Principles of Solubility

Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume VI)


Solubility is defined as the maximum quantity of a substance that can be completely dissolved in a given amount of solvent, and represents a fundamental concept in fields of research such as chemistry, physics, food science, pharmaceutical, and biological sciences. The solubility of a substance becomes especially important in the pharmaceutical field because it often represents a major factor that controls the bioavailability of a drug substance. Moreover, solubility and solubility-related properties can also provide important information regarding the structure of drug substances, and in their range of possible intermolecular interactions. For these reasons, a comprehensive knowledge of solubility phenomena permits pharmaceutical scientists to develop an optimal understanding of a drug substance, to determine the ultimate form of the drug substance, and to yield information essential to the development and processing of its dosage forms.


Dissolution Rate Ideal Solution Drug Substance Solubility Parameter Solute Molecule 
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  1. Amidon GL, Yalkowsky SH, Anik ST, and Valvani SC. Solubility of Nonelectrolytes in Polar Solvents V: Estimation of the Solubility of Aliphatic Monofunctional compounds in Water using a Molecular Surface Area Approach. J Phys Chem 1975; 79: 2239–2246.CrossRefGoogle Scholar
  2. Amidon GL, Yalkowsky SH, and Leung S. Solubility of Nonelectrolytes in Polar Solvents II: Solubility of Aliphatic Alcohols in Water. J Pharm Sci 1974; 63: 1858–1866.PubMedCrossRefGoogle Scholar
  3. Barton AFM. CRC Handbook of Solubility Parameters and Other Cohesion Parameters. CRC Press, Boca Raton, FL, 1983, p. 594.Google Scholar
  4. Bernstein J. Polymorphism in Molecular Crystals. Oxford University Press, New York, 2002.Google Scholar
  5. Brittain HG. A Method for the Determination of Solubility of Metastable Crystal Phases Based on Total Light Scattering. Langmuir 1996; 12: 601–604.CrossRefGoogle Scholar
  6. Brittain HG. Polymorphism of Pharmaceutical Solids. Marcel Dekker, New York, 1999.Google Scholar
  7. Brittain HG and Grant DJW. Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In: Brittain HG (ed.), Polymorphism of Pharmaceutical Solids. Marcel Dekker, New York, 1999, pp. 279–330.Google Scholar
  8. Davis SS, Higuchi T, and Rytting JH. Determination of Thermodynamics of Functional Groups in Solutions of Drug Molecules. In: Bean HS, Beckett AH, and Carless JE (eds.), Advances in Pharmaceutical Sciences, Vol. 4. Academic Press, New York, 1974, pp. 73–261.Google Scholar
  9. Eyjolfsson R. Nitrofurantoin: Particle Size and Dissolution. Drug Dev Ind Pharm 1999; 25: 105–106.PubMedCrossRefGoogle Scholar
  10. Ghosh S and Grant DJW. Determination of the Solubilities of Crystalline Solids in Solvent Media that Induce Phase Changes: Solubilities of 1,2-dialkyl-3-hydroxy-4-pyridones and Their Formic Acid Solvates in Formic Acid and Water. Int J Pharm 1995; 114: 185–196.CrossRefGoogle Scholar
  11. Grant DJW and Brittain HG. Solubility of Pharmaceutical Solids. In: Brittain HG (ed.), Physical Characterization of Pharmaceutical Solids. Marcel Dekker, New York, 1995, pp. 321–386.Google Scholar
  12. Grant DJW and Higuchi T. Solubility Behavior of Organic Compounds. John Wiley & Sons, New York, 1990, p. 656.Google Scholar
  13. Grant DJW, Mehdizadeh M, Chow AHL, and Fairbrother JE. Non-linear Van't-Hoff Solubility-Temperature Plots and their Pharmaceutical Interpretation. Int J Pharm 1984; 18: 25–38.CrossRefGoogle Scholar
  14. Gu CH, Young V Jr, and Grant DJW. Polymorph Screening: Influence of Solvents on the Rate of Solvent-Mediated Polymorphic Transformation. J Pharm Sci 2001; 90: 1878–1890.PubMedCrossRefGoogle Scholar
  15. Habib FS and Attia MA. Effect of Particle Size on the Dissolution Rate of Monophenylbutazone Solid Dispersions in the Presence of Certain Additives. Drug Dev Ind Pharm 1985; 11: 2009–2019.Google Scholar
  16. Hancock BC and Parks M. What is the True Solubility Advantage for Amorphous Pharmaceuticals. Pharm Res 2000; 17: 397–404.PubMedCrossRefGoogle Scholar
  17. Hancock BC and Zografi G. Characteristics and Significance of the Amorphous State in Pharmaceutical Systems. J Pharm Sci 1996; 86: 1–12.CrossRefGoogle Scholar
  18. Hansen C and Beerbower A. Solubility Parameters. In: Standen A (ed.), Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed. Supplement Volume, John Wiley & Sons, New York, 1971, pp. 889–910.Google Scholar
  19. Higuchi T. Solubility. In: Lyman R (ed.), Pharmaceutical Compounding and Dispensing, Lippincott Philadelphia, PA, 1949, pp. 176–177.Google Scholar
