IncompatibilitiesIncompatibilities

Kh Sadique FaisalKh Sadique Faisal

Asst. LecturerAsst. Lecturer

Northern University BangladeshNorthern University Bangladesh

IncompatibilitiesIncompatibilities

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

Incompatibility may be :Incompatibility may be :

-Pharmaceutical -Pharmaceutical

-Therapeutic-Therapeutic

Pharmaceutical incompatibilitiesPharmaceutical incompatibilities

- Physical orPhysical or- Chemical incompatibilities. Chemical incompatibilities.

- Are usually unintentional- Are usually unintentional

- Occur in vitro between drugs and - Occur in vitro between drugs and other components during other components during preparation, storage or preparation, storage or administration.administration.

Physical IncompatibilityPhysical Incompatibility

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

unpalatable product product is formed.unpalatable product product is formed. Difficult to measure an accurate dose.Difficult to measure an accurate dose.

Result of Result of insolubility and immiscibility, insolubility and immiscibility, precipitation, liquefaction, Adsorption and precipitation, liquefaction, Adsorption and complexation of solid materialscomplexation of solid materials..

Can be corrected by applying Can be corrected by applying pharmaceutical skillpharmaceutical skill

Correction(Physical Correction(Physical incompatibilities )incompatibilities )

By one or more methods:By one or more methods: Order of mixing Order of mixing alteration of solvents alteration of solvents change in the form of ingredientschange in the form of ingredients alteration of volumealteration of volume Emulsification and addition of suspending Emulsification and addition of suspending

agent, agent, addition, substitution or omission of addition, substitution or omission of

therapeutically inactive substances.therapeutically inactive substances.

1. Insolubility and immiscibility1. Insolubility and immiscibility

It is the result of the mixture of two or more It is the result of the mixture of two or more immiscible immiscible

liquid or an immiscible solid with a liquidliquid or an immiscible solid with a liquid

-Acceptable liquid product can be obtained by -Acceptable liquid product can be obtained by emulsification or solubilization emulsification or solubilization

(a) (a) RxRxOlive oil 30mlOlive oil 30mlWater up to 120mlWater up to 120mlmake an emulsionmake an emulsion use a suitable emulsifying agentuse a suitable emulsifying agent

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

Rx,Rx,Sulphamethoxazole 4.0g Sulphamethoxazole 4.0g Trimethoprim 0.8gTrimethoprim 0.8gNa- CMC 0.5gNa- CMC 0.5gPurified water qs to 100mlPurified water qs to 100ml

Sulphamethoxazole &Trimethoprim are Sulphamethoxazole &Trimethoprim are indiffusible in water. To make them diffusible a indiffusible in water. To make them diffusible a

suspending agent is usedsuspending agent is used

c.c. Insoluble Powders (Sulpher, certain Insoluble Powders (Sulpher, certain

Corticosteroids and Antibiotic) Corticosteroids and Antibiotic) ++ Water Water ==Non-wetted, non – distributed liquid powderNon-wetted, non – distributed liquid powderProduct.Product.

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

..

2. Precipitation2. Precipitation

a. A solubilised substance may a. A solubilised substance may precipitate from it solution if a non precipitate from it solution if a non solvent for the substance is added to solvent for the substance is added to the solution. the solution.

i. Alcohlic solution of Resins + water = i. Alcohlic solution of Resins + water = precipitated Resinsprecipitated Resins

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

But significant amount are tolerated if well diluted and added in small But significant amount are tolerated if well diluted and added in small amount with vigorous stirringamount with vigorous stirring

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

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

3. Liquefaction3. Liquefaction

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

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

or asprin with Phenazoneor asprin with Phenazone

In order to overcome such incompatibility, the eutectic In order to overcome such incompatibility, the eutectic forming ingredient may either be dispensed separately or forming ingredient may either be dispensed separately or these may be mixed separately with enough quantity of these may be mixed separately with enough quantity of adsorbent powder like magnesium carbonate or Kaolin to adsorbent powder like magnesium carbonate or Kaolin to form free flowing product. Alternately, if liquefaction has form free flowing product. Alternately, if liquefaction has already occurred, the liquid may be adsorbed on a surface of already occurred, the liquid may be adsorbed on a surface of sufficient quantity of powder , filled into capsule and sufficient quantity of powder , filled into capsule and dispenseddispensed

