Incompatibility occurs as a result of mixing of two or
more antago nistic substances and an undesirable
product is formed which may affect the safety, efficacy
and appearance of the pharmaceutical preparation.
Incompatibility may occur not only during
compounding and dispensing but also at any stage
during formulation, manufacturing. packaging or
administration of drugs
Types of Incompatibilities The incompatibilities
are of three
types
(A) Physical incompatibility
(B) Chemical incompatibility
(C) Therapeutic incompatibility
(A) PHYSICAL INCOMPATIBILITY
When two or more than two substances are
combined together, a physical change takes place
and an unacceptable product is formed Physical
incompatibility is usually due to immiscibility,
insolubility. precipitate formation or liquefaction of
solid materials. These changes are usually visible and
can be easily corrected by applying the
pharmaceutical skill to obtain a product of uniform
dosage
The physical incompatibility may be corrected by
using any one or more of the following methods.
(1) Change the order of mixing of ingredients of
the prescription
2) Emulsification
3)Addition of suspending agent
4) Change in the form of ingredients
5) By addition, substitution or omission of
therapeutically inactive substance to help in
compounding of the prescription.
Examples of Physical Incompatibilities and Their Methods of
Correction
1. Immiscibility: Oils and water are immiscible with each other
They can be made miscible with water by emulsification.
Example castor oil is immiscible with water To overcome
Castor oil 15ml
Water upto 60ml this incompatibility an emulsifying agent is used
Make an emulsion. to make a good emulsion
2. Insolubility: Insolubility means the inability of material to
dissolve in a particular solvent systemThe majority of physical
incompatibilities are due to insolubility of the inorganic as well
as organic compounds in a particular solvent.
Example:
Ephedrine sulphate 0.25gm
Menthol 0.02ml
Liquid paraffin (sufficient to make)... .30ml
Note-The ephedrine sulphate is an alkaloidal salt and is not soluble liquid paraffin, but
anhydrous ephedrine is soluble in it. Hence ephedrine sulphate is substituted with
anhydrous ephedrine to make a clear solution.
3. Precipitation: A drug in solution may be precipitated, if the
solvent in which it is insoluble is added to the solution eg. resins
are insoluble in [Link] can be prevented by slowly adding the
undiluted tincture with vigorous stirring
to the diluted suspension or by adding some suitable thickening
agent
Example 2.3 Prepare and dispense 100 ml
Tincture benzoin compound 5.0ml
Glycerin 15.0ml
Rose water in sufficient quantity to make 100 ml
Tincture benzoin compound contain resins. The change in solvent system results in an
unavoidable precipitate. Addition of tincture with rapid stirring yields a fine colloidal
dispersion. So there is no need of any suspending agent.
4. Liquefaction: When certain low melting point solids are mixed together, a
liquid or soft mass known as 'eutectic mixture' is produced. This occurs due
to the lowering of the melting point of mixture to below room
[Link] medicaments showing this type of behaviour are camphor.
menthol, thymol, phenol, chloral hydrate and aspirin.
Example 2.4
Menthol
Camphor 5g
Ammonium chloride 30g
Light magnesium carbonate 60g
Make an insufflation.
In this prescription menthol, camphor and ammonium chloride get liquefied on mixing with
each other. To dispense this preseription, menthol, camphor and ammonium chloride are
triturated together to form liquid. Add light magnesium carbonate and mix it thoroughly to
make free flowing powder.
(B) CHEMICAL INCOMPATIBILITY
Chemical incompatibility may be as a result of chemical
interactions between the ingredients of a prescription and a
toxie or inactive product may be [Link]
incompatibilities often occur due to oxidation-reduction, acid
base hydrolysis or combination reactions. These reactions may
be noticed by precipitation, effervescence, decomposition,
colour change or by explosion. The prescription having
chemical incompatibility should be dispensed only after its
correction by the prescriber.
(1) Tolerated: In tolerated incompatibilities, the chemical interac tion
can be minimised by changing the order of mixing or mixing the
solutions in dilute forms but no alteration is made in the formulation.
