Incompatibilities

IncompatibilitiesIncompatibilities
Kh Sadique FaisalKh Sadique Faisal
Asst. LecturerAsst. Lecturer
Northern University BangladeshNorthern University Bangladesh

IncompatibilitiesIncompatibilities
 It is the result of prescribing or mixing twoIt is the result of prescribing or mixing two
or more substances which are antagonistor more substances which are antagonist
in nature and an undesirable product isin nature and an undesirable product is
formed which may affect the safety,formed which may affect the safety,
purpose or appearance of the preparation.purpose 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 other- Occur in vitro between drugs and other
components during preparation, storagecomponents during preparation, storage
or administration.or administration.

Physical IncompatibilityPhysical Incompatibility
 A visible physical change takes placeA 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 ofResult of insolubility and immiscibility,insolubility and immiscibility,
precipitation, liquefaction, Adsorption andprecipitation, liquefaction, Adsorption and
complexation of solid materialscomplexation of solid materials..
 Can be corrected by applying pharmaceuticalCan be corrected by applying pharmaceutical
skillskill

Correction(PhysicalCorrection(Physical
incompatibilities )incompatibilities )
By one or more methods:By one or more methods:
 Order of mixingOrder of mixing
 alteration of solventsalteration of solvents
 change in the form of ingredientschange in the form of ingredients
 alteration of volumealteration of volume
 Emulsification and addition of suspending agent,Emulsification and addition of suspending agent,
 addition, substitution or omission ofaddition, 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 immiscibleIt is the result of the mixture of two or more 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 solubilizationemulsification or solubilization
(a)(a)
RxRx
Olive oil 30mlOlive oil 30ml
Water up to 120mlWater up to 120ml
make an emulsionmake an emulsion
 use a suitable emulsifying agentuse a suitable emulsifying agent

b. Liquid preparation with Indiffusible solidsb. Liquid preparation with Indiffusible solids
( Sulphamethoxasole, phenacetin, Zinc oxide,( Sulphamethoxasole, phenacetin, Zinc oxide,
calamine etc.)calamine etc.) ++ a suspending agenta suspending agent == aa
uniform distribution of the solids in the liquiduniform distribution of the solids in the liquid
phase for sufficiently long time so as to facilitatephase for sufficiently long time so as to facilitate
accurate measurement of dose.accurate measurement of dose.
 Rx,Rx,
Sulphamethoxazole 4.0gSulphamethoxazole 4.0g
Trimethoprim 0.8gTrimethoprim 0.8g
Na- CMC 0.5gNa- CMC 0.5g
Purified water qs to 100mlPurified water qs to 100ml

Sulphamethoxazole &Trimethoprim areSulphamethoxazole &Trimethoprim are
indiffusible in water. To make them diffusible aindiffusible in water. To make them diffusible a
suspending agent is usedsuspending agent is used
c.c. Insoluble Powders (Sulpher, certainInsoluble Powders (Sulpher, certain
Corticosteroids and Antibiotic)Corticosteroids and Antibiotic) ++ WaterWater ==
Non-wetted, non – distributed liquid powderNon-wetted, non – distributed liquid powder
Product.Product.
Insoluble non-wetted drug PowdersInsoluble non-wetted drug Powders ++ WaterWater ++
wetting Agent (Saponins for sulpher drugwetting Agent (Saponins for sulpher drug
containing lotions and Polysorbate forcontaining lotions and Polysorbate for
corticosteroids and Antibioticcorticosteroids and Antibiotic == uniformlyuniformly
dispersed Powder product in waterdispersed Powder product in water
..

2. Precipitation2. Precipitation
 a. A solubilised substance may precipitatea. A solubilised substance may precipitate
from it solution if a non solvent for thefrom it solution if a non solvent for the
substance is added to the solution.substance is added to the solution.
i. Alcohlic solution of Resins + water =i. Alcohlic solution of Resins + water =
precipitated Resinsprecipitated Resins
ii. Aqueous dispersion of Hydrophillicii. Aqueous dispersion of Hydrophillic
colloids (polysaccharide mucilage + highcolloids (polysaccharide mucilage + high
conc. of Alcohol or salts = Precipitatedconc. of Alcohol or salts = Precipitated
colloids.colloids.