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

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

d. Adsorption and Complexationd. Adsorption and Complexation

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

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

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

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

Chemical IncompatibilitiesChemical Incompatibilities

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

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

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

Provided the product is harmless Provided the product is harmless the interaction fall into:the interaction fall into:

a. Tolerated-: the reaction is minimised a. Tolerated-: the reaction is minimised by applying some suitable order of by applying some suitable order of mixing or mixing the solution in dilute mixing or mixing the solution in dilute form but no alteration is made in the form but no alteration is made in the active ingredients of the preparation.active ingredients of the preparation.

b. Adjusted-: the reaction is prevented b. Adjusted-: the reaction is prevented by addition or substitution of one of by addition or substitution of one of the reacting substances with another the reacting substances with another of equal therapeutic value but does of equal therapeutic value but does not affect the medicinal of the not affect the medicinal of the preparation (substitution of caffeine preparation (substitution of caffeine citrate wih caffeine in sodiun citrate wih caffeine in sodiun salicylate and caffeine citrate mixture)salicylate and caffeine citrate mixture)

Precipitate yielding combinationPrecipitate yielding combination

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

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

Hence the reacting substances should be diluted Hence the reacting substances should be diluted

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

agent if the precipitate is non-diffusible.agent if the precipitate is non-diffusible.

Method AMethod A

This is suitable for diffusible precipitatesThis is suitable for diffusible precipitates Divide all or most of the vehicle into two Divide all or most of the vehicle into two

portionsportions Dissolve the reactants in separate portions Dissolve the reactants in separate portions Mix the two portions by slowly adding one to Mix the two portions by slowly adding one to

the other with stirring rapidly.the other with stirring rapidly.

(Sometimes a small volume must be reserved for (Sometimes a small volume must be reserved for

dissolving other ingredients, rinsing measures, dissolving other ingredients, rinsing measures, and and

adjusting to volume.)adjusting to volume.)

Method BMethod B

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

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

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

Chemically incompatibility is generally caused by Chemically incompatibility is generally caused by pH change, a pH change, a double decomposition reaction or complex formation.double decomposition reaction or complex formation.

pH effectspH effects Modern medicament are often salts of weak acids Modern medicament are often salts of weak acids

and bases. These salts are usually soluble in water and bases. These salts are usually soluble in water while most of the unionized acids and bases are while most of the unionized acids and bases are practically insoluble. practically insoluble.

Consequently if a salt of weakly basic drug is Consequently if a salt of weakly basic drug is made alkaline , the free base may be precipitated, made alkaline , the free base may be precipitated, while precipitation of free acid may occur if a while precipitation of free acid may occur if a solution of a weakly acidic drug is acidified.solution of a weakly acidic drug is acidified.

Whether precipitation occur or not depends on Whether precipitation occur or not depends on a) The solubility of the unionized acid or base.a) The solubility of the unionized acid or base. b) The pH of the solution.b) The pH of the solution. c) The dissociation exponent (pKa) of the acid or c) The dissociation exponent (pKa) of the acid or

base base

Solubility of the Unionized Acid or BaseSolubility of the Unionized Acid or Base

1. Alkaloids 1. Alkaloids Most alkaloidal salts are soluble in water but Most alkaloidal salts are soluble in water but

alkaloidal bases practically insoluble in water alkaloidal bases practically insoluble in water and are freely soluble in organic solvents.and are freely soluble in organic solvents.

When an alkaline substance like When an alkaline substance like aromatic aromatic spirit of ammonia, solution of ammonia, spirit of ammonia, solution of ammonia, ammonium bicarbonate, Sodium bicarbonate, ammonium bicarbonate, Sodium bicarbonate, BoraxBorax, etc., is added to an alkaloidal salt , etc., is added to an alkaloidal salt solution the free alkaloid may be precipitated. solution the free alkaloid may be precipitated.

