–8.CrossRefGoogle Scholar
  11. 11.
    Ban K, Sonohara R, Yoshida M, Sako K, Uchida S, Namiki N. Pharmaceutical development of a parenteral formulation of conivaptan hydrochloride. PDA J Pharm Sci Technol. 2013;67:336–53.CrossRefGoogle Scholar
  12. 12.
    Jouyban A, Shayanfar A, Panahi-Azar V, Soleymani J, Yousefi BH, Acree WE Jr, et al. Solubility prediction of drugs in mixed solvents using partial solubility parameters. J Pharm Sci. 2011;100:4368–82.CrossRefGoogle Scholar
  13. 13.
    Farjami A, Jouyban A. Lamotrigine solubility in some nonaqueous solvent mixtures at 298.2 K. J Chem Eng Data. 2015;60:2490–4.CrossRefGoogle Scholar
  14. 14.
    Nokhodchi A, Shokri J, Barzegar-Jalali M. Prediction of benzodiazepines solubility using different cosolvency models. II. Farmaco. 2002;57:555–7.CrossRefGoogle Scholar
  15. 15.
    Hancock BC, York P, Rowe RC. The use of solubility parameters in pharmaceutical dosage form design. Int J Pharm. 1997;148:1–21.CrossRefGoogle Scholar
  16. 16.
    Greenhalgh DJ, Williams AC, Timmins P, York P. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci. 1999;88:1182–90.CrossRefGoogle Scholar
  17. 17.
    Vaughan CD, Wright FJ. Solubility parameter and anti-microbial activity. Pharm Acta Helv. 1986;61:95–6.Google Scholar
  18. 18.
    Shakeel F, Anwer MK, Shazly GA, Jamil S. Measurement and correlation of solubility of bioactive compound silymarin in five different green solvents at 298.15 K to 333.15 K. J Mol Liq. 2014;195:255–8.CrossRefGoogle Scholar
  19. 19.
    Rowe RC. Some fundamental properties of polymeric materials and their application in film coating formulations a review. Int J Pharm Technol Prod Manuf. 1982;3:3–8.Google Scholar
  20. 20.
    Bajpai AK. Determination of solubility parameter of gelatin by swelling measurements. Rev Roum Chim. 1996;41:219–22.Google Scholar
  21. 21.
    Michaels AS, Wong PSL, Prather R, Gale RM. A thermodynamic model of predicting transport of steroids in polymer matrices. Am Inst Chem Eng J. 1975;21:1073–80.CrossRefGoogle Scholar
  22. 22.
    Bakalyar SR, McIlwrick R, Roggendorf E. Solvent selectivity in reversed phase high pressure liquid chromatography. J Chromatgr. 1977;142:353–65.CrossRefGoogle Scholar
  23. 23.
    Thimmasetty J, Subrahmanyam CVS, Sathesh Babu PR. Solubility behavior of pimozide in polar and nonpolar solvents: partial solubility parameters approach. J Solut Chem. 2008;37:1365–78.CrossRefGoogle Scholar
  24. 24.
    Adjei A, Newburger J, Stavchansky S, Martin A. Membrane solubility parameter and in situ release of theophylline. J Pharm Sci. 1984;73:742–5.CrossRefGoogle Scholar
  25. 25.
    Martinez F, Gómez A. Estimation of the solubility of some sulfonamides in aqueous media from partition coefficients and entropies of fusion. Phys Chem Liq. 2002;40:411–20.CrossRefGoogle Scholar
  26. 26.
    Delgado DR, Peña MÁ, Martínez F. Extended Hildebrand solubility approach applied to some structurally related sulfonamides in ethanol + water mixtures. Rev Colomb Quím. 2016;45:34–43.CrossRefGoogle Scholar
  27. 27.
    Rathi PB. Solubility prediction of satranidazole in propylene glycol-water mixtures using extended Hildebrand solubility approach. Indian J Pharm Sci. 2011;73:670–4.CrossRefGoogle Scholar
  28. 28.
    Holguín AR, Delgado DR, Martínez F. Indomethacin solubility in propylene glycol + water mixtures according to the extended Hildebrand solubility approach. Lat Am J Pharm. 2012;31:720–6.Google Scholar
  29. 29.
    Constantinides PP, Han J, Davis SS. Advances in the use of tocols as drug delivery vehicles. Pharm Res. 2006;23:243–55.CrossRefGoogle Scholar
  30. 30.
    Reller HH, Kretschmar HC. Analgesic and anti-inflammatory compositions for topical application. US Patent 4,199,576. 1980 Apr 22.Google Scholar
  31. 31.
    Cooper ER, Loomans ME, Wickett RR. Penetrating topical pharmaceutical compositions. US Patent 4,954,487. 1990 Sep 4.Google Scholar
  32. 32.
    Hsu TM, Roos EJ. Transdermal formulations for administering prazosin. US Patent 5,688,524. 1997 Nov 18.Google Scholar
  33. 33.
    1,4-Butanediol (1, 4 BD) Critical review report expert committee on drug dependence thirty-sixth meeting Geneva, 16–20 June 2014.
  34. 34.
    Hazardous Substances Data Bank [Internet]. 1,4-Butanediol. Bethesda: National library of medicine (US), division of specialized information services; 1986. [Cited 10 Feb 2018]Google Scholar
  35. 35.
    Reillo A, Bustamante P, Escalera B, Jimenez MM, Selles E. Solubility parameter-based methods for predicting the solubility of sulfapyridine in solvent mixtures. Drug Dev Ind Pharm. 1995;21:2073–84.CrossRefGoogle Scholar
  36. 36.
