Pharmaceutical Incompatibility

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.

It is defined as when two or

more ingredients of a prescription are mixed together ,
the undesired changes that may takes place in the
physical, chemical or therapeutic properties of the
medicament is termed as incompatibility.”
Incompatibilities occur during:-
Compounding
 Formulation

 Manufacturing

 Packaging

 Dispensing

 Storage

 Administration of drugs

 The incompatibilities may be detected by

changes in the physical, chemical, and

therapeutic qualities of the medicine.
TYPES OF INCOMPATIBILITIES:-
Physicochemical Incompatibility
A) Physical incompatibility
B) Chemical incompatibility
c)Therapeutic incompatibility

Physical incompatibilities

Chemical incompatibilities

Therapeutic
incompatibilities
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.
 PHYSICAL INCOMPATIBILITY
➢When two or more than two substances combined
together a physical change takes place & unacceptable
product is formed.

➢ Interaction between two or more substances which may

lead to change in color, odor, taste, viscosity and
morphology. It is also called as pharmaceutical
incompatibility.

➢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 substance 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
Castor oil 15ml
water upto 60ml Water

Make an emulsion.

To overcome this incompatibility an emulsifying agent is used to

make a good emulsion.
 Causes: -In this prescription castor oil is immiscible
with water due to high interfacial tensions, which is a
sign of incompatibility.

 Remedy:-To overcome this type of incompatibility

emulsification is necessary with the help of an
emulsifying agent.

 The corrected prescription is

 Castor oil emulsion

Rx
 Castor oil – 15ml
 Acacia – 2% W/V
 Water– upto 60ml
2. Insolubility:
➢ It means the inability of material to dissolve in a particular solvent
system.
➢ The majority of incompatibilities is due to insolubility of the
inorganic as well as organic compounds in particular solvents.

➢ The liquid preparations containing Indiffusible solids such as chalk,

aromatic chalk powder, acetyl salicylic acid, 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 substance.

Compound powder of tragacanth or mucilage of tragacanth is used as

a suspending agent to make a stable suspension.
3. Precipitation:
➢ A drug in solution may be precipitated , if the solvent in
which it is insoluble is added to the solution .It occurs due
to solvent is insoluble when it is added to solution.

➢ e.g. resins are insoluble in water. Alcoholic solution of resins

+ water =precipitated resins.

➢ 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.
E.g.:- Lotion of compound tincture of benzoin
Rx
Tincture benzoin compound – 5g
Glycerin – 10ml
Rose water upto 100ml

Causes: - Tincture benzoin compound contain resins.This

change in solvent system results in an unavoidable
precipitate.

Remedy: - Addition of tincture with rapid stirring yields a fine

colloidal dispersion. So there is no need of any suspending
4. 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.

Causes: - This mixture is a physical incompatibility because
both the ingredients in the prescription are liquefiable of mixed
together.
 Remedy:-These substances can be dispensed by any one
of the following method.
 Triturate together to form liquid and mixed with an

absorbent (light kaolin, magnesium carbonate) to

produce the following powder.
 The individual medicaments is powdered separately and
mixed with an adsorbent and then combined together tightly
and filled in a suitable container.
 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.
 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.

➢ Chemical incompatibility is the reaction between two or more

substances which lead to change in chemical properties of
pharmaceutical dosage form.

➢ It is due to oxidation-reduction, acid base hydrolysis or combination

reactions.

➢ These reactions may be noticed by effervescence, decomposition,

colour change .
 Occurrence:-

 Chemical incompatibilities These reactions may be

noticed by
occur, due to the chemical
properties of drugs and  Precipitation

additive like,  Effervescence

 PH change
 Decomposition
 Oxidation-reduction reactions
 Acid-base hydrolysis  Color change
CHEMICAL INCOMPATIBILITIES : TYPES

 Based on chemical interactions

 Tolerated incompatibility: - In this type

incompatibility, the chemical interactions can be
changing the order of mixing the solutions in dilute
forms, without or by changing the order of mixing.

 Adjusted incompatibilities: - In adjusted

incompatibility change in the formulation is needed
with a compound having equal therapeutic value.
 CHEMICAL INCOMPATIBILITIES : TYPES

 Based on the prescriber

 Intentional:- When the prescriber knowingly prescribes
the incompatible drugs.