But significant amount are tolerated if well diluted and added in smallBut 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 ofb. High concentration of electrolytes cause Cracking of
soap emulsion by salting out the emulsifying agents.soap emulsion by salting out the emulsifying agents.
c.Vehicles (one or more organic liquids) use to dissolvec.Vehicles (one or more organic liquids) use to dissolve
medicaments of low solubility, water soluble adjunctsmedicaments of low solubility, water soluble adjuncts
particularly inorganic salts may be precipitated in suchparticularly inorganic salts may be precipitated in such
vehicles.vehicles.

3. Liquefaction3. Liquefaction
 Certain low melting point solids sometimes liquefy when mixedCertain low melting point solids sometimes liquefy when mixed
together due to the formation of eutectic mixture or liberation oftogether due to the formation of eutectic mixture or liberation of
water .water .
 For example, if any two of the following medicaments are combinedFor example, if any two of the following medicaments are combined
together, they form a eutectic mixture: Menthol, Thymol, Camphor,together, they form a eutectic mixture: Menthol, Thymol, Camphor,
Phenol, Salol, Naphthol and chloral hydrate. Also Sodium salicylatePhenol, Salol, Naphthol and chloral hydrate. Also Sodium salicylate
or asprin with Phenazoneor asprin with Phenazone
 In order to overcome such incompatibility, the eutectic formingIn order to overcome such incompatibility, the eutectic forming
ingredient may either be dispensed separately or these may beingredient may either be dispensed separately or these may be
mixed separately with enough quantity of adsorbent powder likemixed separately with enough quantity of adsorbent powder like
magnesium carbonate or Kaolin to form free flowing product.magnesium carbonate or Kaolin to form free flowing product.
Alternately, if liquefaction has already occurred, the liquid may beAlternately, if liquefaction has already occurred, the liquid may be
adsorbed on a surface of sufficient quantity of powder , filled intoadsorbed on a surface of sufficient quantity of powder , filled into
capsule and dispensedcapsule and dispensed

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, theyIn this case, if the ingredients are mixed together, they
shall liquefy due to formation of a eutectic mixture.shall liquefy due to formation of a eutectic mixture.
Hence, to dispense them in the form of a powder, it isHence, to dispense them in the form of a powder, it is
necessary to mix them separately with sufficient quantitynecessary to mix them separately with sufficient quantity
of a suitable adsorbent like magnesium carbonate. Theof a suitable adsorbent like magnesium carbonate. The
three mixture then mix together to obtain a powder.three mixture then mix together to obtain a powder.

d. Adsorption and Complexationd. Adsorption and Complexation
 Certain substances including drugs and excipients mayCertain substances including drugs and excipients may
interact to form physical complex which may alter theinteract 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 poseAttapulgite or suspended antacids may pose
incompatibility problems due to adsorptionincompatibility problems due to adsorption
 Adsorption of Cyanocobalamin by Talc, a tablet lubricantAdsorption of Cyanocobalamin by Talc, a tablet lubricant
may decrease the absorption from GIT.may decrease the absorption from GIT.
 Similarly Adsorption of antimicrobial preservatives suchSimilarly Adsorption of antimicrobial preservatives such
as parabens on to the drugs or excipients may lead toas parabens on to the drugs or excipients may lead to
loss of their antimicrobial activity.loss of their antimicrobial activity.
--