    Rathi PB, Deshpande KV. Extended Hildebrand approach: an empirical model for solubility prediction of etodolac in 1, 4-dioxane and water mixtures. J Solut Chem. 2014;43:1886–903.CrossRefGoogle Scholar
  37. 37.
    Wu PL, Martin A. Extended Hildebrand solubility approach: p-hydroxybenzoic acid in mixtures of dioxane and water. J Pharm Sci. 1983;72:587–92.CrossRefGoogle Scholar
  38. 38.
    Ruidiaz MA, Delgado DR, Martínez F. Correlating the solubility of indomethacin in 1,4-dioxane + water mixtures by means of the Jouyban-Acree model. Rev Colomb Cienc Quím Farm. 2010;39:211–26.Google Scholar
  39. 39.
    Cárdenas ZJ, Almanza OA, Jouyban A, Martínez F, Acree WE Jr. Solubility and preferential solvation of phenacetin in methanol + water mixtures at 298.15 K. Phys Chem Liq. 2018;56:16–32.CrossRefGoogle Scholar
  40. 40.
    Delgado DR, Peña MA, Martínez F. Extended Hildebrand solubility approach applied to some sulphapyrimidines in some {methanol (1) + water (2)} mixtures. Phys Chem Liq. 2017;256:176–88.Google Scholar
  41. 41.
    Rhee YS, Park CW, Kim KJ, Chi SC, Park ES. Behavior of itraconazole and benzyl alcohol in aqueous solution containing nonionic surfactants. Arch Pharm Res. 2007;30:240–8.CrossRefGoogle Scholar
  42. 42.
    Rhee YS, Park CW, Nam TY, Shin YS, Chi SC, Park ES. Formulation of parenteral microemulsion containing itraconazole. Arch Pharm Res. 2007;30:114–23.CrossRefGoogle Scholar
  43. 43.
    Katarzyna G, Andrzej P. Organic solvents in the pharmaceutical industry. Acta Pol Pharm. 2011;67(1):3–12.Google Scholar
  44. 44.
    Martin A, Newburger J, Adjei A. Extended Hildebrand solubility approach: solubility of theophylline in polar binary solvents. J Pharm Sci. 1980;69:487–91.CrossRefGoogle Scholar
  45. 45.
    Martin A, Wu PL, Velasquez T. Extended Hildebrand solubility approach: sulfonamides in binary and ternary solvents. J Pharm Sci. 1985;7:277–82.CrossRefGoogle Scholar
  46. 46.
    Martin A, Miralles MJ. Extended Hildebrand solubility approach: solubility of tolbutamide, acetohexamide and sulfisomidine in binary solvent mixtures. J Pharm Sci. 1982;71:439–42.CrossRefGoogle Scholar
  47. 47.
    Walker EE. Solvent action of organic substances on polyacrylonitrile. J Appl Chem. 1952;2:470.CrossRefGoogle Scholar
  48. 48.
    Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4:117–22.Google Scholar
  49. 49.
    Fedors RF. A method of estimating both the solubility parameters and molar volumes of liquids. Polym Eng Sci. 1974;14:147–54.CrossRefGoogle Scholar
  50. 50.
    Barton AFM. CRC handbook of solubility parameters and other cohesion parameters. New York: CRC Press; 1983. p. 7–59, 157-85.Google Scholar
  51. 51.
    Patrick JS. Martin’s physical pharmacy and pharmaceutical sciences, vol. 595-96. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 245–6.Google Scholar
  52. 52.
    Kharwade M, Achyuta G, Subrahmanyam CVS, Satesh Babu PR. Solubility behavior of lornoxicam in binary solvents of pharmaceutical interest. J Solut Chem. 2012;41:1364–74.CrossRefGoogle Scholar
  53. 53.
    Martin A, Bustamante P, Chun AHC. Physical chemical principles in the pharmaceutical sciences. 4th ed. Philadelphia: Lea & Febiger; 1993.Google Scholar
  54. 54.
    Sotomayor RG, Holguín AR, Cristancho DM, Delgado DR, Martínez F. Extended Hildebrand solubility approach applied to piroxicam in ethanol + water mixtures. J Mol Liq. 2013;180:34–8.CrossRefGoogle Scholar
  55. 55.
    Cárdenas ZJ, Jiménez DM, Delgado DR, Peña MA, Martínez F. Extended Hildebrand solubility approach applied to some sulphonamides in propylene glycol + water mixtures. Phys Chem Liq. 2015;53:763–75.CrossRefGoogle Scholar
  56. 56.
    Ruidiaz MA, Delgado DR, Martínez F. Meloxicam solubility in ethanol+water mixtures according to the extended Hildebrand solubility approach. J Solut Chem. 2013;42:1706–16.CrossRefGoogle Scholar
  57. 57.
    Yalkowsky SH, Roseman TJ. Solubilization of drugs by cosolvents. In: Yalkowsky SH, editor. Techniques of solubilization of drugs. New York: Marcel Dekker; 1981.Google Scholar
  58. 58.
    Yasuhiro M, Nawel K, Katsumi M, Rodolfo P. Solubility enhancement of hydrophobic compounds by cosolvents: role of solute hydrophobicity on the solubilization effect. Int J Pharm. 2010;393:48–54.CrossRefGoogle Scholar
  59. 59.
    Powell JR, Miller BJ, Acree WE. Solubility of anthracene in binary alcohol + 1, 4-dioxane solvent mixtures. J Chem Eng Data. 1995;40:1124–6.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PharmaceuticsMarathwada Mitramandal’s College of PharmacyPuneIndia
  2. 2.Department of PharmacologyGovernment College of PharmacyAurangabadIndia

Personalised recommendations