The Pharmaceutics and Compounding Laboratory
Factors Influencing
the Solubility of Drugs

Solute and Solvent Structure/Polarity

Solute molecules are held together by certain intermolecular forces (dipole-dipole, induced dipole-induced dipole, ion-ion, etc.), as are molecules of solvent. In order for dissolution to occur, these cohesive forces of like molecules must be broken and adhesive forces between solute and solvent must be formed.

The solubility of a drug in a given solvent is largely a function of the polarity of the solvent. Solvents may be considered polar, semi-polar or non-polar. Polar solvents will dissolve ionic and other polar solutes (i.e. those with an asymmetric charge distribution [like dissolves like]), whereas, non-polar solvents will dissolve non-polar molecules. Semi-polar solvents (eg. alcohols and ketones) may induce a certain degree of polarity in non-polar molecules and may thus act to improve the miscibility of polar and non-polar liquids. The relationship between polarity and solubility may be used in practice to alter the solubility of a drug in a pharmaceutical solution.

One approach is to alter the polarity of the solute by shifting it between its molecular (undissociated) and ionic (dissociated) states. A shift toward the ionic form improves solubility of the solute in water and other polar solvents. A shift toward the molecular species improves solute solubility in non-polar solvents. Such shifts may be produced by altering the pH of the solution (or using the salt form of the compound).

Another approach is to mix solvents of different polarities to form a solvent system of optimum polarity to dissolve the solute. Such solvents must, obviously, be miscible. This method is referred to as solvent blending or cosolvency and uses the dielectric constant as a guide to developing the cosolvent system. Since many solvents may be toxic when ingested, most solvent blends are limited to mixtures containing water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 or sorbitol solution. The list is somewhat expanded for solutions for external application.

The dielectric constant (δ) of a compound is an index of its polarity. A series of solvents of increasing polarity will show a similar increase in dielectric constant.

Compound Dielectric constant, δ, @ 20°C
N-methylformamide 190
Water 80
Sorbitol Solution USP (70% w/w) 62
Syrup USP 56
Glycerol (glycerin) 46
Methanol 33
Propylene glycol 32.1
Ethanol 25
n-Propyl alcohol 22
Acetone 21
Polyethylene glycol 400 12.4
Chloroform 5
Castor oil 4.6
Ethyl ether 4.3
Sucrose 3.3
Olive oil 3.1
Sesame oil 3.1
Benzene 2.2
Carbon tetrachloride 2.2
Octane 1.9

Solvents may be classified according to their dielectric constants as polar (δ > 50), semi-polar (δ = 20 - 50), or non-polar (δ = 1 - 20).

The value of the dielectric constant for a mixture is obtained by multiplying the volume fraction of each solvent times its dielectric constant and summing.

A + B + ... = fAδA + fBδB + ...

There are many pharmaceutical substances which are non-polar or which are weak acids and bases whose ionized salt forms are unstable in solution. In order to dispense solutions of these substances, we must derive a solvent of appropriate polarity (or non-polarity).

Practically speaking, this is a fairly simple problem to solve. Solutions are prepared containing varying concentrations of ethanol or acetone in water, ranging from 0 to 100%. The required concentration of drug is added to each solution and the solutions are refrigerated overnight, then viewed for precipitation.

% v/v ETOH 0 10 20 30 40 50 60 70 80 90 100
Precipitation + + + + + + - - - - -

In our example, we see that at least 60% v/v ethanol is required to solubilize our drug. This leaves us with a problem since, from a flavoring standpoint, 60% ethanol is not considered pharmaceutically elegant. (Why?) We can now take this information and determine the dielectric constant of the solvent system which provides drug solubility.

fwaterδwater = 80 × 0.4 = 32 - fETOHδETOH = 25 × 0.6 = 15

From this information it is possible to formulate a vehicle, substituting other solvents, which is of the necessary polarity and is pharmaceutically elegant.

These calculated values of δ are only approximate. Interactions between multiple solutes and solvents may increase or decrease solubility. Nonetheless, the use of the dielectric constant in formulating solvent systems gives us a simple and scientific approach to estimating our needs. It is, therefore, a useful tool.

e.g. Formulate a vehicle containing water, ethanol, and glycerin with a δ = 47. Limit ethanol to 20% by volume.

    (δETOH = 25, δwater = 80, δglycerin = 46) (0.2)(25) + (X)(80) + (0.8-X)(46) = 47 - 5 + 80X + 36.8 - 46X = 47 - 34X = 5.2 - X = 0.15 - 0.8-X = 0.65

    Thus, the vehicle is 20% v/v ethanol, 15% v/v water, and 65% v/v glycerin.