  20. Higuchi WI, Rowe EL, and Hiestand EN. Dissolution Rates of Finely Divided Drug Powders. II: Micronized Methylprednisolone. J Pharm Sci 1963; 52: 162–164.PubMedCrossRefGoogle Scholar
  21. Hilderbrand JH, Prausnitz JM, and Scott RL. Regular and Related Solutions. Van Nostrand Reinhold, New York, 1970, pp. 64–67.Google Scholar
  22. Hilderbrand JH and Scott RL. Solubility of Nonelectrolytes, 3rd edn. Reinhold Pub., New York, 1950, p. 488.Google Scholar
  23. Hilderbrand JH and Scott RL. Regular Solutions. Prentice-Hall, Englewood Cliffs, NJ, 1962, p. 180.Google Scholar
  24. Hildebrand JH and Wood SE. Derivation of Equations for Regular Solutions. J Chem Phys 1933; 1: 817–822.CrossRefGoogle Scholar
  25. Hixson AW and Crowell JH. Dependence of Reaction Velocity upon Surface and Agitation. I: Theoretical Consideration. Ind Eng Chem 1931; 23: 923–931.CrossRefGoogle Scholar
  26. Kornblum SS and Hirschorn JO. Dissolution of Poorly Water-Soluble Drugs. I: Some Physical Parameters related to Method of Micronization and Tablet Manufacture of a Quinazoline Compound. J Pharm Sci 1970; 59: 606–609.PubMedCrossRefGoogle Scholar
  27. Krishnan CV and Friedman HL. Solvation Enthalpies of Hydrocarbons and Normal Alcohols in Highly Polar Solvents. J Phys Chem 1971; 75: 3598–3606.CrossRefGoogle Scholar
  28. Kumar R and Prausnitz JM. Solvents in Chemical Technology. In: Dack MRJ. Solutions and Solubilities, Part 1, Techniques of Chemistry, Vol. VIII, John Wiley & Sons, New York, 1975, pp. 259–326.Google Scholar
  29. Levich VG. Physicochemical Hydrodynamics. Advance Publications, London, UK, 1977, p. 1078.Google Scholar
  30. Martin A. Physical Pharmacy, 4th edn. Lippincott Williams & Wilkins, Philadelphia, PA, 1993, pp. 223–224.Google Scholar
  31. Milosovish G. Determination of Solubility of a Metastable Polymorph. J Pharm Sci 1964; 53:484–487.CrossRefGoogle Scholar
  32. Mooney KG, Rodrigues-Gaxiola M, Mintun M, Himmelstein KJ, and Stella VJ. Dissolution Kinetics of Phenylbutazone. J Pharm Sci 1981; 70: 1358–1365.PubMedCrossRefGoogle Scholar
  33. Nernst W. Theorie der Reaktionsgeschhwindigkeit in Heterogenen Systemen. Z Phys Chem 1904; 47: 52–55.Google Scholar
  34. Noyes AA and Whitney WR. The Rate of Dissolution of Solid Substances in Their Own Solutions. J Am Chem Soc 1897; 19: 930–934.CrossRefGoogle Scholar
  35. Rohrschneider L. Solvent Characterization by Gas-liquid Partition Coefficients of Selected Solutes. Anal Chem 1973; 45:1241–1247.CrossRefGoogle Scholar
  36. Sato T, Okada A, Sekiguchi K, and Tsuda Y. Difference in Physico-pharmaceutical Properties Between Crystalline and Non-crystalline 9,3″-diacetylmidecamycin. Chem Pharm Bull 1981; 29: 2675–2682.Google Scholar
  37. Swanepoel E, Liebenberg W, de Villiers MM, and Dekker TG. Dissolution Properties of Piroxicam Powders and Capsules as a Function of Particle Size and the Agglomeration of Powders. Drug Dev Ind Pharm 2000; 26: 1067–1076.PubMedCrossRefGoogle Scholar
  38. Taft RW, Gurka D, Joris L, Schleyer P, von R, and Rakshys JW. Studies of Hydrogen-bonded complex formation with p-fluorophenol. V. Linear Free Energy Relationships with OH Reference Acids. J Am Chem Soc 1969; 91: 4801–4808.CrossRefGoogle Scholar
  39. Ullah I and Cadwallader DE. Dissolution of Slightly Soluble Powders under Sink Conditions. II: Griseofulvin Powders. J Pharm Sci 1971; 60: 230–233.PubMedCrossRefGoogle Scholar
  40. United States Pharmacopeia, 25th edition. United States Pharmacopeial Convention, Rockville, MD, 2002, p. 2363.Google Scholar
  41. United States Pharmacopeia, 29th edition. United States Pharmacopeial Convention, Rockville, MD, 2006, p. 9.Google Scholar
  42. Walden P. Über die Schmelzwärme, Spezifische Kohäsion und Molekulargrösse bei der Schmelztemperatur. Z Eletrochem 1908; 14: 713–724.CrossRefGoogle Scholar
  43. Yalkowsky SH. Estimation of Entropies of Fusion of Organic Compounds. Ind Eng Chem Fundam 1979; 18: 108–111.CrossRefGoogle Scholar
  44. Yalkowsky SH, Flynn GL, and Amidon GL. Solubility of nonelectrolytes in Polar Solvents. J Pharm Sci 1972; 61: 983–984.PubMedCrossRefGoogle Scholar
  45. Yalkowsky SH, Valvani SC, and Amidon GL. Solubility of Nonelectrolytes in Polar Solvents IV: Nonpolar Drugs in Mixed Solvents. J Pharm Sci 1976; 65: 1480–1494.CrossRefGoogle Scholar
  46. Zhu H and Grant DJW. Influence of Water Activity in Organic Solvent + Water Mixtures on the Nature of the Crystallizing Drug Phase. 2. Ampicillin. Int J Pharm 1996; 139: 33–43.CrossRefGoogle Scholar

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© Springer 2007

Authors and Affiliations

    • 1
    • 1
    • 2
  1. 1.Department of Pharmaceutics, College of PharmacyUniversity of MinnesotaMinneapolis
  2. 2.Center for Pharmaceutical PhysicsMilford

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