However they are not always precipitated, However they are not always precipitated, because all alkaloids are slightly soluble in because all alkaloids are slightly soluble in water and other added substances, for water and other added substances, for examplesexamples

a) Strychninea) Strychnine Strychnine is a constituent of Nux Vomica Strychnine is a constituent of Nux Vomica

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

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

1 x 100 / 7000 = 0.143 gm of Strychnine1 x 100 / 7000 = 0.143 gm of Strychnine Hence the amount of strychnine in 10 ml of Hence the amount of strychnine in 10 ml of

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

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

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

Generally Chemical incompatibilities results from:Generally Chemical incompatibilities results from: 1. Acid- Base reactions1. Acid- Base reactions Acid base reactions often result into precipitation, Acid base reactions often result into precipitation,

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

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

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

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

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

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

Example 1Example 1

Sodium salicylate 4gSodium salicylate 4g Lemon syrup 20mlLemon syrup 20ml Purified water to 100mlPurified water to 100ml make a mixturemake a mixture Since Lemon syrup contains citric acid, it Since Lemon syrup contains citric acid, it

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

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

Example IIExample II

Strychnine hydrochloride solution 5mlStrychnine hydrochloride solution 5ml Aromatic spirit of ammonia 3mlAromatic spirit of ammonia 3ml purified water to 100 mlpurified water to 100 ml make a mixturemake a mixture Strychnine HCl used in the mixture is an alkaloidal saltStrychnine HCl used in the mixture is an alkaloidal salt whereas aromatic spirit of ammonia is an alkaline whereas aromatic spirit of ammonia is an alkaline

substance.substance. On reaction between the two, insoluble strychnine is On reaction between the two, insoluble strychnine is

precipitated. precipitated. since the precipitate formed is diffusible, the since the precipitate formed is diffusible, the

incompatibility may be taken care by suitable incompatibility may be taken care by suitable formulation.formulation.

In this case, strychnine HCl solution should be dissolved In this case, strychnine HCl solution should be dissolved in half the required quantity of water while aromatic in half the required quantity of water while aromatic spirit of ammonia should dissolved in the remaining spirit of ammonia should dissolved in the remaining portion of water. The two portion should be mixed portion of water. The two portion should be mixed slowly.slowly.

b. Gas formationb. Gas formation

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

Example: carbonates or bicarbonates with Example: carbonates or bicarbonates with an acid or acidic drug resulting in the an acid or acidic drug resulting in the

evolutionevolution of carbon dioxideof carbon dioxide

Example 1:Example 1:

Reaction of sodium bicarbonate, borax Reaction of sodium bicarbonate, borax and glyceroland glycerol

RxRx Sodium bicarbonate 1.5gSodium bicarbonate 1.5g Borax 1.5gBorax 1.5g Phenol 0.75gPhenol 0.75g glycerin 25 mlglycerin 25 ml water to 100mlwater to 100ml Prepare a sprayPrepare a spray

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

Na2B4O7 + 3H2O = Na2B2O4 + 2H3BO3Na2B4O7 + 3H2O = Na2B2O4 + 2H3BO3 Borax Sodium metaborate Boric acidBorax Sodium metaborate Boric acid Boric acid thus formed further reacts Boric acid thus formed further reacts

with glycerin to form Glyceryl boric with glycerin to form Glyceryl boric acidacid

2C3H5(OH)3 + 3H3BO32C3H5(OH)3 + 3H3BO3 ---- ---- (C3H3)2(HBO3) + (C3H3)2(HBO3) + 6H2O6H2O

Glycerin Glycerin Boric acidBoric acid Glyceryl Glyceryl boric acidboric acid

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

Example IIExample II

Reaction of alkali bicarbonates with soluble calcium Reaction of alkali bicarbonates with soluble calcium and magnesium salts, land magnesium salts, l

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

2NaHCO3 + CaSO4 ----------- Ca(HCO2NaHCO3 + CaSO4 ----------- Ca(HCO33))2 2 + + Na2SO4Na2SO4

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

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

33. Breaking of structure of disperse system. Breaking of structure of disperse system

Gelling agent such as carbomers, sodium Gelling agent such as carbomers, sodium carboxymethyl cellulose etc. very rapidly lose carboxymethyl cellulose etc. very rapidly lose viscosity by change in PH outside an optimum range. viscosity by change in PH outside an optimum range.

