INCOMPATIBILITIES

INCOMPATIBILITIES IN PRESCRIPTIONS.COLLEGE of PHARMACYCDU

INCOMPATIBILITIES

It is the result of prescribing or mixing two or more substances which are antagonist in nature and an undesirable product is formed which may affect the safety, purpose or appearance of the preparation.

Incompatibility may be : -Pharmaceutical -Therapeutic

PHARMACEUTICAL INCOMPATIBILITIES- Physical or- Chemical incompatibilities. - Are usually unintentional- Occur in vitro between drugs and other

components during preparation, storage or administration.

PHYSICAL INCOMPATIBILITY

A visible physical change takes place An unacceptable, non-uniform,

unsighty, unpalatable product product is formed.

Difficult to measure an accurate dose. Result of insolubility and

immiscibility, precipitation, liquefaction, Adsorption and complexation of solid materials.

Can be corrected by applying pharmaceutical skill

CORRECTION(PHYSICAL INCOMPATIBILITIES ) By one or more methods: Order of mixing alteration of solvents change in the form of ingredients alteration of volumeEmulsification and addition of

suspending agent, addition, substitution or omission of

therapeutically inactive substances.

1. INSOLUBILITY AND IMMISCIBILITYIt is the result of the mixture of two or more

immiscible liquid or an immiscible solid with a liquid.

-Acceptable liquid product can be obtained by emulsification or solubilization

-SALTING OUT, DEHYDRATION, CHANGE IN SYSTEM, TEMPERATURE CHANGE

(a) RxOlive oil 30mlWater up to 120mlmake an emulsion use a suitable emulsifying agent

b. Liquid preparation with Indiffusible solids ( Sulphamethoxasole, phenacetin, Zinc oxide, calamine etc.) + a suspending agent = a uniform distribution of the solids in the liquid phase for sufficiently long time so as to facilitate accurate measurement of dose.

Rx,Sulphamethoxazole 4.0g Trimethoprim 0.8gNa- CMC 0.5g Purified water qs to100ml

SULPHAMETHOXAZOLE &TRIMETHOPRIM ARE INDIFFUSIBLE IN WATER. TO MAKE THEM DIFFUSIBLE A SUSPENDING AGENT IS USEDc. Insoluble Powders (Sulfur, certainCorticosteroids and Antibiotic) + Water =Non-wetted, non – distributed liquid powderProduct.

Insoluble non-wetted drug Powders + Water + wetting Agent (Saponins for sulfur drug containing lotions and Polysorbate for corticosteroids and Antibiotic = uniformly dispersed Powder product in water.

2. PRECIPITATION a. A solubilised substance may precipitate

from it solution if a non solvent for the substance is added to the solution.

i. Alcohlic solution of Resins + water = precipitated Resins

ii. Aqueous dispersion of Hydrophillic colloids (polysaccharide mucilage + high conc. of Alcohol or salts = Precipitated colloids.

BUT SIGNIFICANT AMOUNT ARE TOLERATED IF WELL DILUTED AND ADDED IN SMALL AMOUNT WITH VIGOROUS STIRRING

b. High concentration of electrolytes cause Cracking of soap emulsion by salting out the emulsifying agents.

c.Vehicles (one or more organic liquids) use to dissolve medicaments of low solubility, water soluble adjuncts particularly inorganic salts may be precipitated in such vehicles.

3. LIQUEFACTION

Certain low melting point solids sometimes liquefy when mixed together due to the formation of eutectic mixture or liberation of water .

For example, if any two of the following medicaments are combined together, they form a eutectic mixture: Menthol, Thymol, Camphor, Phenol, Salol, Naphthol and chloral hydrate. Also Sodium salicylate or asprin with Phenazone

In order to overcome such incompatibility, the eutectic forming ingredient may either be dispensed separately or these may be mixed separately with enough quantity of adsorbent powder like magnesium carbonate or Kaolin to form free flowing product.