(2) Adjusted In adjusted incompatibilities the chemical interaction
can be prevented by addition or substitution of one of the reacting
ingredients of a prescription with another of equal therapeutic value
For example, caffeine citrate can be substituted with caffeine in
sodium salicylate and caffeine citrate mixture
The chemical incompatibility may be (1) Intentional: When the
prescriber knowingly prescribes the incompatible drugs, (2)
Un-intentional - When the prescriber preseribes the drugs without
knowing that there is incompatibility between the prescribed
drugs
precipitate Yielding Interaction
The precipitates so formed may be diffusible or indiffusible. The method A and B is
followed in dispensing the prescription yielding diffusible and indiffusible
precipitates respectively. Method A The method is followed when diffusible
precipitates are formed in very small quantity Divide the vehicle into two equal
portions Dissolve one of the reacting substances in one of the portion and the other
in the other portion Mix the two portions by slowly adding one portion to the other
by rapid stirring
Method B- The method is followed when indiffusible precipitates are formed in large
quantity Divide the vehicle into two equal portions Dissolve one of the reacting
substances in one portion. Weigh a suitable quantity of compound tragacanth
powder (2 g per 100 ml of finished product) and transfer in a mortar and use part of
second portion of vehicle to produce a smooth mucilage. Then add other reacting sub
stances. Mix the two portions by slowly adding one portion to the other with rapid
stirring
A secondary label "Shake the bottle before use" should be fixed on the container
whenever method A or method B is followed in dispensing the prescription.
Examples of Chemical Incompatibilities and Methods of Their
Correction:
(1)Alkaloidal Incompatibility
(i) Alkaloidal salts with alkaline substances: Alkaloids are weak bases.
They are almost insoluble in water but alkaloidal salts are soluble in
water. If these salts are dispensed with alkaline preparations, such as
strong solution of ammonium acetate, aromatic spirit of ammonia, solu
tion of ammonia, ammonium bicarbonate, sodium bicarbonate, the
free alkaloid may be precipitated. However, they are not always
precipitated, because all alkaloids are slightly soluble in water.
(ii) Alkaloidal salts with soluble iodides: In cough mixture, potas sium
iodide is generally prescribed as an expectorant along with tincture
ipecacuanha (containing emetine). The quantity of emetine present is
usually so low that it cannot react with potassium iodide to get precipi
tated as hydroiodide.
Similarly, when strychnine is prescribed along with soluble iodides it
forms a very insoluble hydroiodide, the precipitates of which are diffus
ible. Hence, follow method A for precipitate yielding interaction.
iii) Alkaloidal salts with tannins: The alkaloidal salts when com
bined with a drug containing tannins, the alkaloids form tannates
which are separated as diffusible precipitates. So follow method A
for precipitate yielding interaction.
The tannates of most alkaloids are insoluble in water, hence strong
tea or tannic acid solution is commonly used in alkaloidal
poisoning.
(iv) Alkaloidal salts with salicylates: When quinine compounds are
combined with salicylates, They form indiffusible precipitates of
quinine salicylate. Therefore, follow method B for precipitate
yielding combina tions
(v) Alkaloidal salts with soluble iodides and bromides: Alkaloids
like strychnine, morphine, codeine etc. form insoluble
hydroiodides and hydrobromide with soluble iodides and
bromides. These precipitates are insoluble but diffusible,
hence method A should be followed while dispensing.
(2) Soluble Salicylates Incompatibilities
(i) Soluble salicylates with ferric salt: Ferric salt reacts with sodium
salicylate to liberate indiffusible precipitates of ferric salicylate.
Therefore, follow method B for precipitate yielding interactions.
(ii) Soluble salicylates with alkali bicarbonates: When sodium salicylate is
administered orally it reacts with hydrochloric acid present in the
stomach to form salicylic acid which is precipitated and may irritate the
gastrice mucosa, causing pain in the stomach. Hence, when sodium
salicylate is prescribed, it is usually given along with double the quantity
of sodium bicarbonate as that of sodium salicylate, to partially neutralise
the gastric juice and thus minimising the formation of precipitates of
salicylic acid.
When sodium salicylate is dispensed in the solution form, especially along
with alkaline substance like sodium bicarbonate, the mixture absorbs
oxygen from the atmosphere and become reddish brown in colour. 'This
change does not affect the therapeutic efficiency of the mixture, but may
lead to confusion in the mind of the patient. To avoid this, a colouring
agent like liquid extract of liquorice may be added to darken the colour of
the mixture or patient may be warned about the colour change. The
colour change can be retarded by adding an antioxidant such as sodium
metabisulphite (0.1% w/v) with the permission of the prescriber.
