Tablets - Solubility

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Preformulation and Solubility

Solubility is one of the very critical variable when making a formulation decision. Its important to understand the solubility of a drug substance in preformulation because the solubility of the durg substance is related to pKa, log P / log D.

Significance of solubility1-4

If a newly discovered molecule to become an active compound it should traverse through multitute of physiological barriers, both aqueous and nonaqueous. These barriers exist to protect our body from toxic foreign agents. Our body system by nature chose to protect us is based on the solubility of compounds. Compound which is highly soluble or highly insoluble in water would not be able to penetrate the deeper tissues and thus rendered ineffective.

Early preformulation studies yields information that how well a compound is distributed throgh out the body tissues and the liphophilic / hydrophilic balance of the molecular structure of the compound.

Solubility of a potential drug substance can be the controlling factor in determining the bioavailability of a compound. Degree of aqueous solubility alters the course of drug development and gives the green signal for the continued development. Low aqueous solubility can either delay or limit drug absorption. In addition, drug solution is prefered for conducting pharmacological, toxicological and pharmacokinetic studies during drug development stage. Poor aqueous solubility not only limits a drug biological application but also challenges its pharmaceutical development. Knowledge on solubility also finds application in development of analytical methods of drugs.

Measurement of Solubility

Methods for the determination of solubility have been reviewed thoroughly with respect to characterization of solids

General methods

  • Analytical
    • Traditional Shake Flask method
    • Flow column method
  • Synthetic

Accurate measurement of solubility is a challenging excersice. A number of experimental variables may affect the solubility results inducing high degrees of scatter in data.5

Before designing any solubility experiment its essential to identify whether the requirements is to determine thermodynamic equilibrium solubility or a kinetic dissolution rate. If the goal is to prepare a liquid formulation the equilibrium solubility information is meaningful. Conventional method for measuring equilibrium solubility are based on the phase solubility technique proposed by Higuchi & Connors6-8


  1. Grant DJW, Higuchi T. Solubility Behavior of Organic Compounds. New York: John Wiley and Sons, 1990.

  1. Mader WJ, Vold RD, Vold MJ. Physical Methods of Organic Chemistry. 3rd ed. Vol. 1. Part I. Weissberger A, ed. New York, New York: Interscience Publishers, 1959:655-88.

  1. Yalkowsky SH, Banerjee S. Aqueous Solubility Methods of Estimation for Organic Compounds. New York: Marcel Dekker, 1992:149-54.

  1. Qiu, Chen, Zhang. Developing Solid Oral dosage forms. Pharmaceutical Theory & Practice. MA: Academic Press, Elsevier, 2009

  1. Deshwal, B.R. Lee K.C. & Singh K.C. (2006) Journal od Molecular Liquids 123, 38-42

  1. Fligge T.A. Shuler A. (2006) Journal of pharmaceutical and biomedical analysis 42, 449-454

  1. Ledwidge M.T. Corrigan O.I. (1998) Int Journal of Pharmaceutics 174, 187-200

  1. Highuchi T. Lach J. (1954) Journal of American Pharmaceutical Association 43, 349.

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