PHRM Incompatibility

DISPENSING PHARMACY
Pharmaceutical incompatibility
Dr. Zirwa Asim

Pharm. D., M. Phil.
Lecturer
Shifa Tameer-e-Millat University, Islamabad
Learning Objectives
Understanding of drug incompatibility and its types.
How physical incompatibility occurs (mechanisms)

and the factors responsible for it, prevention.
What is chemical incompatibility, its types and factors
causing chemical incompatibility, its prevention.
What is meant by therapeutic incompatibility, its
types and factors responsible for it.
What is Incompatibility
Incompatibility refers to the inability of something or
some process to co-exist with another process or thing.
So, Pharmaceutical incompatibility refers to the

inability of a pharmaceutical substance to exist in
combination with another pharmaceutical entity.
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.
OR
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.
Importance of Determining Incompatibility:
Incompatible products may effect:

 Safety of medicament.
 Efficacy of product.
 Appearance of a medicine.
 Purpose of medication
Types of Drug Incompatibility
Incompatibility can be classified into three groups:
1. Physical incompatibility
2. Chemical incompatibility
3. Therapeutic incompatibility
1. Physical Incompatibility
Physical incompatibilities are often called pharmaceutical
incompatibilities.
DEF: Interaction between two or more substances

which lead to change in color, odor, taste, viscosity
and
morphology.
Mechanisms of physical incompatibility:
a. Insolubility of prescribed agent in vehicle.
b. Immiscibility of two or more liquids.
c. Liquefaction of solids mixed in a dry state (called
eutexia).
a. Insolubility:
The following factors affect the solubility of prescribed
agent in vehicle and may render it less soluble:
1. Change in pH
2. Milling
3. Surfactant
4. Chemical reaction
5. Complex formation
6. Co-solvent
a. Insolubility:
Example 1:
a. Insolubility:
Example 2:
b. Immiscibility of two or more liquids
This manifestation appears clearly in emulsion, creams,
lotions, some types of ointments.
Separation in two phases is noticed in these
pharmaceutical dosage forms.
The following factors lead to immiscibility:
1. Incomplete mixing
Example: Flavoring agent such as orange oil, lemon oil or
their alcoholic solution are added in aquous preparation
they may not mix well and droplets of the oils may b float
on the water surface. They make the solution turbid,
having a hazy appearance.
b. Immiscibility of two or more liquids
2. Addition of surfactant with:
- Unsuitable concentration
- False time of addition
- Unsuitable for the type of emulsion
3. Presence of microorganisms
- Some bacteria grow on constituents of mixture i.e. gelatine
Arabic gum
- Others produce enzymes which oxidize the surfactant
4. Temperature
Storage must be in room temperature to prevent separation
c. Liquefaction of solids mixed in a dry state (eutexia)
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 the solid substance is

soluble in another solid substance which lead to decrease
of its melting point and conversion to a liquid in certain
ratios.
2. Exit of crystalline water: By mixing hydrated crystals and
dry crystals, crystalline water diffuse to dry crystals.
c. Liquification of solids mixed in a dry state (eutexia)
Example:
Certain low melting points solids when mixed together liquefy
due to formation of eutectic mixtures, they form a soft mass
when mixed together thus the physical integrity of the
preparation may be lost.
Menthol, thymol, aspirin form eutectic mixture when two of

them are mixed together.
Rectifying Liquefaction:
By the use of absorbent like kaolin, light magnesium carbonate
Physical Incompatibility
Insolubility Immiscibility Liquefaction
1. Change in pH 1. Incomplete mixing

2. Milling 2. Addition of 1. Formation of
3. Surfactant surfactant liquid mixture
4. Chemical reaction 3. Presence of 2. Exit of
5. Complex formation microorganisms
6. Co-solvent 4. Temperature
crystalline water
Preventing pharmaceutical or physical incompatibiliy:
1. Addition of suspending agents or thickening agents:
In the following prescription tragacanth (mucilage or
compound powder) is used as a suspending agent.
Phenacetin 3g
Caffeine 1g
Orange Syrup 12ml
Water upto 90ml
As Phenacetin is an indiffusible substance.
On the other hand, tinctures of resins are made soluble in

water by the addition of some thickening agents or with
vigorous stirring and shaking.
Preventing pharmaceutical or physical incompatibiliy:
2. Emulsification:
Water and oil are immiscible in each other and they can be
made miscible by the addition of Emulsions. This is known as
Emulsification.
3. Changing the mixing or order of prescription
4. Changing the form of ingredients i.e. from liquid to solid

form or from hydrous form to anhydrous form:
This is often helpful in increasing the solubility of a substance
e.g.a solution of ephedrine sulfate, an alkaloidal salt, and liquid
paraffin is not possible as alkaloidal salt of ephedrine sulfate is
not soluble in liquid paraffin but anhydrous form of ephedrine
is soluble in it. So we use anhydrous form.
2. Chemical Incompatibility
Reaction between two or more substances which lead
to change in chemical properties of pharmaceutical
dosage form.
Chemical incompatibility is also called as immediate

