The Problem of Chemical Incompatibility of Ingredients in Dispensing Pharmacy

This term signifies the chemical changes which occur due to the interaction of the prescribed substances leading to the formation of a harmful or dangerous product.

Chemical incompatibilities often occur due to oxidation-reduction, hydrolysis or combination reactions. A chemical incompatibility, which is visualized rapidly by effervescence, precipitation or colour change, is called immediate incompatibility.

An incompatibility without immediate and visible physical change is known as delayed incompatibility and may or may not result in loss of therapeutic activity.

Unintentional incompatibility may be tolerated i.e. interaction is minimized but composition of the prescription is not altered; or adjusted i.e. interaction is prevented by addition or substitution of constituents without affecting the medicinal action of the preparation. It is recommended that the pharmacist must consult or notify the prescriber about the suggested modification in the prescription while overcoming the incompatibility.

However, this should be done in such a manner as not to raise any doubt in the mind of the patient.

Chemical incompatibilities may be classified as follows:

A. Oxidation-reduction:

Oxidation refers to the loss of electrons and reduction to the gain of electrons. Prescription mixtures are usually oxidized on exposure to air, higher storage temperatures, light, over dilution, incorrect pH adjustment or in presence of catalysis.

Use of antioxidants such as ascorbic acid, sodium sulphite or sodium metabisulphite is often helpful.

Trace metal ion catalysis may be counteracted by complexing agents such as disodium edetate and sodium calcium edetate. Auto-oxidation in fats and oils, phenolic substances, aldehydes and vitamins is controlled by agents such as propyl gallate, thymol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and hydroquinone etc. Silver, mercury and gold salts may be reduced by light to the metallic form although such reactions are rare in prescriptions.

B. Acid-base reactions:

Such reactions result into precipitation, gas formation, colour development or colour change.

Change in or Development of Colour:

Most of the dyes employed in pharmaceutical practice and their colour are influenced by their ionization depending on pH of the solution. Laxative phenolphthalein is colourless in acid solution but red in alkaline mixtures.

Gentian violet is a basic purple compound but on addition of acid, the compound changes the colour through green to yellow. Such incompatibilities are corrected by the addition of a buffer or change of the vehicle to prevent formation of free acid or base from the salt.

C. Hydrolysis:

Many substances hydrolyse in water and their reaction may be facilitated by heat catalysts, hydrogen ions and hydroxyl ions. Esters, amides and metals like Zn and Fe etc., are common examples. Soluble salts of barbituric acid derivatives and sulphonamides hydrolyze in water and yield insoluble free acids. Phenyl salicylate hydrolyses in basic media to salicylic acid and phenol.

Addition of any of the species formed as a result of hydrolysis is a common method employed to prevent or reverse the ionic hydrolysis. Examples of drug substances which may undergo hydrolytic decomposition include procaine, sulphonamides, chlorothiazide, barbituric acid derivatives, aspirin, some alkaloids, and penicillin.

Similarly gelatin, sucrose, sodium acetate, flavouring oils and chlorobutanol; some of the common ingredients in prescriptions; are also liable to decomposition by hydrolysis.

D. Explosive combinations:

Oxidizing agents are chemically reactive with reducing agents and some of these combinations may be potentially explosive.

E. Racemization:

It is the conversion of an optically active form of a drug substance to an optically inactive form without a change in chemical constitution but is usually associated with a reduction in pharmacological activity.

Examples of substances undergoing racemization are adrenaline, ephedrine, norephedrine etc. In alkaline solution but not in acid solutions, 1-hyoscyamine may undergo racemization to form atropine.

F. Other changes:

Other types of chemical incompatibility may occur as a result of cementation (due to formation of hydrates e.g., plaster of Paris, polymerization, or conversion to new crystal habits), development of heat or lowering in temperature, polymerization, double decomposition, substitution, addition etc.