Chemical IncompatibilitiesChemical Incompatibilities
 Chemical Incompatibilities is usually aChemical Incompatibilities is usually a
result of chemical interaction takingresult of chemical interaction taking
place among the ingredients of aplace among the ingredients of a
prescription.prescription.
 Such interactions may take placeSuch interactions may take place
immediately upon compounding whenimmediately upon compounding when
these are termed asthese are termed as immediate inimmediate in
compatibilitiescompatibilities and are evident asand are evident as
effervescence, precipitation or coloureffervescence, precipitation or colour
change.change.
 More often the interaction are notMore often the interaction are not
evident immediately on compounding butevident immediately on compounding but
take place over a period of time. Suchtake place over a period of time. Such
interaction are termedinteraction are termed delayeddelayed

Provided the product is harmlessProvided the product is harmless
the interaction fall into:the interaction fall into:
a. Tolerated-: the reaction is minimised bya. Tolerated-: the reaction is minimised by
applying some suitable order of mixing orapplying some suitable order of mixing or
mixing the solution in dilute form but nomixing the solution in dilute form but no
alteration is made in the activealteration is made in the active
ingredients of the preparation.ingredients of the preparation.
b. Adjusted-: the reaction is prevented byb. Adjusted-: the reaction is prevented by
addition or substitution of one of theaddition or substitution of one of the
reacting substances with another ofreacting substances with another of
equal therapeutic value but does notequal therapeutic value but does not
affect the medicinal of the preparationaffect the medicinal of the preparation
(substitution of caffeine citrate wih(substitution of caffeine citrate wih
caffeine in sodiun salicylate and caffeinecaffeine in sodiun salicylate and caffeine
citrate mixture)citrate mixture)

Precipitate yielding combinationPrecipitate yielding combination
 Generally reaction between strong solutions proceed atGenerally reaction between strong solutions proceed at
a faster rate and the precipitates formed are thick and doa faster rate and the precipitates formed are thick and do
not diffuse readily.not diffuse readily.
 Reaction between the dilute solutions proceed at a slowReaction between the dilute solutions proceed at a slow
rate and the precipitates formed are light and diffuserate and the precipitates formed are light and diffuse
readily in the solution.readily in the solution.
 Hence the reacting substances should be diluted asHence the reacting substances should be diluted as
much as possible before mixing.much as possible before mixing.
 The preparation should contain a thickening agent if theThe preparation should contain a thickening agent if the
precipitate is non-diffusible.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 portionsDivide all or most of the vehicle into two portions
 Dissolve the reactants in separate portionsDissolve the reactants in separate portions
 Mix the two portions by slowly adding one to theMix the two portions by slowly adding one to the
other with stirring rapidly.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, anddissolving other ingredients, rinsing measures, 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 portionDissolve one reacting substance in one portion
 Place the other portion in a morter and Incorporate aPlace the other portion in a morter and Incorporate a
suitable amount of Tragacanth powder (2gm/100ml ofsuitable amount of Tragacanth powder (2gm/100ml of
the finished product) with constant trituration untill athe finished product) with constant trituration untill a
smooth mucilage is produced, then add and dissolve thesmooth mucilage is produced, then add and dissolve the
other reacting substancesother reacting substances
 Mix the two portions by slowly adding one portion to theMix the two portions by slowly adding one portion to the
other with rapid stirring.other with rapid stirring.

Chemically incompatibility is generally caused byChemically incompatibility is generally caused by pH change, apH 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 andModern medicament are often salts of weak acids and
bases. These salts are usually soluble in water whilebases. These salts are usually soluble in water while
most of the unionized acids and bases are practicallymost of the unionized acids and bases are practically
insoluble.insoluble.
 Consequently if a salt of weakly basic drug is madeConsequently if a salt of weakly basic drug is made
alkaline , the free base may be precipitated, whilealkaline , the free base may be precipitated, while
precipitation of free acid may occur if a solution of aprecipitation of free acid may occur if a solution of a
weakly acidic drug is acidified.weakly acidic drug is acidified.
Whether precipitation occur or not depends onWhether 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 basec) The dissociation exponent (pKa) of the acid or base