Alternately, if liquefaction has already occurred, the liquid may be adsorbed on a surface of sufficient quantity of powder , filled into capsule and dispensed

Example: Menthol 2.0g Camphor 2.0g Ammonium carbonate 20.0g Make a powder. In this case, if the ingredients are mixed

together, they shall liquefy due to formation of a eutectic mixture.

Hence, to dispense them in the form of a powder, it is necessary to mix them separately with sufficient quantity of a suitable adsorbent like magnesium carbonate. The three mixture then mix together to obtain a powder.

D. ADSORPTION AND COMPLEXATION

Certain substances including drugs and excipients may interact to form physical complex which may alter the appearance or activity of themedicament.

For example, mixtures containing clays such as Kaolin, Attapulgite or suspended antacids may pose incompatibility problems due to adsorption

Adsorption of Cyanocobalamin by Talc, a tablet lubricant may decrease the absorption from GIT.

Similarly Adsorption of antimicrobial preservatives such as parabens on to the drugs or excipients may lead to loss of their antimicrobial

activity.

CHEMICAL INCOMPATIBILITIES

Chemical Incompatibilities is usually a result of chemical interaction taking place among the ingredients of a prescription.

Such interactions may take place immediately upon compounding when these are termed as immediate in compatibilities and are evident as effervescence, precipitation or colour change.

More often the interaction are not evident immediately on compounding but take place over a period of time. Such interaction are termed delayed incompatibilities.

PROVIDED THE PRODUCT IS HARMLESS THE INTERACTION FALL INTO:a. Tolerated-: the reaction is minimised by applying some suitable order of mixing or mixing the solution in dilute form but no alteration is made in the active ingredients of the preparation.b. Adjusted-: the reaction is prevented by addition or substitution of one of the reacting substances with another of equal therapeutic value but does not affect the medicinal of the preparation (substitution of caffeine citrate wih caffeine in sodiun salicylate and caffeine citrate mixture)

PRECIPITATE YIELDING COMBINATION

Generally reaction between strong solutions proceed at a faster rate and the precipitates formed are thick and do not diffuse readily.

Reaction between the dilute solutions proceed at a slow rate and the precipitates formed are light and diffuse readily in the solution.

Hence the reacting substances should be

diluted as much as possible before mixing. The preparation should contain a thickening

agent if the precipitate is non-diffusible.

METHOD A This is suitable for diffusible

precipitates Divide all or most of the vehicle into

two portions Dissolve the reactants in separate

portions Mix the two portions by slowly adding

one to the other with stirring rapidly.(Sometimes a small volume must be

reserved for dissolving other ingredients, rinsing measures, and adjusting to volume.)

METHOD B It is used for bulky indiffusible precipitates. Divide the vehicle into two equal portions as in A Dissolve one reacting substance in one portion Place the other portion in a mortar and

Incorporate a suitable amount of Tragacanth powder (2gm/100ml of the finished product) with constant trituration until a smooth mucilage is produced, then add and dissolve the other reacting substances.

Mix the two portions by slowly adding one portion to the other with rapid stirring.

CHEMICALLY INCOMPATIBILITY IS GENERALLY CAUSED BY PH CHANGE, A DOUBLE DECOMPOSITION REACTION OR COMPLEX FORMATION.

pH effects Modern medicament are often salts of weak acids and bases. These salts are usually soluble in water while most of the unionized

acids and bases are practically insoluble. Consequently if a salt of weakly basic drug is made alkaline , the free base may be precipitated, while precipitation of free acid may occur if a solution of a weakly acidic drug is acidified.Whether precipitation occur or not

depends on a) The solubility of the unionized acid or base. b) The pH of the solution. c) The dissociation exponent (pKa) of the acid or base

SOLUBILITY OF THE UNIONIZED ACID OR BASE

1. Alkaloids Most alkaloidal salts are soluble in water but alkaloidal bases practically insoluble in water and are freely soluble in organic solvents.When an alkaline substance like aromatic spirit of ammonia, solution of ammonia, ammonium bicarbonate, Sodium bicarbonate, Borax, etc., is added to an alkaloidal salt solution the free alkaloid may be precipitated. However they are not always precipitated, because all alkaloids are slightly soluble in water and other added substances, for example.

a) Strychnine Strychnine is a constituent of Nux Vomica

Tincture which is used in some official mixtures as a bitter to stimulate the appetite.

