OBJECTIVES: What are the types of incompatibilities

The business of the retail pharmacist of the present day consisted of three branches: that of manufacturing galenical preparations, that of selling patent medicines, and that of dispensing physicians prescriptions.

There is one department which is still the Pharmacists own. A department which distinguishes him as a professional man and elevates him above the ordinary merchant.

And that is

The Prescription Department

Incompatibility
According to definition of various dictionaries, means incapable of existing together in agreement or harmony.

 We call a prescription incompatible when its

ingredients are of such a nature that, if brought together, one or more of the ff. changes would take place: 1. Mutual decomposition of ingredients 2. Precipitation (chemical or physical) 3. Explosion 4. Liquiefaction 5. Deterioration of one /more ingredients

Two classses of incompatibilities:

1. Intentional

where the prescriber wants that the prescription, be dispensed as it is. 1. Unintentional where the prescriber has inadvertently combined such drugs as to give unexpected results (e.g. precipitation of drug) which is not what the prescriber wanted.

In this type, two or more drugs react to give new compounds which may be toxic or inactive. Remedy lies in replacing one or more ingredients of the same medical usefulness, yet inert.

All chemical incompatibilities must be corrected before the prescriptions are dispensed unless the prescriber wants that the incompatible combination be dispensed. Chemical interactions between the drugs of prescription lead to chemical incompatibility. These include:

Effervescence Precipitation Colour changes Formation of toxic substances

At times, the incompatibility is immediately apparent and at other times, the changes occur at a slower rate and the incompatibility is not detectable immediately.

Chemical incompatibility: It occurs as a result of interaction between ingredients of prescription. It is of 2 types: 1. Usual chemical incompatibility: Occurs immediately upon compounding thats why it is called as immediate incompatibility. It occurs either due to precipitation or color change. Delayed chemical incompatibility: Mixture reactant such a slow rate that no appropriate change occurs thats why it is called as delayed incompatibility. These may occur without immediate physical evidence of change. It takes sometime to occur. This may or may not result in loss of therapeutic activity.

2.

Precipitation: When 2 or more pharmaceuticals are combined, a chemical change may take place with a formation of an insoluble substance, which precipitates from solution. Example: Soluble in organic salts except for the alkali metal react with basic hydroxide to yield water insoluble compounds. Soluble salts of phenol, carboxylic acid and barbituric acid in an alkaline solution will yield the free acid in presence of relatively strong acid. Precipitation depends upon the solubility of these acids in a particular solvent system. Soluble salts of the amine drugs will release free base in presence of relatively strong base. Precipitation will depend upon the solubility of this base in solvent system

Effervescence: Carbonate in the presence of acids, stronger than carbonic acid will form carbon dioxide. Weak acids such as boric acid will not react with carbonate.

Oxidation reduction: Oxidation is defined as loss of electron and reduction as the gain of electron. Oxidation and reduction must occur together and it depends not only on the ability of the compound to donate an electron but also on the ability of the compound to accept the electron. Example: Phenothiazine tranquilizers are oxidized by ferric ion. Mercurrus salts are easily reduced to free mercury in the presence of moisture, iron, light or heat. Stannus salts, of which the fluoride is most important, are readily oxidized by air and most mild oxidizing agents to stannic form. Bismuth compounds are easily reduced to metallic bismuth by organic compound such as glycerin and natural gums. Silver slats are reduced to metallic silver by light and compounds such as reducing sugars.

Color change or formation of color: Various types of chemical changes may result in alteration in color; the color of medication is often the most important property for patient acceptance. Occasionally the same mixture may have a slight different color, when compounded a second time or by a different pharmacist. But the actual changing of the product color is due to the chemical reaction. Basically there are 2 things to consider: The change in color of pharmaceutical preparation caused by age, exposure to light and temperature variation. Rapid change in product color occurring at or immediately after mixing.

Most dyes or indicators in pharmacy are acidic or basic and generally form watersoluble ionized salts with anions or cations. The color of these materials is influenced by their ionization and thus a change in pH of the solution, that is sufficient to effect the ionization, which generally change the color. Phenolphthalein is a colorless acidic compound. On addition of an aqueous solution of base such as NaOH . a red ionized disodium salt is formed. Gentian violet is a basic purple compound. However on the addition of sufficient acid, the compound changes color through green to yellow.

Hydrolysis: The reaction of the compound with the water divided into 2 broad categories,
Ionic hydrolysis Molecular hydrolysis

Ionic hydrolysis: It involves the reaction of an ionized specie or either hydrogen ion or hydroxyl ion to form unionized insoluble product. These hydrogen and hydroxyl ions results in the change in the pH of the solution. Both organic and inorganic salts may undergo this type of hydrolysis. Incompatibilities resulting from this type of hydrolysis generally manifest themselves as precipitates of basic salts or hydroxides.

