PHARMACEUTICAL INCOMPATIBILITY

PHYSICAL
AND
CHEMICAL INCOMPATIBILITY
BY

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)

Allianze college of medical sciences

1
 pharmaceutical incompatibility occurs as a
result of mixing of two or more antagonistic
substances and an undesirable product is formed
which may affect the safety, efficacy and
appearance of pharmaceutical preparation.
Pharmaceutical incompatibility may occur not
only during compounding and dispensing but also
at any stage during compounding and dispensing
but also at any stage during formulation,
manufacturing, packing or administration of drugs.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 2 Allian
TYPE OF INCOMPATIBILITIES:

A) Physical incompatibility
B) Chemical incompatibility
C) Therapeutic incompatibility
K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 3 Allian
A)PHYSICAL INCOMPATIBILITY:

When two or more than two substances are

combined together, physical changes take place and
an unacceptable product is formed. These changes
which occurs as a result of physical incompatibility
are usually visible and can be easily corrected by
applying the pharmaceutical skill obtain a product of
uniform dosage, substance to help in compounding
of the prescription.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 4 Allian
An attractive incompatibilities’ may be corrected by using any one or
more of the following method.
•Change the order or mixing of the prescription
•Emulsification
•Adding of suspending agent
•Change in the form of ingredients
By adding, substitution or omission of therapeutically inactive

Examples of physical incompatibilities

vIMMISCIBILITY
vINSOLUBILITY
vPRECIPITATION
vLIQUEFACTION
K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 5 Allian
IMMISCIBILITY
Oils and water immiscible with each other.
They can be made miscible with water by
emulsification.
Example:
Castor oil 15ml
Water 60ml
Make on emulsion.
In this prescription castor oil is immiscible with
water .
To overcome this incompatibility an
emulsifying agent is used to make a good emulsion

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 6 Allian

INSOLUBILITY
Insolubility means the inability of material to dissolve in a
particular system. The major of incompatibilities are due to insolubility of
the inorganic as well as organic compounds in a particular solvent.
Example: 1
Ephedrine sulphate 0.25gm
Menthol 0.02ml
Liquid paraffin (sufficient to make) 30ml
The ephedrine sulphate is an alkaloidal salt and is not soluble in
liquid paraffin, but anhydrous ephedrine is soluble in it. Hence ephedrine
sulphate is substituted with anhydrous ephedrine to make a clear
solution.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 7 Allian

Example: 2
Phenacetin 3g
Caffeine 1g
Orange syrup 12 ml
Water up to 90ml
In this prescription Phenacetin is an
indiffusible substance. Compound powder of
tragacanth or mucilage of tragacanth is used as a
suspending agent to make a suitable suspension

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 8 Allian

PRECIPITATION
A drug in solution may be precipitated, if the solvent
in which it is insoluble is added to the solution.
Example:
The resins are insoluble in water. When the
tincture containing resins is added in water, resin
agglomerates forming indiffusible precipitates.

This can be prevented by slowly adding the

undiluted tincture with vigorous stirring to the diluted
suspension
Or
By adding some suitable thickening agent

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 9 Allian

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 temperature and liberation of water of hydration.
Many chemicals form hydrates, compounds with water of
hydration.
The medicaments showing this type of behavior are
camphor, menthol, thymol, phenol, chloral hydrate and aspirin.
This type of substance create problem when they are dispensed
in powder form.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)10 Allian

 Example:
Menthol 5g
Camphor 5g
Ammonium chloride 30g
Light magnesium carbonate 60g
In this prescription menthol, camphor and
ammonia chloride get liquefied on mixing with each
other. To dispense this prescription, menthol
camphor and ammonium chloride are triturated
together to form liquid. Add light magnesium
carbonate and mix it thoroughly to make free
flowing powder.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)11 Allian
CHEMICAL INCOMPATIBILITY

Chemical incompatibility may be as a result of

chemical interactions between the ingredients of a
prescription and a toxic or inactive product may be formed.