incompatibility.
Chemical interaction occurs between the ingredients & a
toxic & inactive product will be formed.
Chemical incompatibilities often occur due to oxidation-
reduction, hydrolysis or combination reactions. A
chemical incompatibility, which is visualized rapidly by
effervescence, precipitation or colour change, is called
immediate incompatibility.
An incompatibility without immediate and visible

physical change is known as delayed incompatibility and
may or may not result in loss of therapeutic activity.
interaction is minimized but composition of the
prescription is not altered; or adjusted i.e. interaction is
prevented by addition or substitution of constituents
without affecting the medicinal action of the preparation
It is recommended that the pharmacist must consult or

notify the prescriber about the suggested modification in
the prescription while overcoming the incompatibility.
Types of chemical changes:
1. Oxidation
2. Hydrolysis
3. Polymerization
4. Isomerization
5. Decarboxylation
6. Absorption of Co2
7. Combination
8. Formation of insoluble complexes
1. Oxidation
Oxidation is defined as loss of electrons or gain of oxygen
Auto-oxidation: It is a reaction with oxygen of air which

occur spontaneously without other factors.
Pre-oxidants: are substances catalyze oxidation process

i.e. metals, some impurities.
Factors lead to oxidation:

Presence of oxygen
Light: it can cause photo-chemical reactions: chemical
reaction occur in presence of light
Temperature: elevated temperature accelerate oxidation
reaction
PH: each drug has its ideal pH for stability. Any change in
pH affect drug stability and may accelerate oxidation
reaction
Pharmaceutical dosage form: oxidation reaction occur in
solutions faster than in solid dosage forms
Factors lead to oxidation:
 Presence of pre-oxidants as metals and peroxides

Type of solvent used: oxidation reaction occur faster in
aqueous solution than others.
Presence of unsaturated bonds : as double and triple
bonds (oils) which undergo easier than saturated bonds
(margarine) for oxidation.
Protection of drugs from oxidation:
Addition of Antioxidants: Vitamin E, vitamin C and
inorganic sulfur compounds: thiosulfate and polysulfide.
Addition of chemicals which form complexes with metals
i.e. EDTA, Benzalkonium chloride.
Protection from light:
a. Using of dark container

b. Storage in dark places
c. Packaging with substances which absorbed light i.e.
Oxybenzene
Protection of drugs from oxidation:
Choice of suitable pharmaceutical dosage forms which
reduce the possibility of oxidation process (solid dosage
forms are better than solutions)
Maintenance of pH by using buffer solution
choice of suitable solvent (rather than water)
Storage in low temperature
protection from air by:
a. using good closed containers

b. Replacement of oxygen by nitrogen
Chemical groups which undergo oxidation:
1. Phenolic compounds: Phenylephrine
2. Catechol derivatives: Adrenaline and noradrenaline

3. Some antibiotics: Tetracyclines
4. Oils (fixed and volatile)
5. Vitamins (lipid and water soluble)

How to identify oxidation in pharmaceutical dosage
form?
1. Change of color, odor, viscosity of dosage form
2. For fixed and volatile oils: change of color, taste, odor, and
viscosity.
2. Hydrolysis:
A chemical reaction in which water is used to break down a
compound; this is achieved by breaking a covalent bond
in the compound by inserting a water molecule across the
bond
Types of hydrolysis:
1. Ionic hydrolysis:
2. Molecular hydrolysis:
Types of hydrolysis:
1. Ionic hydrolysis:
- In which the compound is broken into ions by water.
- The covalent bond between ions of compound is broken
down.
- It is reversible
Ex: Codeine phosphate Codeine + Phosphate
- This type take place spontaneously
- Most affected are weak bases and salts.
Types of hydrolysis:
2. Molecular hydrolysis:
- In which the molecule itself is broken down.

- It is slow process and irreversible.
- It must be avoided.
- Ex: Acetylsalicylic acid Salicylic acid + Acetic acid
- So there is no solutions as dosage forms for Aspirin
Chemical groups which undergo hydrolysis:
Esters
Amides
Nitriles
Factors induce hydrolysis:

Presence of water
pH (Ex. Atropine: optimal pH=3.1-4.5)
High temperature (Problem by autoclave i.e. procaine)
Protection from hydrolysis:
1. Protection from moisture by :
- Packaging with substances impermeable for moisture
- Addition of substances that absorb water (CaCO3)
2. Using of solvent rather than water
3. Maintenance of pH by using buffer system
4. Formation of complexes: which protect the drug from the
effect of water
5. Using of surfactants (micelle formation)
6. Reducing of solubility of substance (i.e. Suspension
instead of solution)
3. Polymerization:
In polymerization, small repeating units called monomers
are bonded to form a long chain polymer.
Example:
Factors induce Polymerization:
1. Temperature
2. Light
3. Solvent
4. pH
5. Impurities
4. Isomerization:
It means conversion of drug to its isomer
Isomers have:
- Identical molecular formulas.
- A different arrangement of atoms.
Types of isomerization:
a. Optical isomerization:
 Conversion of optical active drug into less active.
Example:
a. L-Adrenaline is converted to d-adrenaline by change of
pH or temperature.
b. L-adrenaline is more therapeutically active than d-
adrenaline.
Factors affect optical isomerization :
1. Temperature
2. pH
3. Solvent
4. Impurities
b. Geometric isomerization:
- One type of isomers

- Expressed by cis or trans
- Cis: means the groups A in the same direction:

- Trans: means the group A in opposite direction:
- Cis is more therapeutically active than trans (ex.:
Vitamin A)
5. Decarboxylation:
Example:
NaHCO3 Na + CO2
All drugs contain bicarbonate are not sterilized in high
temperature.
6. CO2 – absorption:
When some pharmaceutical dosage forms contain CO2,
precipitate is formed:
Example:
Ca(OH)2 + CO2 CaCO3
7. Combination:
Take place when the pharmaceutical dosage form
contain substances with different charges
Ex: Surfactants with positive and negative charges
8. Formation of insoluble complexes:

Ex: Tetracycline + heavy metals
Oxidation
Hydrolysis
Ionic hydrolysis
Molecular hydrolysis
Formation of insoluble complexes
Combination
Absorption of Co2
Isomerization
Optical isomerization
Geometric isomerization
Polymerization
Decarboxylation
Chemical Incompatibility
1. Tolerated
In this type of incompatibility, chemical reaction can be
reduced by mixing the solution in dilute forms or by
changing the order of mixing.
2. Adjusted
In this type of incompatibility, change in the formulation
is needed with a compound of equal therapeutic value
e.g. in the mixture of caffeine citrate and sodium
salicylate, caffeine citrate is replaced with caffeine.
3. Therapeutic incompatibility
Therapeutic incompatibilities are unintentional
pharmacodynamic or pharmacokinetic interactions that
take place in vivo after administration of medicinal
products.
OR
It is the modification of the therapeutic effect of one drug

by the prior, concomitant administration of another. (It is
also called drug interactions)
Therapeutic incompatibility
Pharmacokinetics
Altered GIT absorption

a. Altered pH
b. Altered bacterial flora
c. Formation of drug chelates or complexes
d. Drug induced mucosal damage and altered GIT motility
Altered distribution
Displaced protein binding
Altered metabolism
Enzyme induction
Enzyme inhibition
Altered renal execration

Inhibition of renal tubular secretion
Alteration of urine flow and pH

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DISPENSING PHARMACY

Dr. Zirwa Asim

How physical incompatibility occurs (mechanisms)

So, Pharmaceutical incompatibility refers to the

Drug Incompatibility refers to interactions between two or

Incompatible products may effect:

Incompatibility can be classified into three groups:

DEF: Interaction between two or more substances

Mechanisms of physical incompatibility:

a. Insolubility of prescribed agent in vehicle.

b. Immiscibility of two or more liquids.

c. Liquefaction of solids mixed in a dry state (called

It means that when two solid substances are mixed together,

1. Formation of liquid mixture: when the solid substance is

Menthol, thymol, aspirin form eutectic mixture when two of

Insolubility Immiscibility Liquefaction

1. Change in pH 1. Incomplete mixing

As Phenacetin is an indiffusible substance.

On the other hand, tinctures of resins are made soluble in

3. Changing the mixing or order of prescription

4. Changing the form of ingredients i.e. from liquid to solid

Chemical incompatibility is also called as immediate

An incompatibility without immediate and visible

It is recommended that the pharmacist must consult or

Auto-oxidation: It is a reaction with oxygen of air which

Pre-oxidants: are substances catalyze oxidation process

Factors lead to oxidation:

Factors lead to oxidation:

 Presence of pre-oxidants as metals and peroxides

a. Using of dark container

a. using good closed containers

1. Phenolic compounds: Phenylephrine

2. Catechol derivatives: Adrenaline and noradrenaline

4. Oils (fixed and volatile)

5. Vitamins (lipid and water soluble)

1. Change of color, odor, viscosity of dosage form

- In which the molecule itself is broken down.

Factors induce hydrolysis:

Factors affect optical isomerization :

- One type of isomers

- Cis: means the groups A in the same direction:

8. Formation of insoluble complexes:

Formation of insoluble complexes

It is the modification of the therapeutic effect of one drug

Altered GIT absorption

Altered renal execration

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