Examples: All zinc salts with the exception of sulfate and nitrate, hydrolyzed readily. All aluminum slats hydrolyzed yielding insoluble basic salts and hydroxides.

Molecular hydrolysis: It is a reaction of water with organic compounds such as amides, Easters and lactum. This type of hydrolysis proceeds at much slower rate and is often a function of hydrogen or hydroxylion. Because of the relatively slow rate of reaction, molecular hydrolysis is not of major concern to the dispensing pharmacist. In most cases, the prescription will have been consumed before significant hydrolysis occurs, however this hydrolysis often reduces the therapeutic efficacy of drug and is not always detectable by a physical change.The pharmacist should aware of compounds that may exhibit this type of incompatibility. Examples: Aspirin is readily hydrolyzed to acetic and salicylic acid in presence of moisture. Some antibiotics tend to hydrolyze to inactive form in aqueous solution. The rate usually depends upon hydrogen and hydroxyl ion concentration.

Methods of correction/prevention of chemical incompatibilities

Replacement of reacting ingredient: One of the most common types of incompatibility is the formation of precipitate as aresult of exchange of ions. If the solution is desired, it is frequently possible to replace one of the reacting substances with another of equal therapeutic value that will not cause precipitate. Example of prescription: Sodium citrate 1 Calcium bromide 1 Simple isopril elixir q.sto make 120ml MFT solution. Although both sodium citrate and calcium bromide are soluble in aqueous liquid. They react in solution to form insoluble calcium citrate, which is precipitated. This incompatibility can be prevented by using sodium bromide in place of calcium bromide.

Adding color inhibiting agent: Color changes are sometimes important from the therapeutic point of view and at the same time,their influence upon the trust of customer and patient. Uniformity in the appearance of prescription and preparation in therefore highly considered. The order in which ingredients are mixed, effects the color of finished preparation and it is a good policy for a compounder to indicate on a prescription, the method of compounding used for any preparation containing colored ingredients.Color change may sometimes be prevented or modified by the addition of inhibiting agent. Example of prescription: Liquid phenol/phenol Iron tincture Glycerin Aqua mentha preparata MFT solution.

2 4 5 Q.s to make 90ml

The phenol and iron chloride form an inky black color in solution and the product is very unsightly. By adding citric acid or sodium citrate as an inhibitor, this color formation is prevented and much more pleasant appearance of solution is prepared.

Oxidation-reduction: Incompatibility resulting from mixing of oxidants and reductants can be minimized by removal of one of the species.Light catalyzed air oxidation can be minimized by storage in tight container or by the addition of materials, which will be preferentially oxidized such as sodium Meta disulfide.

Hydrolysis: Ionic hydrolysis usually can be prevented or reversed by the addition of any of the species formed as a result of hydrolysis.Prevention of molecular hydrolysis is more involved and require knowledge of conditions that effects stability of drug involved. Whenever the rate of hydrolysis is sufficiently fast to cause significant degradation of drug beforeit could normally be expected to be consumed. Correction and prevention of incompatibility is essential.

Alphabetical summaries of some incompatibilities

Acids, unless very dilute and in small amount, should be

prescribed alone. They combine with bases to form salts, and are incompatible with oxides, alkalies, alkaline salts, hydrates and carbonates. They all precipitate albumin. Alkalies and Alkaline Carbonates should rarely be prescribed in solution with other drugs. They form salts with acids and precipitate many metallic and alkaloidal salts. Alkaloidal Salts should rarely be combined with other drugs in solutions. They are precipitated by alkalies, alkaline carbonates, earthly carbonates, preparations containing tannic acid, and by iodides in solution.

 Bromides in solution should not be combined with

alkaloids. They precipitate the salts of morphine, quinine, and strychnine from neutral solutions. Ferric and Ferrous Salts should generally be prescribed alone. They are incompatible with tannic acid and all drugs containing it; with alkaline carbonates, ammonia, and acacia. Resins, including oleoresins, and fluid extracts and tinc hires containing resins, should not be prescribed in watery solutions, though they may be ordered in emulsion by suspending them with the mucilage of acacia or tragacanth. They are all precipitated bywater. Silver Nitrate solutions and solutions of all silver salts must be ordered alone, and kept in dark bottles. If silver salts are prescribed for internal administration they must be alone or combined with some earth, and given in capsules.

SOURCES:
PRACTICAL PHARMACEUTICS by: Dr.P.V. Kasture
http://home.us.archive.org/stream/treatiseonprescr00

robiuoft/treatiseonprescr00robiuoft_djvu.txt

 Therapeutic Incompatibility in this type, problems

arise by combining drugs or doses prescribed. It is the responsibility of a physician. However it forms a part of the duty of the pharmacist to bring this problem to the notice of the prescriber