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 adjusted incompatibility.
General Methods used to remove
incompatibilities.
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.
 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
v) By addition, substitution or omission of therapeutically inactive
sub.to help in compounding of the prescription.
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 15ml
water upto 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.

E.g Acacia,Tragacanth,SLS,etc
Example:

Rx
Phenacetin 3g
Caffeine 1g
Orange syrup 12ml
Water upto 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.

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
substances.
iii) Allowing completion of liquefaction & absorbing
the liquid using adsorbent such as substances like
kaolin.
 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 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
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 prepare
solution.
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
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 &
vitamins.
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
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 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
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.

c) Dispense reacting substances seperately

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

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
reaction.
 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
prescriber.
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
from shelves pharmacist
should be alert.
He should remove the correct
medicine.
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
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.

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
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.