The solubility of drugs

5.1 Definitions 140

5.2 Factors influencing solubility 141

5.3 Measurement of solubility 155

5.4 The solubility parameter 156

5.5 Solubility in mixed solvents 157

5.6 Cyclodextrins as solubilising

5.8 Partitioning 164

5.9 Biological activity and partition coefficients: thermodynamic activity and Ferguson's principle 166

5.10 Using log P 168 Summary 175 References 176

agents 158

5.7 Solubility problems in formulation 160

There are many reasons why it is vital to understand the way in which drugs dissolve in solution and the factors that maintain solubility or cause drugs to come out of solution, that is, to precipitate. These include the facts that:

• Many drugs are formulated as solutions or are added in powder or solution form to the liquids, such as infusion fluids, in which they must remain in solution for a given period.

• In whatever way drugs are presented to the body, they must usually be in a molecularly dispersed form (that is in solution) before they can be absorbed across biological membranes*.

• The solution process will precede absorption unless the drug is administered as a solution, but even solutions may precipitate in the stomach contents or in blood, and the precipitated drug will then have to re-dissolve before being absorbed.

• Drugs of low aqueous solubility (e.g. Taxol) frequently present problems in relation to their formulation and bioavailability.

* In section 9.2.1 we discuss the special circumstances under which microparticulate materials can be taken up by specialised cells in the gut and, by way of the lymphatic circulation, reach the liver and blood and other organs. It may be that very insoluble colloidal drug suspensions are absorbed by this route also.

In this chapter we will consider the factors controlling the solubility of drugs in solution, in particular the nature of the drug molecule and the crystalline form in which it exists, its hydrophobicity, its shape, its surface area, its state of ionisation, the influence of pH of the medium and the importance of the pKa of the drug. The equation linking solubility to solution pH and drug pKa (equation 5.11) is possibly one of the most important in this book. Experimental methods of measurement of solubility are essential in drug development, as is the ability to predict the solubility of a drug from a knowledge of its chemical structure, recognising hydrophilic and hydrophobic groups and their influence on solubility. How additives such as salts, cosolvents, surfactants and other agents can affect the solubility of a drug should to an extent be predictable from the theory, bearing in mind the complexity of many formulations.

Pharmaceutical solutions might appear to be extremely simple systems, but it is in the solution state that degradation takes place most rapidly, and the solubilisation of poorly soluble compounds is often very difficult. It is ideal if a drug can be formulated as a simple stable aqueous solution when required for injection, but resort to additives such as water-miscible solvents and surfactants, hydrotropes and cyclodextrins to increase the water solubility of the drug complicates the formulation. Here we deal with simple solutions. Some of the special problems related to peptide and protein solubility are discussed in Chapter 11.

Aqueous solvents are the most common in pharmaceutical and, of course, in biological systems, so this chapter is concerned mainly with solutions of aqueous and mixed aqueous solvents, such as alcohol-water mixtures. The solution of drugs in nonaqueous media (such as oils) is also considered because of the many pharmaceutical applications of nonaqueous solutions and formulations such as oil-in-water emulsions, and because of the need to understand the process of the transport of drugs across biological and artificial membranes, which are effectively structured nonaqueous phases. A primary factor in passive membrane transport is the relative solubility of the drug in an aqueous medium and in the lipid cell membrane, the relative affinities being quantified in the partition coefficient of the compound, a topic discussed at the end of this chapter.

5.1 Definitions

A solution can be defined as a system in which molecules of a solute (such as a drug or protein) are dissolved in a solvent vehicle. When a solution contains a solute at the limit of its solubility at any given temperature and pressure, it is said to be saturated. If the solubility limit is exceeded, solid particles of solute may be present and the solution phase will be in equilibrium with the solid, although under certain circumstances supersaturated solutions may be prepared, where the drug exists in solution above its normal solubility limit.

The maximum equilibrium solubility of a drug in a given medium is of practical pharmaceutical interest because it dictates the rate of solution (dissolution) of the drug (the rate at which the drug dissolves from the solid state). The higher the solubility, the more rapid is the rate of solution when no chemical reaction is involved.

5.1.1 Expressions of solubility

The solubility of a solute in a solvent can be expressed quantitatively in several ways (see Chapter 3, section 3.1). Other less-specific forms of noting solubility include parts per parts of solvent (for example, parts per million, ppm). The British Pharmacopoeia and other chemical and pharmaceutical compendia frequently use this form and also the expressions 'insoluble', 'very highly soluble' and 'soluble'. These are imprecise and often not very helpful. For quantitative work specific concentration terms must be used.

Most substances have at least some degree of solubility in water and while they may appear to be 'insoluble' by a qualitative test, their solubility can be measured and quoted precisely. In aqueous media at pH 10, chlorpromazine base has a solubility of 8 x 10-6 mol dm -3, that is it is very slightly soluble, but it might be considered to be 'insoluble' if judged visually by the lack of disappearance of solid placed in a test-tube of water.

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