Solubility of the Unionized Acid or BaseSolubility of the Unionized Acid or Base
 1. Alkaloids1. Alkaloids
 Most alkaloidal salts are soluble in water butMost alkaloidal salts are soluble in water but
alkaloidal bases practically insoluble in wateralkaloidal bases practically insoluble in water
and are freely soluble in organic solvents.and are freely soluble in organic solvents.
 When an alkaline substance likeWhen an alkaline substance like aromatic spiritaromatic spirit
of ammonia, solution of ammonia, ammoniumof ammonia, solution of ammonia, ammonium
bicarbonate, Sodium bicarbonate, Boraxbicarbonate, Sodium bicarbonate, Borax, etc., is, etc., is
added to an alkaloidal salt solution the freeadded to an alkaloidal salt solution the free
alkaloid may be precipitated.alkaloid may be precipitated.
 However they are not always precipitated,However they are not always precipitated,
because all alkaloids are slightly soluble in waterbecause all alkaloids are slightly soluble in water
and other added substances, for examplesand other added substances, for examples

 a) Strychninea) Strychnine
 Strychnine is a constituent of Nux Vomica Tincture whichStrychnine is a constituent of Nux Vomica Tincture which
is used in some official mixtures as a bitter to stimulateis used in some official mixtures as a bitter to stimulate
the appetite.the appetite.
 The amount of strychnine present is 0.125 gm perThe amount of strychnine present is 0.125 gm per
100ml of tincture nux vomica and the solubility of100ml of tincture nux vomica and the solubility of
strychnine is about 1 in 7000, i. e., 100 ml of water willstrychnine is about 1 in 7000, i. e., 100 ml of water will
dissolvedissolve
 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 tincture willHence the amount of strychnine in 10 ml of tincture will
dissolve easily in 100 ml of water and therefore, 10 % ofdissolve easily in 100 ml of water and therefore, 10 % of
the tincture in water will not precipitate in alkalinethe tincture in water will not precipitate in alkaline
conditions.conditions.

 Further , tinctures contain certain amount ofFurther , tinctures contain certain amount of
alcohol due to which the precipitation is furtheralcohol due to which the precipitation is further
prevented.prevented.
 Moreover the solubility of strychnine is muchMoreover the solubility of strychnine is much
more in alcohol (i. e. 1 in 150) than in water.more in alcohol (i. e. 1 in 150) than in water.
Therefore it follows that in mixtures sufficientTherefore it follows that in mixtures sufficient
amount of alcohol strychnine will not beamount of alcohol strychnine will not be
precipitated even when more than 10 ml ofprecipitated even when more than 10 ml of
tincture per 100 ml is present in thetincture per 100 ml is present in the
prescription.prescription.

 Generally Chemical incompatibilities resultsGenerally Chemical incompatibilities results
from:from:
 1. Acid- Base reactions1. Acid- Base reactions
 Acid base reactions often result intoAcid base reactions often result into
precipitation, gas formation, breaking ofprecipitation, gas formation, breaking of
structure of disperse systems or colour change.structure of disperse systems or colour change.
 a. Precipitationa. Precipitation
 Most medicaments in use are often salts ofMost medicaments in use are often salts of
weak acids or bases.weak acids or bases.
 These salts have a very good water solubilityThese salts have a very good water solubility
whereas their corresponding unionised acids orwhereas 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 isif 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 ifSimilarly, precipitation of free base may occur if
a solution of a salt of weakly basic drug isa solution of a salt of weakly basic drug is

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, itSince Lemon syrup contains citric acid, it
will acidify the solution and causewill acidify the solution and cause
precipitation of the free acid (salicylicprecipitation 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 sweeteningit is necessary to use other sweetening
and flavouring agent instead of lemonand 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
 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 alkalinewhereas aromatic spirit of ammonia is an alkaline
substance.substance.
 On reaction between the two, insoluble strychnine isOn reaction between the two, insoluble strychnine is
precipitated.precipitated.
 since the precipitate formed is diffusible, thesince the precipitate formed is diffusible, the
incompatibility may be taken care by suitable formulation.incompatibility may be taken care by suitable formulation.
 In this case, strychnine HCl solution should be dissolvedIn this case, strychnine HCl solution should be dissolved
in half the required quantity of water while aromatic spiritin half the required quantity of water while aromatic spirit
of ammonia should dissolved in the remaining portion ofof ammonia should dissolved in the remaining portion of
water. The two portion should be mixed slowly.water. The two portion should be mixed slowly.

