Definition of Incompatibility:
Incompatibility occurs as a result of
mixing of two or more “Antagonistic Substances” & an undesirable
product is formed which may affect the safety, efficacy & appearance
of the pharmaceutical preparation.
Types of Incompatibility:
Physicochemical Incompatibility
A) Physical incompatibility
B) Chemical incompatibility
Therapeutic incompatibility
Physicochemical Incompatibilty
If mixing two or more drugs or a drug &
excipients, by particular method, results in a
physicochemical change in the properties of drug
or dosage form, or production of a new chemical
substance having different pharmacological
action, it is called as physicochemical
If incompatibility is prevented by addition,
substitution or elimination of one or more
ingredient is called as adjusted incompatibility.
General Methods used to remove
1.Modify the order of mixing
2.Dispense with labels like Shake well before use
3.Recommend storage condition.
4.Add physical stabilizer. (Suspending or
emulsifying agent)
5.Add chemical stabilizer. (Antioxidant/Buffer)
6.Add preservative.
7.Select soluble , compatible or stable form of
dosage form.
 When two or more than two substances combined together a
physical change takes place & unacceptable product is formed.
Physical changes involves such as Immiscibility, Insolubility,
Precipitation formation or liquefaction of solid materials.
 The physical incompatibilities may be corrected by using any one or
more of the following methods:
Change the order of mixing of ingredients of the prescription.
Addition of suspending agent
Change in the form of ingredients
By addition, substitution or omission of therapeutically inactive help in compounding of the prescription.
Example of Physical Incompatibility & Their Methods
of Correction:
Oils & Water are immiscible with each other.
They can be made miscible with water by emulsification.
Castor oil
Make an emulsion.
To overcome this incompatibility an emulsifying agent is used to
make a good emulsion.
2. Insolubility:
It means the inability of material to dissolve in a particular solvent
The liquid preparations containing Indiffusible solids such as chalk,
aromatic chalk powder, acetyl salicylic acid, phenacetin, zinc oxide &
calamine etc.
 Suspending agent
- Increase the thickness of the preparation.
-Uniform distribution of the insoluble substances which
facilitating uniform measurement of each dose.
E.g Acacia,Tragacanth,SLS,etc
Orange syrup
Make a mixture.
In this prescription phenacetin is an indiffusible sub.
Compound powder of tragacanth or mucilage of tragacanth is used as
a suspending agent to make a stable suspension.
3. Settling Suspending agent
solids(Suspension), during storage settles at the bottom.
Insoluble solids are of two types.
Diffusible Solids – Kaolin & light magnesium
carbonate remains evenly distributed.
Indiffusible solids – Chalk , Calamine --- Has to
increase viscosity of vehicles by adding
suspending agent like gum tragacanth.
4. Poor Wettability Levigating agent
Some drugs are poorly wetted with given
vehicle hence these may float or sink at
the bottom of vehicle. Hence levigation of
these solids with wetting agent such as
glycerine, propylene glycol, or hydrophilic
surfactant helps in the uniform
distribution of hydrophobic drug in water.
Eg. Sulphur lotion.
5. Precipitation:
A drug in solution may be precipitated , if the solvent in
which it is insoluble is added to the solution e.g. resins are
insoluble in water.
Volatile oils are soluble in alcohol. When water is added
into the alcoholic solution of volatile oil, the non aromatic
portion of the oil get precipitated & turbidity appears.
 Cap – locking  Co-solvents
Liquid preparations especially those containing syrups may
show crystallization of sugar in the closure , resulting in cap
locking. It can be minimized by adding co-solvents like
glycerine, propylene glycol or sorbitol
6. Grainy Semisolids  Non uniform cooling
Partial solidification of higher melting point
waxes may occur when cool spatula is used
for mixing or when a hot product is poured in
a cool container.
Grains are also developed during preparation
of creams, if the aqueous phase & oil phase
do not have same temperatures at the time
of mixing. This can be prevented by avoiding
localized cooling.
7. Liquefaction:
Eutectic mixture
 If 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 the room temp. & liberation of water of hydration.
 e.g camphor, menthol, thymol.
Liquefication can be corrected by
i) Dispensing individual ingredient separately
ii) Compounding powder using diluents such as
lactose, magnesium oxide or magnesium
hydroxide are separately mixed with eutectic
substances and such mixtures are mixed to
produce final product.