Chemical incompatibilities often occur due to

oxidation –reduction. Acid base hydrolysis or combination
reaction. These reactions may be noticed by precipitation
effervescences, decomposition, colour change or by
explosion.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)12 Allian
CHEMICAL INCOMPATIBILITY IS TWO TYPES:
1) Tolerated:
In tolerated incompatibilities. The chemical interaction can be
minimized 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.

Example:

Caffeine citrate can be substituted with caffeine in sodium

salicylate and caffeine citrate mixture.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)13 Allian

CHEMICAL INCOMPATIBILITY MAY BE:

INTENTIONAL:
When the prescriber knowingly prescribes the
incompatibility drugs.
UNINTENTIONAL:
When the prescriber prescribes the drugs
without knowing that there is incompatibility
between the prescribed drugs.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)14 Allian

PRECIPITATE YIELDING INTERACTIONS
The precipitate form through the chemical incompatibility
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.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)15 Allian
METHOD (B)

The method is followed when indiffusible precipitates are formed

in large quantity. Divide the vehicle into two portions. Dissolve one of the
reacting substances in one portion. Weigh a suitable quantity of
compound tragacanth powder (2g per 100 ml of finished product) and
transfer in a mortar and use part of second portion of vehicle to produce
smooth mucilage. Then add other reacting substances. 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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)16 Allian

1.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, solution of
ammonia. Ammonium bicarbonate, the free
alkaloid may be precipitated.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)17 Allian
Example:
Strychnine hydrochloride solution 6 ml
Aromatic spirit of ammonia 4 ml
Water make up to 1200 ml
Strychnine hydrochloride is an alkaloidal salt were as aromatic
spirit of ammonia is an alkaline substance. When they react together,
the strychnine get precipitated because the quantity of strychnine
hydrochloride prescribed in the prescription is much more than its
solubility in water (1 in 7000). The aromatic spirit of ammonia contains
negligible amount of alcohol which can nor dissolves the strychnine.
Hence it gets precipitated as diffusible precipitates. Hence it gets
precipitated as diffusible precipitates. Hence follow method A for
precipitate yielding combination.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)18 Allian
2. SOLUBLE SALICYLATE
INCOMPATIBILITIES:
Soluble salicylate with ferric salt:
Ferric salt reacts with sodium salicylate
to liberate indiffusible precipitates of ferric
salicylate therefore follow method B for
precipitate yielding interactions.
Example:
Ferric chloride solution 2ml
Sodium salicylate 3g
Water make up to 90 ml

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)19 Allian

3. SOLUBLE IODIDES INCOMPATIBILITIES:
Iodides undergo oxidation forming iodine
which is an undesirable product. Hence, following
steps may be taken to avoid this chemical change.
Example:

Oxidation of iodides with potassium chlorate:

When soluble iodides react with potassium
chloride, free iodine is liberated.
KCIO3 + 3FeI2 3FeOI +3I+KCI
To prevent the incompatibility, the two
reacting substances must be dispensed
separately.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)20 Allian
4. CHEMICAL INCOMPATIBILITY CAUSING EVALUTION
OF CARBONDIOXIDE GAS.

Bismuth sub nitrate when combined with sodium

bicarbonate when combined with sodium bicarbonate in the
presence of water, carbon dioxide gas is liberated due to the
following reaction.

2BiONO3 +2NaHCO3  (BiO) 2 CO3 + 2NaNO3 +CO2 +H2O

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)21 Allian

5.INCOMPATIBILITY OF EMULSIFYING AGENTS:
Emulsion prepared with alkali metal, ammonia and
triethanoamine soaps are incompatible with salts producing
polyvalent cations. Due to double decomposition, a
polyvalent soap is formed which inverts the emulsion.
6.COLOUR STABILITY OF DYES:
The colour of the most of the dyes used in
pharmaceutical formulation is influenced by their ionization
which depends on PH of the solution.
The phenolphthalein dye is colorless in acid solution but
red in alkaline mixture.
K.SAMINATHAN. M.pharm, M.B.A,( P.hD)22 Allian
THANK
YOU

K.SAMINATHAN. M.pharm, M.B.A,( P.hD)23 Allian