The amount of strychnine present is 0.125 gm per 100ml of tincture nux vomica and the solubility of strychnine is about 1 in 7000, i. e., 100 ml of water will dissolve

1 x 100 / 7000 = 0.143 gm of Strychnine Hence the amount of strychnine in 10 ml of

tincture will dissolve easily in 100 ml of water and therefore, 10 % of the tincture in water will not precipitate in alkaline conditions.

Further , tinctures contain certain amount of alcohol due to which the precipitation is further prevented.

Moreover the solubility of strychnine is much more in alcohol (i. e. 1 in 150) than in water. Therefore it follows that in mixtures sufficient amount of alcohol strychnine will not be precipitated even when more than 10 ml of tincture per 100 ml is present in the prescription.

GENERALLY CHEMICAL INCOMPATIBILITIES RESULTS FROM:1. Acid- Base reactions Acid base reactions often result into

precipitation, gas formation, breaking of structure of disperse systems or colour change.

a. Precipitation Most medicaments in use are often salts of weak

acids or bases. These salts have a very good water solubility

whereas their corresponding unionised acids or bases are practically insoluble in water.

If a solution of a salt of a weakly acidic drug is acidified,, the free acid may be precipitated.

Similarly, precipitation of free base may occur if a solution of a salt of weakly basic drug is made alkaline.

EXAMPLE 1

Sodium salicylate 4gLemon syrup 20mlPurified water to 100mlmake a mixtureSince Lemon syrup contains citric

acid, it will acidify the solution and cause precipitation of the free acid (salicylic acid).

In order to overcome this incompatibility, it is necessary to use other sweetening and flavouring agent instead of lemon syrup.

EXAMPLE II

Strychnine hydrochloride solution 5ml Aromatic spirit of ammonia 3ml purified water to 100 ml Make a mixture Strychnine HCl used in the mixture is an alkaloidal salt whereas aromatic spirit of ammonia is an alkaline substance. On reaction between the two, insoluble strychnine is precipitated. since the precipitate formed is diffusible, the incompatibility may be taken care by suitable formulation. In this case, strychnine HCl solution should be dissolved in half the required quantity of water while aromatic spirit of ammonia should dissolved in the remaining portion of water. The two portion should be mixed slowly.

B. GAS FORMATION

Gas may be evolved due to chemical reaction between the ingredients of a formulation.

Example: carbonates or bicarbonates with an acid or acidic drug resulting in the evolution of carbon dioxide

EXAMPLE 1:Reaction of sodium bicarbonate,

borax and glycerolRxSodium bicarbonate 1.5gBorax 1.5gPhenol 0.75gGlycerin 25 mlWater to 100mlPrepare a spray

In this case , borax decomposes in presence of glycerin to form sodium metaborate and boric acid

Na2B4O7 + 3H2O = Na2B2O4 + 2H3BO3Borax Sodium metaborate Boric acid

Boric acid thus formed further reacts with glycerin to form Glyceryl boric acid

2C3H5(OH)3 + 3H3BO3 ---- (C3H3)2(HBO3) + 6H2O

Glycerin Boric acid Glyceryl boric acid

For compounding of such preparation, the ingredients should be allowed to react in an open vessel and only when the reaction is complete, should the preparation be transferred to the final container, otherwise there may be a chances of explosion. The reaction may be hastened by the use of hot water

EXAMPLE II

Reaction of alkali bicarbonates with soluble calcium and magnesium salts,

When alkali bicarbonate are combined with soluble calcium and magnesium salts, double decomposition reaction occurs resulting in the formation of corresponding insoluble carbonate and carbon dioxide

2NaHCO3 + CaSO4 ------Ca(HCO3)2 + Na2SO4

4Ca(HCO3)3 --- 3CaCO3 + Ca(OH)2 +5CO2 +3H2O

Since the reaction proceeds slowly at room temperature, it should be accelerated by using a hot vehicle and the resulting mixture should not be pocked until reaction is complete.

