The Problem of Physical Incompatibility of Ingredients in Dispensing Pharmacy

Physical incompatibility is mostly due to insolubility. However, liquefaction and physical complexation are not uncommon. Such incompatibilities are easier to predict, detect and correct by applying proper technique, mixing, selection of additives etc.

Physical incompatibilities are commonly manifested by non-uniform, unsightly or unpalatable products. Physical incompatibilities may be classified as follows:

A. Insolubility

Insolubility or immiscibility results in non-homogeneous product when two or more substances are combined. Separation of two phases when oil and water are shaken together (i.e. emulsion) is the classical example of such incompatibility but it is corrected by the use of an emulsifying agent whereby a uniform dispersion of one phase into the other is obtained. Gums are insoluble in alcohol and resins are insoluble in water. Insoluble substances like phenacetin, salol, precipitated sulphur etc. in mixtures require the use of a thickening agent. Use of another solvent or a cosolvent usually resolves the problem of insolubility.

In this preparation terpin hydrate is not soluble in syrup and hence half of the vehicle may be replaced by alcohol or isoalcoholic elixir. Alternate remedy would be to use any suspending agent (acacia, tragacanth or methocel) and dispense the product with a ‘shake well’ label.

B. Precipitation:

A drug in solution may be precipitated upon addition of a solvent in which it is insoluble. Thus resins are precipitated from alcoholic solution on addition of water. Mucilaginous and albuminous substances may be precipitated from aqueous solution on addition of alcohol.

Precipitation from a saturated solution is often referred to as salting out.

1. Camphor and volatile oils may get salted out of aromatic waters when salts of metals are dissolved in the liquid.

2. Addition of electrolytes to colloidal solutions often results into precipitation.

3. Addition of tragacanth is responsible for precipitation of boric acid from a saturated solution.

C. Separation of immiscible liquids:

A prescription containing ethyl nitrite spirit and substantial amount of potassium citrate will separate out and a layer of spirit will float. Example 5

Chloral hydrate 15.00 g

Sodium bromide 11.25 g

Elixir aromatic q.s. ad 60.00 ml

Soluble bromide is responsible for separating an immiscible layer consisting of chloral alcoholate, chloral and alcohol. In order to obtain a clear solution the alcoholic strength of the prescription should be above 50% or below 10%.

A simple remedy would therefore be to dilute it with water to bring alcohol concentration to below 10% and inform the physician.

D. Liquefaction of Solid:

Liquefaction of dry solid materials may result from eutexia, release of water of hydration or absorption of water. Many drugs containing a phenol, aldehyde, or ketone group possess this tendency.

Phenol, menthol, thymol and salol when mixed with one another, form eutectic mixtures. Liquefaction occurring at room temperature due to depression in melting point of a solid in contact with certain other components is known as eutexia. Eutectic forming ingredients may be dispensed separately or if a pasty mass has already resulted, the eutectic may be absorbed on sufficient inert diluent such as kaolin, talc, starch, magnesium carbonate, light magnesium carbonate, light magnesium oxide; and suitably dispensed.

E. Physical complexation:

Preparations containing carbowax and phenols, salicylic acid or tannic acid are known to show loss in elegance and acceptability due to physical complexation. Their complexation is attributed to hydrogen bonding between the hydroxyl groups of the active ingredient and the ether oxygen of the polyether chain. Complexation of benzoic acid, salicylic acid, sulphonamides and barbiturates with urea is also reported.

F. Miscellaneous:

Drugs insoluble in water are not uniformly distributed in the bulk of the preparation and these results in non-uniform dose delivery.

The problem is solved by (i) increasing the viscosity of the vehicle, and (ii) using suspending agents. In fact the suspending agents also act by enhancing the viscosity of the vehicle thus minimizing the settling of the solids. Suspending agents which are commonly used include acacia, tragacanth, methylcellulose derivatives; clays like bentonite; glycerin and syrups.