Pharmacy Incompatibility: Chemical Incompatibility

Chemical Incompatibility – Whenever the ingredients in the prescription undergo chemical reaction whereby their original composition is altered, chemical incompatibility is said to take place.

Or simply it may be defined as that form disagreement in prescription which involve a chemical reaction. These chemical reactions are generally indicated by a change in the physical appearance, (usually precipitation) a change in color, an explosion or simply an effervescence.

Sometimes the chemical change improves the product, in this case it is not considered as an incompatibility. For example a prescription is not considered an incompatibility although potassium-mercuric iodide is formed, because it improves to the product. Such cases are rare, however, being neutralization of a base by an acid forming the corresponding salt and a few special reactions such as the saponification of an oil by an alkali.

In the modern concept, a chemical reaction is considered to take place between two soluble bodies when one or more products of the reaction is insoluble or gaseous. Thus, if sodium chloride and potassium bromide are mixed in solution although there is formation of Potassium chloride and sodium bromide, no chemical reaction is considered to take place because both substances formed are soluble. On the other hand if sodium chloride and silver nitrate solutions are mixed there is the precipitation of silver chloride, hence, a chemical reaction is said to take place.

It is important, therefore, to have a general consideration of the solubilities of the reaction products. While silver bromide requires 1-2 million times its weight of water to dissolve, Potassium iodide only requires 7/10 its own weight of water. So substances like silver bromide are generally termed as insoluble, although strictly speaking all substances dissolve (some in very minute amounts).

To memorize individual solubilities of substances is impossible so that the table below is a generalized classification and limited only to those substances commonly used in compounding of prescriptions. Substances like copper and zinc salts are omitted because no general rule can be adopted in their case.

Considered Soluble:

1. All acetates
2. All nitrates
3. Sulfates except Ba, Sr, Pb and Ag.
4. All sodium salts
5. Potassium salts except Bitartrates
6. Chlorides except silver and mercurous.

Considered Insoluble:

1. Carbonates except those of the alkalis.
2. Phosphates

Evidences of Chemical Incompatibilities:

1. Formation of Precipitate → Among the more important cases of precipitation; which are therefore considered incompatibilities are the following:

A – Formation of an insoluble salts. (The above tabulation can be used as a guide)

B – Formation of special insoluble organic salts such as tannates of iron (ink) when tannin bearing drugs are combined with iron salts; Meconate of lead, when opium preparations are combined with lead solutions; and the production of the insoluble blood-red iron salicylates, when iron preparations are combined with salicylates.

C – Precipitation of alkaloids by alkaloidal reagents like the precipitation of cinchona alkaloids when preparations of this drug are combined with potassium iodide and mercuric chloride.

D – Formation of insoluble bodies when synthetic organic chemicals are combined with certain reagents. An example of this is the formation of green crystals of iso-nitroso-antipyrine, when antipyrine is treated with spirit of nitrous ether.

2. Evolution of gas, like the mixing of an acid and a carbonate or bicarbonate (should be compounded in open containers to avoid explosion).
3. Color changes brought about by the chemical reaction or formation of a new substances.
4. Production of an explosion, like triturating or mixing a strong oxidizing agent with reducing substances or organic materials.

It should be stated here that all “Explosive Prescriptions” must be known in advance by the compounder, otherwise an explosion may occur, producing dangerous results. Explosion are produced by a sudden evolution of gases, and all substances liable to produce such gaseous evolution on trituration must be handled with the utmost caution.

The following sketchy summary will be very useful to the compounder:

a) All oxidizing agents, such as potassium chlorate, chromic acid, potassium permanganate, silver oxide, are liable to explode when combined with organic matter, and such oxidizable inorganic matter as sulfur or carbon.

Strong nitric acid and its preparations produces effervescence with preparations containing tannin, or with oil of turpentine, sometimes with explosive violence.

b) Hypophosphites are liable to explode when heated above 100^oC, or when combined with oxidizing substances such as nitrates, chromates or permanganates.

c) Iodine is liable to explode when treated with ammonia or with oil of turpentine.