3. BREAKING OF STRUCTURE OF DISPERSE SYSTEM Gelling agent such as carbomers, sodium

carboxymethyl cellulose etc. very rapidly lose viscosity by change in PH outside an optimum range.

Carbomer dispersion liquify by decreasing their PH below 5 or increasing it above 10.

Similarly, below a PH 3, alginic acid is precipitated from dispersion of sodium alginate and carboxy methyl cellulose is precipitated from its sodium derivatives.

Emulsion prepared using soap as emulsifying agent are liable to break in presence of mineral acids which destroy the emulsifying activity of soap by precipitating the acids

D. COLOUR CHANGE

d. Colour change The colour of most of the dyes used in

formulations is influenced by their ionization which in turn depends on the PH of the solution,

Thus crystal violet which is also used as antiseptic is a purple coloured compound but changes colour through green to yellow on acidification. similarly phenolphthelin (used as laxative) is colourless in acidic solution but becomes pink in alkaline media.

Colour change due to change in PH can be prevented by properly buffering the vehicle or by preventing reaction that cause formation of free acid or base in the medium.

2.OXIDATION - REDUCTION REACTION

Certain prescription mixtures may oxidise on exposure to air, heat, light or due to change in PH or reaction with trace metal ions. Use of antioxidants like ascorbic acid, Sodium metabisulphite etc, is often helpful in each cases.

Oxidation due to trace metal ions can be prevented by the use of chelating agents like Disodium EDTA.

Example IRX Potassium Chlorate 4g Ferric iodide syrup 10 ml Purified water to 60 mlMake a mixture In this case potassium chlorate react with

ferric iodide. Initially the mixture is quite clear but on standing, crystals of iodine is deposited.

It is therefore essential to dispense the two compounds separately with instructions to mix the two before administration.

EXAMPLE II

RX,Sodium salicylate 4gSodium biocarbonate 4gPeppermint water to 60mLmake a mixtureSodium salicylate gets oxidized in

presence of sodium biocarbonate and the mixture darkens on storage.

This alkaline catalyzed oxidation may however be prevented by the use of a suitable antioxidants like 0.1% sodium metabisulphate.

COMPLEXATION

Many macromolecular adjuncts used in formulation form complexes in which medicaments and preservatives are bound to the macromolecules or trapped within micelles. This behavior is most common with non-ionic macromolecules.

Because these complex are too large to penetrate cell membranes, the activity of the medicament or preservatives may be greatly reduced.

A number of medicaments and excipients like suspending agent (polysaccharides), emulgents (macrogel esters and ethers) and solubilisers (polysorbates) exhibit this phenomenon.

COMPLEXATION Complexation may sometimes be useful specially when it is reversible. In such case a large amount of drug is available in the unbound form and when this drug is utilised, it is replaced from the complex. Thus the complex provides a reservoir of drug from which a safe but sufficient concentration is available to the tissue over a prolonged period. A 10 to 15 % aqueous solution of Povidone has been found suitable for this purpose. Complex formation may also reduce the irritancy and improve the stability of a drug, as in Iodophores, which are complexes of Iodine in which the Halogen is bound to a water soluble polymer (Povidone) or solubilised in the micelles of surfactants .

4. IONIC REACTIONSThe therapeutic or pharmaceutical properties of many organic compounds are usually associated with a large cation or anion. Interaction of such ions of opposing types may yield compounds which may totally lack the useful properties of the interacting molecules.For instances, Cream prepared using cationic emulgent may crack if mixed with a cream prepared using an anionic emulgent. Similarly an anionic solubilizers may lower the antimicrobial activity of a cationic medicament or preservative.

4. IONIC REACTIONS Ionic incompatibilities may however be

prevented by carefully selecting the medicaments and adjuvants in a proposed formulation so as to exclude combination of anionic and cationic ingredients in a single formulation.

In case of emulsified system containing an ionic medicament or preservative, it may be advantageous to use a non-ionic emulsifier.

5. EXPLOSIVE COMBINATION

Oxidising agents are chemically incompatible with reducing agent and a combination of the two in a formulation may lead to an explosive reaction.