(ii) Soluble salieylates and benzoates with acids: Most of the acids
and acid syrups (e.g. syrup lemon) decompose sodium salicylate as
well as sodium benzoate to form precipitates of salicylic acid and
benzoic acid respectively. These precipitates are indiffusible in
nature, so follow method B for precipitate yielding interaction.
(3) Soluble Iodides Incompatibility
lodides undergo oxidation forming iodine which is an undesirable product. Hence, following
steps may be taken to avoid this chemical change
(i) Oxidation of iodides with ferric salts: When ferric salt reacts with soluble iodide it get
converted into ferrous salt. There is no satisfactory method to adjust this incompatibility.
Fe+++ +2I -----} Fe+++ 12
To prevent incompatibility, the prescriber may substitute ferric salts with iron and ammonium
citrate. Alternatively, the iron is converted into an organic compound which does not yield
ferric ions.
(i) Oxidation of iodides with potassium chlorate: When soluble iodides react with potassium
chlorate, free iodine is liberated.
KCI03+3Fel2----} 3FeOI+ 3I+ KCI
To prevent this incompatibility, the two reacting substances must be dispensed separat ely
(iii) Oxidation of iodides with quinine sulphate: Quinine sulphate is not freely soluble in water.
It is made soluble in the presence of dilute sulphuric acid. The sulphuric acid liberates
hydroiodic acid from the potassium iodide, and the hydroiodic acid is partly oxidised by the
sulphuric acid, yielding iodine. The iodine, hydroiodic acid and quinine sulphate then combine
to form a compound called 'herapathite or iodosulphite of quinine, The compound has the
following chemical formula:
(C20H2404N2).3H2804.2HI.212. 6H20
(4) Chemical Incompatibilities Causing Evolution of Carbon Di oxide Gas:
When carbonates or bicarbonates are dispensed in the presence of an acid or acidic drug in a
mixture, they react together with the evolution of carbon dioxide gas. If the reaction is not
allowed to complete before transferring the mixture into a dispensing bottle and corked, there
are chances of explosion with the bursting of the bottle To prevent explosion, the reaction must
be completed before dispensing the mixture. To speed up the reaction mix the ingredients in an
open vessel and allow the reaction to complete until effervescence ceases. Hot water can also
be used to hasten the reaction.
i) Sodium bicarbonate with soluble calcium or r nesium salts: When sodium bicarbonate is
combined with soluble calcium or magne stum salts, due to double decomposition reaction,
there is formation of insoluble carbonate and carbon dioxide.
MgS04 + 2NaHC03----} Mg (HC03)2 + Na2804
4 Mg(HC03)2 ---} 3MgC03+ Mg(OH)2 + 5CO,+ 3H,OO
The reaction proceeds slowly at ordinary temperature. To accelerate the reaction, hot water
should be used. The mixture should be dispensed only when effervescence ceases
The precipitates of carbonates formed are diffusible in nature so follow method A for
precipitate yielding interaction.
(ii) Bismuth subnitrate and sodium bicarbonate
Bismuth subnitrate when combined with sodium bicarbonate in the presence of water,
carbondioxide gas is liberated due to the following reaction:
2BIONO3 + 2NaHC03---} (BIO)2C03 + 2NaNO3 + C02 + H20
The reaction proceeds slowly at ordinary temperature, hence reaction should be accelerated by
using hot water and the mixture should not be transferred to a bottle until the effervescence
ceases.
(ii) Borax with sodium bicarbonate and glycerin: When borax with glycerin are mixed together
the sodium metaborate and boric acid is formed.
Na2B407+ 3H20 ------} Na2B204+2H3B03
The boric acid so formed reacts with glycerin to form monobasic glyceryl borie acid which
liberates carbon dioxide from the bicarbonate. To hasten the reaction ingredients should be
mixed in an open vessel using hot water as vehicle.
2C3H5(OH)3 + 3H3BO3-----} (C3H5)2(HB03)3 + 6H20
The mixture should not be transferred to a bottle until effervescence ceases.
6) Miscellaneous Chemical Incompatibilities
(1) Soluble barbiturates with ammonium bromide: When soluble barbiturate is
combined with ammonium bromide in the presence of water, the barbitone is
separated as indiffusible precipitates which are insoluble in water. Hence,
follow method B for precipitate yielding interactions for dispensing the
prescription.