b. Gas formationb. Gas formation
 Gas may be evolved due to chemical reactionGas may be evolved due to chemical reaction
between the ingredients of a formulation.between the ingredients of a formulation.
 Example: carbonates or bicarbonates with anExample: carbonates or bicarbonates with an
acid or acidic drug resulting in the evolutionacid or acidic drug resulting in the evolution ofof
carbon dioxidecarbon dioxide


Example 1:Example 1:
 Reaction of sodium bicarbonate, boraxReaction of sodium bicarbonate, borax
and glyceroland glycerol
 RxRx
 Sodium bicarbonate 1.5gSodium bicarbonate 1.5g
 BoraxBorax
1.5g1.5g
 PhenolPhenol
0.75g0.75g
 glycerin 25glycerin 25
mlml
 water towater to
100ml100ml

 In this case , borax decomposes inIn this case , borax decomposes in
presence of glycerin to form sodiumpresence 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 withBoric acid thus formed further reacts with
glycerin to form Glyceryl boric acidglycerin to form Glyceryl boric acid

2C3H5(OH)3 + 3H3BO32C3H5(OH)3 + 3H3BO3 -------- (C3H3)2(HBO3) +(C3H3)2(HBO3) +
6H2O6H2O
 GlycerinGlycerin Boric acidBoric acid Glyceryl boricGlyceryl boric
acidacid

 For compounding of such preparation, theFor compounding of such preparation, the
ingredients should be allowed to react iningredients should be allowed to react in
an open vessel and only when thean open vessel and only when the
reaction is complete, should thereaction is complete, should the
preparation be transferred to the finalpreparation be transferred to the final
containercontainer, otherwise there may be a, otherwise there may be a
chances of explosion. The reaction maychances of explosion. The reaction may
be hastened by the use of hot waterbe hastened by the use of hot water


Reaction of alkali bicarbonates with soluble calcium andReaction of alkali bicarbonates with soluble calcium and
magnesium salts, lmagnesium salts, l
 When alkali bicarbonate are combined withWhen alkali bicarbonate are combined with
soluble calcium and magnesium salts, doublesoluble calcium and magnesium salts, double
decomposition reaction occurs resulting in thedecomposition reaction occurs resulting in the
formation of corresponding insoluble carbonateformation of corresponding insoluble carbonate
and carbon dioxideand carbon dioxide
 2NaHCO3 + CaSO4 ----------- Ca(HCO2NaHCO3 + CaSO4 ----------- Ca(HCO33 ))22 ++
Na2SO4Na2SO4
 4Ca(HCO3)4Ca(HCO3)33 ----------------- 3CaCO3 + Ca(OH)2----------------- 3CaCO3 + Ca(OH)2
+5CO2 +3H2O+5CO2 +3H2O
 Since the reaction proceeds slowly at room temperature,Since the reaction proceeds slowly at room temperature,
it should be accelerated by using a hot vehicle and theit should be accelerated by using a hot vehicle and the
resulting mixture should not be pocked until reaction isresulting mixture should not be pocked until reaction is
complete.complete.