For example, if Potassium chlorate is prescribed with an oxidisable substance like sulfur, tannic acid, etc and the two are triturated or heated together , there is a fair chance of an explosive reaction taking place.

In such case, it is better to dispense the components separately or if it is necessary to mix them together, the mixing should be done very lightly.

THERAPEUTIC INCOMPATIBILITY Results from errors in writing and interpreting

prescription order and the pharmacist is in the position to detect and help avoid problems.

May be reduced or delayed as a result of chemical or physical reactions.

May be manifested:Improper doses (overdosage and underdosage)Antagonistic combinationsWring drugWrong dosage prescribedContraindicated drugsToxic products from physical/ chemical incomp

POST-LABS1. Incorporation of deliquescent salts/

hygroscpic salts in powder ppns:

2. A presciption w/ a cathartic and an astringent.

3. A prescription w/ tincture of myrrh mixed w/ an aqueous liquid

4. Aqueous soln of Magnesium SO4 mixed w/ an alcoholic tincture or soln.

POST-LABS5.A prescription containing a tannin bearing

drug combined w/ an iron salt.

6.Precipation of the cinchona alkaloid when preparation of this drug is combined w/ KI and mercuric chloride.

POST-LABS-PHYSICAL INCOMP1. MANIFESTATION OR EVIDENCE OF

INCOMPATIBILITYINSOLUBILITY OCCURS-MIXTURE IS NOT UNIFORMLY DISTRIBUTED

EVIDENCED BY THE FORMATION OF LAYERS.PHENOL AND ZINC OXIDEZINC OXIDE AND WATER

2. INGREDIENTS THAT WILL CAUSE INCOMPATIBILITY.

PHENOL AND ZINC OXIDEZINC OXIDE AND WATERPOLYETHYLENE AND PHENOL

POST-LABS

3. CORRECTION TO THE INCOMPATIBILITYREDUCTION OF PHENOL CONTENTADDITION OF BENTONITE MAGMA

(SUSPENSING AGENT TO AVOID LAYER FORMATION)

POST-LABS

4. BENTONITE MAGMABENTONITE 50 GPURIFIED WATER QS TO MAKE 1000G-SPRINKLE THE BENTONITE IN PORTIONS,

UPON800 G OF HOT PURIFIED WATER, ALLOWING EACH PORTION TO BECOME THOROUGHLY WETTED W/O STIRRING. ALLOWIT TO STAND W/ OCCASIONAL STIRRING FOR 24 HRS. STIR UNTIL A UNIFORM MAGMA IS OBTAINED. ADD PURIFIED WATER TO MAKE 1000 G AND MIX.

POST-LABS

5. CAMPHOR WATER

CAMPHOR 1GALCOHOL 90% 2MLPURIFIED H20 1000MLWEIGH REQUIRED QUANTITY OF CAMPHOEDISSOLVE CAMPHOE IN 90% ALCOHOLADD THIS MIXTURE IN SUCCESSIVE PORTIONS

TO PURIFEDE WATER IN SMALL PROPORTIONSSHAKE WELL AFTER EACH ADDITION.SET ASIDE FOR AN HR.FILTER AND ADJUST VOLUME.

POST-LABS

6. WHAT INSTRUCTION SHOULD BE GIVEN TO THE PX WHEN THE CORRECTION TO BE MADE ÏS “DOUBLE THE VOLUME, DOUBLE THE DOSE.”

ADDING THE VOLUME WOULD EQUATE TO DOUBLING THE DOSE.

POST-LABS

MANIFESTATION OR EVIDENCE OF INCOMPATIBILITY

POSSIBLE OVERDOSETOXIC MANIFESTATION TO THE PEDIATRIC PX

POST-LABS-THERAPEUTIC INCOMP

INGREDIENTS THAT CAUSE INCOMPATIBILITYERYTHROMYCIN (TOO LARGE)

POST-LABS

CORRECTION TO THE INCOMPATIBILITYREDUCTION OF THE DOSE APPROPRIATE FOR

THE CHILD.

POST-LABS