Pharmaceutics I Experiment 1a Factors affecting the solubility of drugs

and their application in the formulation of Solutions

whether a drug is administered orally, instilled into the eye, ear or nose, injected or applied
externally to the skin, the therapeutic effect will take place much more rapidly if the drug is in
solution. Whenever possible water is the solvent of choice in the formulation of
pharmaceutical dosage forms. This is particularly true for the preparation of products for oral
use since water is the physiological fluid of the body. In some instances, however, the solvent
action of water is inadequate and use of a co-solvent or solubilising agent might be necessary.

This unit of the practical work investigates factors which are important in solution formulation.
The following projects serve to illustrate some of the factors that affect solubility and how the
solubility of a drug can be increased.

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General Introduction
Definitions
A solution (or molecular dispersion) may be defined as a mixture of two or more components
that form a single homogenous phase. The component in which the dispersion occurs is termed
the solvent and the component(s) which are dispersed throughout the solvent are termed the
solute. In most cases the solvent is present in the greatest amount, but a well known
pharmaceutical exception is syrup, where the solute (sugar) is present in the greater amount.
Generally in a pharmaceutical solution the solvent is water and the solute can be either a solid
or a liquid.

Dissolution is the process where, when a solute is placed in contact with a solvent, molecules
or ions detach themselves from the surface of the solute and diffuse throughout the solvent, i.e.
the solute passes into solution. Some of the material returns to the surface of the solid and thus
passes out of solution. The process continues until an equilibrium exists between the solid and
the solvent. When a solvent, at a given temperature, has dissolved all the solute it can it is
said to be a saturated solution.

A saturated solution contains the maximum concentration of solute which can dissolve in the
solvent. This value is called the solubility of the solute. The solubility of a solute is dependant
on temperature, pressure, pH, and the presence of other components.

Theory of Solubility
The molecules in a solid drug are held together by inter-molecular forces such as, for example,
dipole-dipole, dipole-induced dipole, dipole-ion, ion-ion and hydrogen bonding interactions.
Molecules of solvent are also associated by similar types of intermolecular forces.

For a solute to dissolve in a liquid, (or when two liquids mix together), the bonds between
solvent-solvent molecules must be broken and replaced by solvent-solute bonds. If the process
is to be energetically possible, the solvent-solute bonds must be stronger than both
solvent-solvent, and solute-solute bonds.

There are certain broad guidelines which can be used to predict whether a solute will be soluble
in a given liquid i.e. whether the liquid will be a suitable solvent. The factors which influence
the solubility of a solute are:

- the polarity of the solvent

- the ability of the solute to form hydrogen bonds
- ratio of the polar to non-polar groups

Solvent polarity
Solvents may be polar, semi-polar, or non-polar. The dielectric constant is a rough measure of
a liquids polarity. In general the more polar the substance the higher the dielectric constant.
Generally ionic and other strongly polar solutes dissolve in polar solvents e.g. water. Solutes
of low polarity tend to be soluble in non-polar solvents e.g. oils. Polar solvents reduce the
interionic attractions in ionic crystals, and in general dissolve polar solutes e.g. electrolytes.

Conversely non-polar solvents do not greatly reduce interionic attractions in ionic crystals and
generally will not dissolve electrolytes. Secondly they are aprotic and therefore cannot break
covalent bonds. As a result ionic and polar solutes are only slightly soluble in non and
semi-polar solvents. On the other hand non-polar liquids can dissolve non-polar solutes through

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induced dipole interactions. The solute molecules are then kept in solution by weak Van der
Waals forces. Alcohols are regarded as semi-polar as they induce a degree of polarity in
non-polar molecules, their importance in pharmacy is that they can also increase the miscibility
of polar and non-polar liquids, e.g. alcohol will increase the solubility of the drug
phenobarbitone when added to water.

Therefore if the nature of the solute (i.e. if it possesses a low or high polarity) and the dielectric
constant of the solvent is known it may then be possible to predict the suitability of the liquid
as a solvent for the solute.

Ability of form hydrogen bonds

The second factor influencing solubility in water is the ability of the solute to form hydrogen
bonds. Solutes which can do this readily are usually water soluble e.g. alcohols, aldehydes,
ketones and amines. These compounds all form H-bonds and are all soluble in water.

Ratio of the polar to non-polar groups

The solubility of a substance also depends on the ratio of the polar to non-polar groups in the
molecule. For example ethyl alcohol (2 carbons) is completely miscible with water, however as
the chain length of the alcohol increase its solubility in water rapidly reduces e.g. straight chain
alcohols with more than 4 or 5 carbons cannot enter into the hydrogen bonded structure of
water and are therefore only slightly soluble.

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 Laboratory
Factors Affecting Drug Solubility

Part I. Miscibility of liquids

The miscibility of liquids can be considered as the mutual solubility of these liquids in each
other i.e. either one of the liquids can be the solvent or solute depending on the relative
proportions.

1. Before attempting any experiments in this section, predict from Table A which of the
liquids in Table B will be miscible. Record in Table B by entering M (miscible) or I
(immiscible) in the appropriate space in pencil.

Dielectric constant Solvent

78.5 Water

42.5 Glycerol

27 95% alcohol

21 Acetone

13 Propylene glycol

4.8 Chloroform

4.5 Castor oil

2.0 Light liquid paraffin

1.9 Octane

Table A

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 Water Glycerol 95% Propylene Chloroform Light liquid
(glycerine) Alcohol glycol paraffin
Dielectric
Constant (D)
Water M IM
IM M M IM
Glycerol M
IM IM IM IM IM
95% M
Alcohol M IM IM M IM
Propylene M
glycol M IM IM M IM
Chloroform M
IM IM M M M
Light liquid M
paraffin
IM IM IM IM M
Table B

2. Check your predictions by preparing binary mixtures comprising equal quantities (1ml) of
each liquid in a test tube. Enter your results in Table B (in ink)

Note: Use pipettes to measure your volumes.

If any of your predictions were wrong, please explain the reasons below:

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Part II. Solubility of drugs in common solvents

Solvents are said to be polar, semi-polar or non-polar, depending on their dielectric constant as
well as their ability to dissolve polar semi-polar or non-polar solutes.

In order to predict the solubility of a solute in a solvent, one can generally say that LIKE
DISSOLVES LIKE.

Experimental Procedure
1. Look up and record the structural formula and pharmaceutical use of each of the substances
you are testing and enter in Table C.
2. Predict the solubility of each drug to be tested and enter your prediction in Table C.
3. You are provided with the five drug solutes and the five commonly used pharmaceutical
solvents which are listed in Table C.
4. To a boiling tube add 100mg (or 2 drops) of solute and 1ml of the first solvent in Table C.
Mix the contents thoroughly with a vortex mixer for one minute.
5. If all the solute has dissolved, record in the observed column of Table C as very soluble
(VS).
6. If all of the solute has not dissolved, add a further 3ml of the same solvent and mix as
before. If the solute has now all dissolved record as soluble (S).
7. If the solute has still not dissolved record as insoluble (IS).

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Questions

A. Explain why methylsalicylate is soluble in propylene glycol but only slightly soluble in
water.

B. Did you observe any discrepancies between the predicted and observed values in Table C.
Explain these discrepancies.

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