33. Breaking of structure of disperse system. Breaking of structure of disperse system
 Gelling agent such as carbomers, sodium carboxymethylGelling agent such as carbomers, sodium carboxymethyl
cellulose etc. very rapidly lose viscosity by change in PHcellulose etc. very rapidly lose viscosity by change in PH
outside an optimum range.outside an optimum range.
 Carbomer dispersion liquify by decreasing their PCarbomer dispersion liquify by decreasing their PHH
belowbelow
5 or increasing it above 10.5 or increasing it above 10.
 Similarly, below a PSimilarly, below a PHH
3, alginic acid is precipitated from3, alginic acid is precipitated from
dispersion of sodium alginate and carboxy methyldispersion of sodium alginate and carboxy methyl
cellulose is precipitated from its sodium derivatives.cellulose is precipitated from its sodium derivatives.
 Emulsion prepared using soap as emulsifying agent areEmulsion prepared using soap as emulsifying agent are
liable to break in presence of mineral acids whichliable to break in presence of mineral acids which
destroy the emulsifying activity of soap by precipitatingdestroy the emulsifying activity of soap by precipitating
the acidsthe acids

d. Colour changed. Colour change
 d. Colour changed. Colour change
 The colour of most of the dyes used in formulations isThe colour of most of the dyes used in formulations is
influenced by their ionization which in turn depends oninfluenced by their ionization which in turn depends on
the PH of the solution,the PH of the solution,
 Thus crystal violet which is also used as antiseptic is aThus crystal violet which is also used as antiseptic is a
purple coloured compound but changes colour throughpurple coloured compound but changes colour through
green to yellow on acidification. similarly phenolphthelingreen to yellow on acidification. similarly phenolphthelin
(used as laxative) is colourless in acidic solution but(used as laxative) is colourless in acidic solution but
becomes pink in alkaline media.becomes pink in alkaline media.
 Colour change due to change in PH can be preventedColour change due to change in PH can be prevented
by properly buffering the vehicle or by preventingby properly buffering the vehicle or by preventing
reaction that cause formation of free acid or base in thereaction that cause formation of free acid or base in the
medium.medium.


2.Oxidation - Reduction Reaction2.Oxidation - Reduction Reaction
 Certain prescription mixtures may oxidise onCertain prescription mixtures may oxidise on
exposure to air, heat, light or due to change inexposure to air, heat, light or due to change in
PH or reaction with trace metal ions. Use ofPH or reaction with trace metal ions. Use of
antioxidants like ascorbic acid, Sodiumantioxidants like ascorbic acid, Sodium
metabisulphite etc, is often helpful in eachmetabisulphite etc, is often helpful in each
cases.cases.
 Oxidation due to trace metal ions can beOxidation due to trace metal ions can be
prevented by the use of chelating agents likeprevented by the use of chelating agents like
Disodium EDTA.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 iodide.In this case potassium chlorate react with ferric iodide.
Initially the mixture is quite clear but on standing,Initially the mixture is quite clear but on standing,
crystals of iodine is deposited. It is therefore essential tocrystals of iodine is deposited. It is therefore essential to
dispense the two compounds separately with instructionsdispense the two compounds separately with instructions
to mix the two before administration.to mix the two before administration.

 RX,RX,
 Sodium salicylate 4gSodium salicylate 4g
 Sodium biocarbonate 4gSodium biocarbonate 4g
 Peppermint water to 60miPeppermint water to 60mi
 Sodium salicylate gets oxidized in presence ofSodium salicylate gets oxidized in presence of
sodium biocarbonate and the mixture darkenssodium biocarbonate and the mixture darkens
on storage. This alkaline catalyzed oxidationon storage. This alkaline catalyzed oxidation
may however be prevented by the use of amay however be prevented by the use of a
suitable antioxidants like 0.1% sodiumsuitable antioxidants like 0.1% sodium
metabisulphate.metabisulphate.

