INCOMPATABILITY

Drug Incompatibility:
Drug Incompatibility refers to interactions between two or more substances which lead to changes in
chemical, physical, therapeutic properties of the pharmaceutical dosage form.

Types of Drug Incompatibility

1. Physical incompatibility
2. Chemical incompatibility
3. Therapeutic incompatibility

1. Physical incompatibility
Physical incompatibilities are often called pharmaceutical incompatibilities.
It is defined as interaction between two or more substances which lead to change in color, odor, taste,
viscosity and appearance.

Manifestations of physical incompatibility:

The following list outlines the various ways incompatibility between or among drug agents may be
manifested.
1) Insolubility of prescribed agent in vehicle
2) Immiscibility of two or more liquids
3) Precipitation formation
4) Liquefaction of solids mixed in a dry state

1) Insolubility:

This means inability of material to dissolve in the prescribed vehicle.

 If the drug is indiffusible in nature like chalk, acetylsalicylic acid, zinc oxide and calamine, a
suspending agent needs to be added. This leads to increase in thickness of preparation and helps to
maintain the uniform distribution of insoluble drug for sufficiently long time after shaking the bottle
and facilitating uniform measurement of each dose.

Example:
Rx
Phenacetin 3g
Caffeine 1g
Orange syrup 12ml
Water to make 90ml
Make a mixture
In this prescription, phenacetin is an indiffusible substance. Compound powder of tragacanth is
added as a suspending agent to make a stable suspension.

 Drugs such as sulphur, antibiotics etc are insoluble in water and difficult to wet with water. Wetting
agents like surfactants are added to distribute these insoluble drugs in water.

2) Immiscibility of two or more liquids

Oils and water are immiscible with each other.
This manifestation appears clearly in emulsion, creams, and some types of ointments.
Separation in two phases is noticed in these pharmaceutical dosage forms.
To stabilize these dosage forms suitable emulsifying agents are added.
 Example
Rx
Castor oil 15ml
Water to make 60ml
Make an emulsion.
In this prescription castor oil is immiscible with water. To make a stable emulsion gum acacia is added
as emulsifying agent.

3) Precipitation:
A drug in solution may be precipitated, if a solvent in which the drug is insoluble is added to its
solution.
E.g. Resins are insoluble in water. When a tincture containing resinous matter is added in water, the
resin agglomerates and forms indiffusible precipitates.
This can be prevented slowly adding the undiluted tincture with vigorous stirring to the diluted
suspension or adding a suitable thickening agent.

Volatile oils are soluble in alcohol. When water is added into alcoholic solution of volatile oil, the
non aromatic portion of oil gets precipitated and turbidity appears.

Example
Rx
Tincture benzoin compound 5ml
Glycerin 15ml
Rose water to make 100ml
Tincture benzoin compound contains resins. The change in solvent system results in unavoidable
precipitate. Addition of tincture with rapid stirring yields a fine colloidal dispersion. So there is no
need of suspending agent.

4) Liquefaction of solids mixed in a dry state

It means that when two solid substances are mixed together, conversion to a liquid state take place.
It happens through the following methods:
1) Formation of liquid mixture: when two solid substances are mixed they reduce melting point of
each other to below room temperature and a liquid or soft mass is produced and the mixture is
called as ‘eutectic mixtures’.
2) Exit of crystalline water: By mixing hydrated crystals and dry crystals, crystalline water gets
liberated out and a liquid or soft mass is produced.

These types of mixtures create problems when dispensed in powder form. These mixtures are
dispensed in any of the following methods:
i. Triturate both solids to form liquid and mix with an absorbent like light kaolin or light
magnesium carbonate to produce a free flowing powder.
ii. The individual medicament is powdered separately and mixed with an adsorbent an then
combiner together lightly and filled in a container.
Rx
Menthol 5g
Camphor 5g
Ammonium Chloride 30g
Light Magnesium Carbonate 60g
Make an insufflation.
In this prescription, menthol, camphor and ammonium chloride get liquefied on mixing with each
other. To dispense this preparation menthol, camphor and ammonium chloride are triturated together
to form a liquid. Add light magnesium carbonate and mix it thoroughly to make a free flowing
powder.
 2. Therapeutic incompatibility
It is the modification of the therapeutic effect of one drug by the prior or concomitant administration of
another. (It is also called drug interactions)

