INCOMPATIBILITIES IN PRESCRIPTION

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 incompatibility.
If incompatibility is prevented by
addition, substitution or elimination of
one or more ingredient is called as

General Methods used

remove incompatibilities.

to

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

A] PHYSICAL INCOMPATIBILITY
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:
i) Change the order of mixing of ingredients of the
prescription.
ii) Emulsification
iii) Addition of suspending agent
iv) Change in the form of ingredients

Example of Physical Incompatibility &

Their Methods of Correction:
1.Immiscibility:

Oils & Water are immiscible

with each other. They can be made miscible with
water by emulsification.

Example:
Rx
Castor oil
water

upto

15ml
60ml

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 system.
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.

Example:
Rx
Phenacetin
Caffeine
Orange syrup
Water
upto

3g
1g
12ml
90ml

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
The drug in mixtures containing insoluble
solids(Suspension), during storage settles at the
bottom.

Insoluble solids are of two

types.
Diffusible Solids Kaolin & light
magnesium carbonate remains
evenly distributed.

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

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

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

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

B] CHEMICAL INCOMPATIBILITY
DEFINITION:
It may be as a result of chemical
interactions between the ingredients of a
prescription & a toxic or inactive product may be
formed.
It is due to oxidation-reduction, acid base
hydrolysis or combination reactions.
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
drug-additives.
When the ppt product is therapeutically
active it is formulated as per the procedure

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 incompatility.
) 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

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
acid.
) 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

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

a) Auto oxidation of oils, fats,

phenolic
substances,
aldehydes & vitamins.
This can be prevented by
addition
of
primary
antioxidants such as alpha
tocopherol, or BHT.
b) Paraaldehyde, tannins,
epinephrine, sulphacetamide &

Hence for such drugs requires against trace

metal ions.
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 explode.
The
inter-particulate
friction
developed during mixing increases
chances of redox reaction.
Therefore such reacting substances
should be dispensed separately or
powders should be mixed lightly by

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
activity.

5. Effervescence :
Two or more ingredients of formulation reacts
to generate CO2,
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.

6. Colour change
The colour change is visible
incompatibility. When the colour
reaction is rapid it is allowed to
complete before dispensing.
The delayed color change in
formulation creates confusion in
the mind of patient.

Eg.
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
Hence

anti-oxidant

like

sodium

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

THERAPEUTIC INCOMPATIBILITY

It is result of prescribing
certain drugs to a patient
with
the
intention
to
produce a specific degree of
pcological
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

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

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

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 from shelves
pharmacist should be
alert.
He should remove the
correct medicine.
SALA medicines should

4. Bagging Errors:

After billing, dosage forms

should
be
packed
in
appropriate bags or covers
& handed over to the right
person.

5. Errors in
administration
i)Breaking the coated or
sustained release tablets.
ii)Suspension administration
without shaking.
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
pcological effects are called antagonism.

 c)Unintentional drug interaction

The effect of one drug is altered by
the prior or simultaneous
administration of another drug.
Tetracycline hydrochloride
250mg
Direction take one capsule with milk
Tetracycline inactive by calcium
which is present in milk.

d) Intentional drug interaction

Rx
Acetophenetidin
150mg
Acetyl salicylic acid
200mg
Caffeine
30mg
Send 10 capsules.
Acetophenetidin & acetyl salicylic acid are
analgesic.
Acetophenetidin depresses the CNS & this
effect is undesirable.
Caffeine is CNS stimulant to neutralise the
side effect of acetophenetidin.