Solubility of Pharmaceutical Solids

Abstract The solubility of a drug is one of its most important physicochemical properties. The determination of drug solubility and ways to alter it, if necessary, are essential components of pharmaceutical development programs. The bioavailability of an orally administered drug depends primarily on its solubility in the gastrointestinal tract and its permeability across cell membranes. This forms the basis for the biopharmaceutical classification system (BCS). Drug molecules are required to be present in a dissolved form in order for them to be transported across biological membranes. Therefore, low aqueous solubility can either delay or limit drug absorption. In addition, a drug solution is preferred for conducting pharmacological, toxicological, and pharmacokinetic studies during the drug development stage. Thus, poor aqueous solubility not only limits a drug’s biological application, but also challenges its pharmaceutical development. As a result, investigation into approaches for solubility enhancement has been a regular element of pharmaceutical research for several decades. The equilibrium solubility of a solute will depend on its relative affinity toward solvent molecules and other solute molecules. Thus, the strength of molecular interactions such as ionic, van der Waals, dispersion and hydrogen bonding interactions affect solubility. Various theoretical approaches to estimate solubility i.e. ideal solution theory, non-ideal solutions, regular solution theory, aqueous solution theory and general solubility equation are discussed in this chapter. The equilibrium solubility is dependent on the properties and nature of interactions in solid state, as well as in solution state. Modifications in the solid state can be accomplished by the use of prodrugs, use of metastable crystal forms, or amorphous state of the drug, salt formation, or co-crystal formation. In solution state, the solubility can be influenced by altering solution pH (for ionizable drugs) or use of additives such as complexing agents, surfactants, or cosolvents. Although solubility experiments are routinely conducted and perceived to be simple, accurate measurement may be challenging. Various aspects related to the solute and solvent of interest, experimental conditions, and the analytical techniques employed, play important roles in the determination of actual solubility. This chapter also covers the various methods that have been conventionally employed for solubility determination. In addition, several factors that may affect the solubility and its measurement are also discussed.