 Unidirectional:- When the prescriber prescribes the

drugs without knowing that there is incompatibility
between the prescribed drugs.
CHEMICAL INCOMPATIBILITIES : TYPES

 Precipitate yielding interactions

 The precipitates so formed may be diffusible or
indiffusible. The method A or B is followed in
dispensing the prescription yielding diffusible and
indiffusible precipitates respectively.
 Method A:
 This method is suitable for diffusible precipitates
following steps are carried out.
 Divide the vehicle into two portions.
 Dissolve the reactants in separate portions and mix
the two portions by slowly by adding one into other
with rapid strring.
CHEMICAL INCOMPATIBILITIES : TYPES

 Method B:
 This method is suitable for in diffusible precipitates following
steps are carried out.
 Divide the vehicle into two equal portions.
 Dissolve the one of the reacting substance in one portion.
 Place second portion of vehicle in mortar and incorporate
suitable amount of Tragacanth powder (2g/100ml of
preparation) with constant trituration until a smooth mucilage is
produced.
 Add other reacting substance to the mucilage.
 Add the solution of first reactant to the mucilage slowly with
constant 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

 Alkaloid incompatibility:-
 1. Alkaloidal salts with alkaloid substances
 2. Alkaloidal salts with soluble iodides
 3. Alkaloidal salts with tannins
 4. Alkaloid salts with salicylates
 5. Alkaloid with soluble iodides and bromides.

 Soluble salicylates incompatibility:-

 1.Soluble salicylates with ferric salts
 2.Soluble salicylates with alkali bicarbonates

 Soluble iodides incompatibility:-

 1.Oxidation of iodides with potassium chlorate
 2.Oxidation of iodides with quinine sulphate.
E.g-2.:Quinine hydrochloride mixture
Rx
Quinine hydrochloride -0.12g
Sodium salicylate -4g
Water -100ml
Causes: - When quinine hydrochloride combined
with the sodium salicylates it forms quinine
salicylates which is an in diffusible precipitate.
Remedy: - Hence follow method B for precipitate
yielding interactions.
 THERAPEUTIC INCOMPATIBILITY

Therapeutic incompatibility may be a result of prescribing certain

drugs to a patient with the intention to produce a specific degree
of pharmacological action but nature or intensity of the action
produced is different from that intended by the prescriber.

 Therapeutic incompatibilities occurs due to following

reasons
 a. Error in dosage
 b. Wrong dose or dosage form
 c. Contra-indicated drugs
 d. Synergistic and antagonistic drugs
 e. Drug interactions
ERROR IN DOSAGE
Many therapeutic incompatibilities result from errors in writing or
interpreting the prescription order.
The most serious type of the dosage error in the dispensing is
overdose of a medication.

E.g., Atropine sulphate capsules

Rx
Atropine sulphate - 0.006g
Phenobarbitone - 0.015g
Aspirin - 0.300g

Causes:- In this prescription, the quantity of the atropine

sulphate in each capsule is more than its recommended dose.
Remedy:- The prescription is referred back to the prescriber to
correct the overdose of the atropine sulphate.
The recommended dose of atropine for a single capsule is 0.25
to 2mg.
WRONFG DOSE OR DOSAGE FORM
There are certain drugs which have quite similar names
and there is always a danger of dispensing the wrong
drug.

E.g., Prednisone and Prednisolone

Digoxin and Dig toxin

Some times many drugs are available in the 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.
The responsibility of the pharmacist becomes to check the
prescription intensively and if he finds these types of
errors he should immediately consult the prescriber for the
clarification.
 PRESCRIBING 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.

 Corticosteroids are contra-indicated in the patients

having peptic ulcers.
 The penicillin and sulphur drugs are contra-
indicated in the patients who are allergic.
 Vasoconstrictors are contra-indicated in
hypertensive patients.
 Barbiturates and morphine should not be given to the
asthmatic patients.
  E.g., Sulphadiazine capsules



 Causes:-Ammonium chloride is a urinary acidifier.

It causes the deposition of the Sulphonamide
crystals in the kidney.

 Remedy: - Before prescribing such substances a doctor

must be careful.


 Such must Immediately be referred back to the

concerned doctor and get corrected.
PRESCRIBING SYNERGISTIC OR ANTAGONISTIC DRUGS

 When two drugs are prescribed together, they tend to

increase the activity of each other which is known as
SYNERGISM.
 When two drugs are prescribed together, they tend to
decrease the activity of each other which is known as
ANTAGONISM.
 E.g.,
 A combination of aspirin and paracetamol
increases the analgesic activity.Prescribe the
drug intentionally for the synergism action of the
drug.

 A combination of penicillin and streptomycin

increases the antibacterial activity.
PRESCRIBING SYNERGISTIC OR ANTAGONISTIC DRUGS

Rx
Acetyl Salicylic acid 0.6g
Probenecid 0.5g

 Causes:-In this prescription, Acetyl Salicylic acid

and Probenecid are use in the treatment of
gout.combination of these two leads to
neutralisation.

 Remedy:- The prescription is referred back to the

prescriber for necessary corrections.
DRUG INTERACTIONS
 The effect of one drug is altered by the prior or
simultaneous administration of another drug. The
drug interaction can usually be corrected by the
proper adjustment of dosage if the suspected
interaction is detected.
 E.g., Tetracycline capsule - 250mg capsules
 Direction: Take one capsule every 6 hours with milk.
 Causes:-Tetracycline is inactivated by calcium
present in milk.
 So, it should not be taken with milk.
 Remedy: In this prescription, the
therapeutic incompatibility is unintentional.
 So, the prescription is referred back to the prescriber
to change the direction
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