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

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

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

d. Colour changed. Colour change

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

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

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

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

2.Oxidation - Reduction Reaction2.Oxidation - Reduction Reaction

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

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

Example IExample I RX,RX, Potassium Chlorate 4gPotassium Chlorate 4g Ferric iodide syrup 10 mlFerric iodide syrup 10 ml Purified water to 60 mlPurified water to 60 ml Make a mixtureMake a mixture In this case potassium chlorate react with ferric In this case potassium chlorate react with ferric

iodide. Initially the mixture is quite clear but on iodide. Initially the mixture is quite clear but on standing, crystals of iodine is deposited. It is standing, crystals of iodine is deposited. It is therefore essential to dispense the two therefore essential to dispense the two compounds separately with instructions to mix compounds separately with instructions to mix the two before administration.the two before administration.

Example IIExample II

RX,RX, Sodium salicylate 4gSodium salicylate 4g Sodium biocarbonate 4gSodium biocarbonate 4g Peppermint water to 60miPeppermint water to 60mi make a mixturemake a mixture Sodium salicylate gets oxidized in Sodium salicylate gets oxidized in

presence of sodium biocarbonate and the presence of sodium biocarbonate and the mixture darkens on storage. This alkaline mixture darkens on storage. This alkaline catalyzed oxidation may however be catalyzed oxidation may however be prevented by the use of a suitable prevented by the use of a suitable antioxidants like 0.1% sodium antioxidants like 0.1% sodium metabisulphate. metabisulphate.

COMPLEXATIONCOMPLEXATION

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

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

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

Complexation may sometimes be useful specially Complexation may sometimes be useful specially when it is reversible. In such case a large amount of when it is reversible. In such case a large amount of drug is available in the unbound form and when this drug is available in the unbound form and when this drug is utilised, it is replaced from the complex. drug is utilised, it is replaced from the complex.

Thus the complex provides a reservoir of drug from Thus the complex provides a reservoir of drug from which a safe but sufficient concentration is available which a safe but sufficient concentration is available to the tissue over a prolonged period.to the tissue over a prolonged period.

A 10 to 15 % aqueous solution of Povidone has A 10 to 15 % aqueous solution of Povidone has been found suitable for this purpose.been found suitable for this purpose.

Complex formation may also reduce the irritancy Complex formation may also reduce the irritancy and improve the stability of a drug, as in and improve the stability of a drug, as in Iodophores,which are complexes of Iodine in which Iodophores,which are complexes of Iodine in which the Halogen is bound to a water soluble polymer the Halogen is bound to a water soluble polymer (Povidone) or solubilised in the micelles of (Povidone) or solubilised in the micelles of surfactants .surfactants .

4. Ionic Reactions4. Ionic Reactions

The therapeutic or pharmaceutical The therapeutic or pharmaceutical properties of many organic compounds are properties of many organic compounds are usually associated with a large cation or usually associated with a large cation or anion. Interaction of such ions of opposing anion. Interaction of such ions of opposing types may yield compounds which may types may yield compounds which may totally lack the useful properties of the totally lack the useful properties of the interacting molecules.interacting molecules.

For instances,For instances, Cream prepared using Cream prepared using cationic emulgent may crack if mixed with a cationic emulgent may crack if mixed with a cream prepared using an anionic emulgent. cream prepared using an anionic emulgent.

Similarly an anionic solubilizers may lower Similarly an anionic solubilizers may lower the antimicrobial activity of a cationic the antimicrobial activity of a cationic medicament or preservative.medicament or preservative.

Ionic incompatibilities may however be Ionic incompatibilities may however be prevented by carefully selecting the prevented by carefully selecting the medicaments and adjuvents in a proposed medicaments and adjuvents in a proposed formulation so as to exclude combination formulation so as to exclude combination of anionic and cationic ingredients in a of anionic and cationic ingredients in a single formulation. single formulation.

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

5. Explosive combination5. Explosive combination

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

For example, if Potassium chlorate is prescribed For example, if Potassium chlorate is prescribed with an oxidisable substance like sulphur, tannic with an oxidisable substance like sulphur, tannic acid, etc and the two are triturated or heated acid, etc and the two are triturated or heated together , there is a fair chance of an explosive together , there is a fair chance of an explosive reaction taking place. In such case, it is better to reaction taking place. In such case, it is better to dispense the components separately or if it is dispense the components separately or if it is necessary to mix them together, the mixing necessary to mix them together, the mixing should be done very lightly.should be done very lightly.