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
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.
||Dielectric constant, δ, @ 20°C
| Sorbitol Solution USP (70% w/w)
| Syrup USP
| Propylene glycol
| n-Propyl alcohol
| Polyethylene glycol 400
| Castor oil
| Ethyl ether
| Olive oil
| Sesame oil
| Carbon tetrachloride
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.
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
|% v/v ETOH
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.
From this information it is possible to formulate a vehicle, substituting
other solvents, which is of the necessary polarity and is pharmaceutically
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.
Thus, the vehicle is 20% v/v ethanol, 15% v/v water, and 65% v/v glycerin.