Mechanisms of therapeutic incompatibility

They are divided into two groups:
1) Pharmacokinetics:
It involves the effect of one drug on another from the point of view of its absorption, distribution ,
metabolism and excretion.
2) Pharmacodynamics
These incompatibilities are related to the pharmacological activity of the interacting drugs e.g synergism,
antagonism, altered cellular transport, effect on the receptor site.
3) Errors in Prescription

1) Pharmacokinetics interactions:
a) Altered GIT absorption because of altered pH, or altered bacterial flora, or formation of drug
chelates or complexes, or drug induced mucosal damage and altered GIT motility.
A few examples are mentioned below:
Altered GIT absorption because of altered pH:
The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized
form does.
Therefore, Antacids when given with acidic drugs like Ketoconazole lead to decrease in the table dissolution
of ketokonazole due to increase in gastric pH caused by Antacids.

b) Altered intestinal bacterial flora

EX., in 10% 0f patients receive digoxin…..40% or more of the administered dose is metabolized by the
intestinal flora.

c) Complexation or chelation:
Therefore tetracyclines should not be advised to be administered with milk and should not be prescribed
along with iron supplements

d) Altered metabolism

The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., WBC, skin, lung, and GIT.
i. Enzyme induction:
A drug may induce the enzyme that is responsible for the metabolism of another drug. For example-
Phenytoin increases hepatic metabolism of theophylline leading to decrease its level and reduces its action.
Therefore higher doses of theophylline lmay be needed in presence of Phenytoin.
ii. Enzyme inhibition
It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the
concentration of the target drug and leading to the increase of its toxicity.
For example- Erythromycin inhibits metabolism of astemazole and terfenadine, Increase the serum
concentration of the antihistaminic agents leading to increasing the life threatening cardio toxicity.

3. Pharmacodynamic interactions
It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.
a) Additive effect-occurs when two or more drugs having the same effects are combined and the result
is the sum of the individual effects relative to the doses used. This additive effect may be beneficial
or harmful to the client.
b) Synergistic effect- occurs when two or more drugs, with or without the same effect, are used
together to yield a combined effect that has an outcome greater than the sum of the single drugs
alone.

 Such combinations should be in reduced amount.

o For example: A combination of aspirin and paracetamol increases the analgesic activity and
therefore the doses of both are reduced when prescribed in combination.
 The synergistic action will sometimes be desired to decrease toxicity or reduce cost of prescription
Examples
 Combinations of sulfonamides show less nephrotoxicity than a single sulfonamide.
 Neomycin – erythromycin combination has a broader spectrum than either antibiotic
alone.
c) Antagonistic-reactions have the opposite effect of synergism and result in a combined effect that is
less than either active component alone.
When two or more drugs having opposite pharmacological action are prescribed together, their actions
cancel each other and the resulting prescription will have no therapeutic action.
 Stimulants with sedatives (hypnotics) e.g. caffeine with chloral hydrate.
 Purgatives with antidiarrheals e.g. MgSo4 with tannins
 Acidifiers with alkalinizers e.g. aspirin with Al(OH)3
E.g. Of useful antagonism
Intentional Therapeutic incompatibilities using antagonism
At times physician may prescribe incompatible drugs together intentionally
Examples:
 Central nervous system stimulants may be used to overcome the drowsiness produced by anti-
histaminic.
 A mild laxative antacid such as Mg(OH)2 may be used to overcome the constipating effect of an
astringent antacid such as Al(OH)3.
 Protamine administered as an antidote to anticoagulant action of heparin

3) Errors in Prescription
a) Dosage Error:
It can result from the administration of a single high dose, or the too frequent administration.
Rx
Codeine phosphate 0.5g
Prepare 10 powders
Direction: One powder to be taken at a time.
This is an example of over dosage. The intention of the prescriber is to prescribe 5mg and yet prescribed
500ng in the prescription. So prescription is refereed back to prescriber.

b) Wrong Dose or dosage form:

There are certain drugs which have similar names and there are chances of dispensing wrong drug
which can be dangerous. For example: Prednisone and prednisolone, digoxin and digitoxin.In such
cases pharmacist must consult the physician for clarification.

Also a single drug is available in many dosage forms and if the dosage form is not mentioned clearly,
pharmacist must consult the physician for clarification

Based on nature of chemical reaction

Immediate incompatibilities: - If the chemical reaction takes place, immediately after combining the
prescription ingredients, they are called immediate incompatibilities. Hence, they should be
dispensed only after correction.

Delayed incompatibility: - When the chemical reaction proceeds at a very slow rate and no
appreciable visible change occurs which may develop on keeping the product for along time are
called delayed incompatibility18