(ii) Potassium chlorate with oxidisable substances: When potas sium chlorate is
prescribed along with charcoal, sulphur, sugar organic compounds or any other
readily oxidisable substance, during dispensing if heating or trituration is
done there are chances of explosion. Mixing of potassium chlorate with any dry
substance is not advisable but if essential, the ingredients should be powdered
separately in a dry and clean mortar and then mixed gently with a clean powder
spatula on a clean ointment tile, without any frietion.
iii) Incompatibility of emulsifying agents: Emulsions prepared with alkali
metal, ammonium and triethanolamine soaps are incompat ible with salts
producing polyvalent cations. Due to double decomposition, a polyvalent soap
is formed which inverts the emulsion Sometimes an emulsifying agent cause
an inversion in an emulsion product.
(iv) Colour stability of dyes: The colour of the most of the dyes used in
pharmaceutical formulations are influenced by their ionization which depends
on pH of the solution The phenolphthalein dye is colourless in acid solution but
red in alkaline mixture.
(v) Incompatibilities of liquorice liquid extract: Liquorice liquid extract is used
as a flavouring agent. The flavouring property is due to glyeyrrhizin which is a
mixture of the potassium and calcium salts of glycyrrhizinic acid. Acids
decompose glycyrrhizin into glycyrrhizinic acid which is insoluble in water and
get precipitated. The precipitate clots and forms a sticky black sediment which
is difficult to diffuse.
The insoluble substances are not possessing flavouring properties and hence
liquorice liquid extract is not useful as a flavouring agent in acidic mixtures.
The prescription may be referred back to the prescriber for the change of
flavouring agent.
Certain salts like calcium chloride and magnesium sulphate cause partial
precipitation of glycyrrhizin. These precipitates remain diffus ible, hence
method A for precipitate yielding combination should be followed in order to
minimise precipitation.
(C)THERAPEUTIC INCOMPATIBILITY=
Therapeutic incompatibility may be as a result of prescribing certain drugs to a patient with
the intention to produce a specific degree of pharmacological action, but the nature or
intensity of the action pro duced is different from that intended by the prescriber. This occurs
due to the following reason8:
1. Error in dosage:
2. Wrong dose or dosage form,
3. Contra-indicated drugs;
4. Synergistic and antagonistie drugs; and
5. Drug interactions.
1. Error in dosage: Many therapeutic incompatibilities result from errors
in writing or interpreting the prescription order. The most serious type of
dosage error in the dispensing is overdose ofa medica tion. It becomes the
duty of a pharmacist to check the prescription before dispensing it.
Pharmacist is often in a position to detect such errors and help to avoid
such problems.
2. Wrong drug or dosage form: There are certain drugs which have quite
similar names and there is always a danger of dispensing the wrong drug.
For example, prednisone and prednisolone, digoxin and digitoxin.
Sometimes many drugs are available in different dosage forms and hence,
if the dosage form is not clearly mentioned on the prescription, it
becomes necessary to seek clarification from the prescriber.
3.
Contra-indicated drugs: There are certain drugs which may be
contra-indicated in a particular disease or a particular patient who is
allergic to it. For example, corticosteroids are contra-indicated in pa tients
having an active peptic uleer. The penicillin and sulpha drugs are
contra-indicated to the patients who are allergic to it. Barbiturates and
morphine should not be given to asthmatic patients.
4. Synergistic and antagonistie drugs: Many drugs exhibit synergism and
antagonism when administered in combination. When two drugs are
prescribed together, they tend to increase the activity of each other. This
is known as synergism. Synergism is usually inten tional because the
prescriber has prescribed the drugs together in order to increase the
activity of the drugs. For example, a combination of aspirin and
paracetamol increases the analgesic activity. Similarly, a combina tion of
penicillin and streptomycin increases the antibacterial activity of
antibiotics. There are certain drugs which when prescribed may lead to
disastrous consequences. The prescription should be referred back to the
prescriber for necessary correction.
5. Drug interactions: The effect of one drug is altered by the prior or
simultaneous administration of another drug. The drug interac tions can
usually be corrected by the proper adjustment of dosage if the suspected
interaction is detected.