COMPLEXATIONCOMPLEXATION
 Many macromolecular adjuncts used in formulation formMany macromolecular adjuncts used in formulation form
complexes in which medicaments and preservatives arecomplexes in which medicaments and preservatives are
bound to the macromolecules or trapped within micelles.bound to the macromolecules or trapped within micelles.
This behavior is most common with non-ionicThis behavior is most common with non-ionic
macromolecules.macromolecules.
 Because these complex are too large to penetrate cellBecause these complex are too large to penetrate cell
membranes, the activity of the medicament ormembranes, the activity of the medicament or
preservatives may be greatly reduced.preservatives may be greatly reduced.
 A number of medicaments and excipients likeA number of medicaments and excipients like
suspending agent (polysaccharides), emulgentssuspending 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 when itComplexation may sometimes be useful specially when it
is reversible. In such case a large amount of drug isis reversible. In such case a large amount of drug is
available in the unbound form and when this drug isavailable in the unbound form and when this drug is
utilised, it is replaced from the complex.utilised, it is replaced from the complex.
 Thus the complex provides a reservoir of drug fromThus the complex provides a reservoir of drug from
which a safe but sufficient concentration is available towhich a safe but sufficient concentration is available to
the tissue over a prolonged period.the tissue over a prolonged period.
 A 10 to 15 % aqueous solution of Povidone has beenA 10 to 15 % aqueous solution of Povidone has been
found suitable for this purpose.found suitable for this purpose.
 Complex formation may also reduce the irritancy andComplex formation may also reduce the irritancy and
improve the stability of a drug, as in Iodophores,whichimprove the stability of a drug, as in Iodophores,which
are complexes of Iodine in which the Halogen is boundare complexes of Iodine in which the Halogen is bound
to a water soluble polymer (Povidone) or solubilised into a water soluble polymer (Povidone) or solubilised in
the micelles of surfactants .the micelles of surfactants .

4. Ionic Reactions4. Ionic Reactions
 The therapeutic or pharmaceutical properties ofThe therapeutic or pharmaceutical properties of
many organic compounds are usually associatedmany organic compounds are usually associated
with a large cation or anion. Interaction of suchwith a large cation or anion. Interaction of such
ions of opposing types may yield compoundsions of opposing types may yield compounds
which may totally lack the useful properties ofwhich may totally lack the useful properties of
the interacting molecules.the interacting molecules.
 For instances,For instances, Cream prepared using cationicCream prepared using cationic
emulgent may crack if mixed with a creamemulgent may crack if mixed with a cream
prepared using an anionic emulgent.prepared using an anionic emulgent.
 Similarly an anionic solubilizers may lower theSimilarly an anionic solubilizers may lower the
antimicrobial activity of a cationic medicament orantimicrobial activity of a cationic medicament or
preservative.preservative.

 Ionic incompatibilities may however beIonic incompatibilities may however be
prevented by carefully selecting theprevented by carefully selecting the
medicaments and adjuvents in a proposedmedicaments and adjuvents in a proposed
formulation so as to exclude combination offormulation so as to exclude combination of
anionic and cationic ingredients in a singleanionic and cationic ingredients in a single
formulation.formulation.
 In case of emulsified system containing an ionicIn case of emulsified system containing an ionic
medicament or preservative, it may bemedicament or preservative, it may be
advantageous to use a non-ionic emulsifier.advantageous to use a non-ionic emulsifier.

5. Explosive combination5. Explosive combination
 Oxidising agents are chemically in compatible withOxidising agents are chemically in compatible with
reducing agent and a combination of the two in areducing agent and a combination of the two in a
formulation may lead to an explosive reaction.formulation may lead to an explosive reaction.
 For example, if Potassium chlorate is prescribed with anFor example, if Potassium chlorate is prescribed with an
oxidisable substance like sulphur, tannic acid, etc andoxidisable substance like sulphur, tannic acid, etc and
the two are triturated or heated together , there is a fairthe two are triturated or heated together , there is a fair
chance of an explosive reaction taking place. In suchchance of an explosive reaction taking place. In such
case, it is better to dispense the components separatelycase, it is better to dispense the components separately
or if it is necessary to mix them together, the mixingor if it is necessary to mix them together, the mixing
should be done very lightly.should be done very lightly.

Incompatibilities

More Related Content

What's hot

Viewers also liked

Similar to Incompatibilities

More from Abubakar Fago

Recently uploaded

Incompatibilities