5. Cementation of ingredients. In some cases all or part of the ingredients of a prescription may set into a mass cement-like hardness.
6. Separation of an immiscible liquid when certain organic chemicals are decomposed by certain reagents, such as the decomposition of chloral, by the action of an alkali into chloroform. (Some authors consider the formation of chloral alcoholate as a chemical incompatibility).
7. Development of heat or cold.
8. Other types of chemical changes, like polymerization, substitution and addition.
9. Hydrolytic changes (hydrolysis)
10. Invisible changes (This is most likely overlooked).
11. Development of poisonous substances (may also be considered under therapeutic incompatibilities).

REMEDIES

Chemical incompatibilities may be remedied by any of the following:

• Prevent the precipitation by the addition of glycerin, syrup or honey to the incompatible ingredients before mixing, as in the following prescription.

Rx

Codeine Sulfate …......................................0.13g

Syrupi Eriodicty, Aromatici, qs …..............30 cc

M. ft. solutio

When prepared as it is, slight turbidity is developed, due partly to the separation of the resinous matter from the aromatic syrup, when the acid-reacting codeine salt is dissolved therein, and also due to the formation of codeine tannate. However, clear solution will be obtained when the codeine salt is triturated with a vehicle made up of an equal volume of glycerin and aromatic syrup of eriodictyon.

• If the precipitate is harmless, suspend and provide the container with a “shake well” label, as in the

Rx

Tr. Myrrh .......................................ii foz

Morph. Acetatis ….........................ii gr

Acidi Tannici .................................ss oz

Syr. Zingiberis ...............................iss foz

M. ft. sol.

Sig. Tsp. t.i.d.

The resinous matter of the tincture will be precipitated by the syrup (physical). By adding the tincture to the syrup in small portions and shaking well after each addition, the resin comes down in a form in which it can be more readily suspended in the liquid. Tannic acid combines with morphine to forma compound insoluble in water. On standing the precipitate may be converted into masses, which will render an even dosage difficult.

However, by adding about 10cc of honey directly to the tincture in place of much syrup, it will help to keep the precipitation matter finely divided and suspended.

• Dilute before mixing.

Rx

Iodine …..............................2.5 g

Alcohol …............................25 ml

Oil of Turpentine, qs …........50ml

M. ft. sol.

Sig. Apply as directed.

If iodine is added directly to the oil of turpentine a violent reaction takes place, much heat is evolved that the mixture may even catch fire. However, if the iodine is first diluted by dissolving in alcohol and then added gradually to the oil of turpentine, the reaction will be very much moderated although some heat may be developed. The mixing is preferably done in an open container.

• When chemical incompatibility is dangerous or undesirable the physician should be notified and make arrangement for a practical solution, like omission or substitution:

a) omission:

Rx

Quinine Sulfate …..........................2 g

Dilute Sulfuric Acid …...................2ml

Sodium acetate ...............................4g

Syrup …..........................................30ml

Dist. Water, qs ................................120ml

M.S.A

Sig. Tsp. t.i.d.

If the quinine sulfate is dissolved by the use of sulfuric acid and mixed with the solution of sodium acetate, a bulky white precipitate of quinine acetate will be formed. The sodium acetate is also partly converted to sodium sulfate and acetic acid.

However, if the acid is omitted a fine suspension of quinine sulfate is produced, this should be provided with a “shake well” label.

b) Substitutes:

Rx

Zinci sulfatis …...............................ss gr

Sodii Boratis /

                       aa ..........................iv gr

Acidi Borici /

Aquae Rosae, qs ............................i foz

M. ft. collyrium

This precription when first compounded is clear, but sooner or later, there may occur a precipitation of the slightly soluble basic zinc borate, which is objectionable for eye application. By replacing sodium borate with boric acid, precipitation will be avoided.

Note: In a survey conducted in the different drugstores in the United States, the following ten individual ingredients arranged in the order of their frequency, were found responsible for most of the incompatibilities in prescription.

1. Distilled water
2. Sodium bicarbonate
3. Acetylsalicylic acid
4. Liquid petrolatum
5. Sodium phenobarbital
6. Compound pepsin elixir
7. Sodium salicylate
8. Aminopyrine
9. Syrup of Wild Cherry
10. Glycerin

Therefore, greater care in compounding should be observed any of the above ingredients are present in a prescription.