This prevents physical contact of liquifiable
iii) Allowing completion of liquefaction & absorbing
the liquid using adsorbent such as substances like
It may be as a result of chemical interactions between the
ingredients of a prescription & a toxic or inactive product may be
 It is due to oxidation-reduction, acid base hydrolysis or combination
These reactions may be noticed by effervescence, decomposition,
colour change .
Chemical incompatibilities
are of following types.
1. Precipitation:
•Precipitation of the drug takes place due to -
i. pH change
ii. A chemical reaction between drug-drug or
•When the ppt product is therapeutically active it is
formulated as per the procedure used to prepare
mixtures containing diffusible & indiffusible solid.
•If the resultant ppt is inactive or toxic the formulation
should be rejected.
a)pH Change:
• Most of the medicines are often salts of weak acids
& weak bases.
• The unionized forms are insoluble in water &
ionisable salts are soluble in water.
• A pH change, not only changes solubility, but it also
changes rate of degradation.
• If the resultant precipitate has therapeutic value &
it is chemical stable, one can tolerate the
• A suitable co-solvent can be used to increase
solubility, otherwise a suspension is formulated.
• Eg. Morphine hydrochloride above 2.5 %
concentration , is insoluble & results in the
formation of diffusible precipitate under
alkaline condition.
• The solubility of precipitated morphine in
alcohol is 1 in 100.
• Thus incompatibility can be treated either by –
i) Preparing suspension of diffusible precipitate
Ii) Using alcohol as co-solvent to prepare
Eg. 2 )
Caffeine citrate above 2.2 %
concentration, under alkaline condition
produces indiffusible precipitate but
when alcohol is used, it tolerates a
higher concentration of caffeine citrate
without precipitation.
b) Precipitation by chemical reaction:
i) Drug-drug interactions:
Eg. Caffeine Citrate
• Active ingredients react with other drugs or additives yielding
diffusible or indiffusible precipitate.
• Caffeine citrate is a mixture of equal weight of caffeine & citric
• The citric acid reacts with sodium salicylate to liberate
salicylic acid in the form of precipitate.
• It causes gastric irritation.
• Hence only caffeine is used, it forms a soluble complexes with
sodium salicylate.
• Therefore, caffeine citrate should be replaced with half the
amount of caffeine to get clear solution.
Flavour• Liquorice looses its flavour due to
precipitation in presence of acid.
• Acid reacts with glycyrrhizin, a
flavouring constituent of liquorice
forming glycyrrhizic acid precipitate.
2.Redox reaction:
Some drugs or their dosage forms undergo
oxidation when exposed to air, excessive
temperature & due to over dilution of liquids,
incorrect pH or presence of catalyst.
The common catalyst includes metal ions,
enzymes & bacteria.
The drug in the liquid state is more sensitive to
oxidation than insoluble state .
a) Auto oxidation of oils, fats,
phenolic substances, aldehydes &
•This can be prevented by addition
of primary antioxidants such as
alpha tocopherol, or BHT.
b) Paraaldehyde, tannins, epinephrine,
sulphacetamide & related compounds
undergo oxidation activated by heat.
•Hence for such drugs requires against trace metal
•This can be achieved by adding antioxidants such as
ascorbic acid, sodium metabisulfite or complexing
agents like EDTA are used to control oxidation.
c) Preparations containing riboflavin, folic acid &
ascorbic acid show incompatibility. Riboflavin is light
sensitive, and easily degraded by heat and light. Hence
should be stored at its stable pH 6 to 6.5.
D) When dry powders contains both
oxidising & reducing agents, the mixture may
•The inter-particulate friction developed
during mixing increases chances of redox
•Therefore such reacting substances should
be dispensed separately or powders should
be mixed lightly by spatulation method.
3. Hydrolysis
•Hydrolysis can be controlled by avoiding moisture contact or by
changing pH.
•Aspirin is more sensitive to water & gets converted to more irritant
acetyl salicylic acid. Hence it is granulared without use of water.
•Paracetamol is stable between ph 5 & 7 .
•While ibuprofen shows more solubility above pH 6.
Therefore compound suspension of these two drugs in
combination pH of solution is 5-6.
4. Racemisation
The conversion of an optically active
form to an optically inactive form
without changing chemical constitution
usually results in reduced therapeutic
5. Effervescence :
Two or more ingredients of formulation reacts to generate
To overcome such reactions either a) Mix the reacting ingredients in open container & allow
to complete reaction before
filling in to container. The rate of reaction can be
increased by using hot water.
b) Change the one or more reacting ingredients.
c) Dispense reacting substances seperately
6. Colour change
incompatibility. When the colour reaction
is rapid it is allowed to complete before
The delayed color change in formulation
creates confusion in the mind of patient.
Sodium Salicylate mixture BPC
During storage
the alkaline solution
undergoes oxidation by atmospheric oxygen
& becomes brownish black.
The coloured product is safe and has
therapeutic value but it may create
confusion in the mind of patient
metabisulphite is added as antioxidant to
control oxidation.
7. Incompatibilty with containers:
The product filled in a container may react
chemically with the container or get absorbed
by the container or the closure.
i) Glass containers alkali leaching.
ii) Rubber closures may adsorb preservatives.
iii) Metal containers catalyse rate of chemical
It is result of prescribing certain
drugs to a patient with the intention
to produce a specific degree of
p’cological action, but nature or
intensity of the action produced is
different from that intended by the
Therapeutic incompatibility is due to :
A) Medication errors
B) Drug interactions
A) Medication Errors:
Medication errors done by doctors, pharmacists, nurses & patients.
Medication errors can be categorized as –
1. Prescription errors
2. Dispensing errors
3. Selection errors
4. Bagging errors
5. Administration errors
1. Errors in prescription writing
The prescription should be neatly & correctly written
by the medical practitioner, otherwise it is major
hassle for the pharmacists.
-Spelling mistakes.
- Illegible handwriting.
a) SALA Medicines(Sound Alike Look Alike):
Tab. Dulcolax a laxative tablet & Tab . Duoclox an antibacterial tablet.
b) Type of dosage form:
Same drug can be available in tablet, capsule or liquid oral
dosage forms for adults, drops for pediatric patients.
Selection of dosage form is based on ability of patients to
take that medicines.
C) Strength of Medicines :
Some medicines, especially those whose
dosing is critical , are available in different
strengths. Eg. Haloperidol , antipsychotic
drug available in the form of tablets of
various strength viz. 0.25, 2mg, 5mg,10mg,
20 mg.
d) Quantity to be dispensed:
Pharmacists should check the dose & see
that the quantity of medicine is sufficient
to complete a course.
e) Dose & Direction:
Pharmacists should check the
dose, dosage regimen & direction
to use.
2. Dispensing Errors:
a)Poor handwriting
b)Long prescription
c)Incomplete patient information
d)Deviation in attention of pharmacist
e)Misunderstanding of verbal orders.
3. Selection of medicine
•While removing medicines
should be alert.
•He should remove the correct
•SALA medicines should not be
kept adjacent to one another.
4. Bagging Errors:
After billing, dosage forms should
be packed in appropriate bags or
covers & handed over to the right
5. Errors in administration
i) Breaking the coated or sustained
release tablets.
ii)Suspension administration without
iii)Taking medicament at wrong time
before or after meal.
B) Drug interactions
1. Contra – indicated drugs:
There are certain drugs which may be contraindicated in a
particular disease or a particular patient who is allergic to it.
Example: the penicillin & sulpha drugs are contraindicated
to the patients who are allergic to it.
2.Synergistic & antagonistic drugs:
Many drugs exhibit Synergism & Antagonism when
administered in combination.
When the two drugs are prescribed together, they tend to
increase the activity of each other, called as synergism.
Example: A combination of aspirin & paracetamol
increase the analgesic activity.
When two drugs having the opposing p’cological effects
are called antagonism.
Example: Acetyl salicylic acid and probenecid
c)Unintentional drug interaction
The effect of one drug is altered by the prior
or simultaneous administration of another
Tetracycline hydrochloride
Direction –take one capsule with milk
Tetracycline inactive by calcium which is
present in milk.
d) Intentional drug interaction
Acetyl salicylic acid
Send 10 capsules.
Acetophenetidin & acetyl salicylic acid are analgesic.
Acetophenetidin depresses the CNS & this effect is
Caffeine is CNS stimulant to neutralise the side effect of

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