By

Khezar Hayat
Lecturer. IPS
UVAS, Lahore
 Pharmaceutical Incompatibilities

Pharmaceutical incompatibility occurs as a result of
mixing of two or more pharmaceutical substances which
results in an undesirable product which may affect the
safety, efficacy and appearance of pharmaceutical
preparation.
 Definition

Incompatibility is an undesirable reaction that occurs between
the drug and the solution, container or another drug. The two
types of incompatibilities associated with intravenous
administration are physical and chemical.

[Josephson 2006, RCN 2005, Douglas et al. 2001]

 Drug Interaction

A drug interaction describes the alteration of a drug effect due to
the influence of another sub-stance (i.e. drug, chemical
substance, nutrition) resulting in a solution that is no longer
optimal for the patient after the substances are mixed.

[Craven et al. 2007a, Josephson 2006, Douglas et al. 2001, Nemec et al. 2008].
 Difference between interactions and
incompatibilities

The preparation of intravenous drugs and solutions is
accompanied with the risk of undesirable reactions of the drug
interacting with other substances.
In this context it is important to distinguish an incompatibility
reaction from an interaction.
 Difference between interactions and
incompatibilities

An interaction occurs inside the body and therefore cannot be
seen.
In contrast to the interaction, an incompatibility reaction occurs
inside a fluid container or infusion line and is usually visible
Importance Of Determining Incompatibility

Safety of
medicament

Efficacy of
product
Incompatible
products may
effect
Appearance of a
medicine

Purpose of
medication
 Types of Incompatibilities


™Physical ™Chemical ™Therapeutic

incompatibility incompatibility incompatibility
 Physical Incompatibility

 W h e n two or more than two substances are
combined together, physical changes take place and an
unacceptable product is formed.
 T h e s e changes which occurs as a result of physical
incompatibility are usually visible and can be easily
corrected by applying the pharmaceutical skill to
obtain a product of uniform dosage.
 Remember

 A visible physical change takes place
 An unacceptable, non-uniform, unpalatable product
is formed.
 D i f f i c u l t to measure an accurate dose.
 C a n be corrected by applying pharmaceutical skill
Examples of physical
incompatibilities

Physical
Incompatibility

Immiscibility Insolubility Precipitation Liquefaction

Consequences
Formation of unsighted product

Non uniform dosage form

Removal of Inaccurate dose

Improper Therapeutic effects

 Immiscibility
 What is a miscible solution?
 The components of an Ideal solution are miscible in all proportions for e.g. water and
ethanol, propylene glycol and water, propylene glycol and acetone etc.

Examples:
 Oil and water .For e.g. Castor oil ,Olive oil.
 Concentrated Hydro alcoholic solutions of volatile oils (spirits and
concentrated water)
 Immiscibility

Oils and water are immiscible with each other. They can be made
miscible with water by emulsification.
Example:
 C a s t o r oil…………………15ml
Distilled W at er (QS)………………………60ml
 M a k e an emulsion.
In this prescription castor oil is immiscible with water. To
overcome this incompatibility an emulsifying agent is used to
make a good emulsion
 Methods Of Rectifying Immiscibility
Immiscibility can be overcome
by:

 Vigorous shaking / stirring.

 Emulsification or solubilization for e.g. Fats soluble Vitamins, Certain
antibiotics like Chloramphenicol, Amphotericin B, Analgesics like
Aspirin, Acetanilide & phenacetin many alkaloids and glycosides etc are
made soluble by the technique of solubilization.
 Insolubility

 I n s o l u b i l i t y means the inability of material to
dissolve in a particular system. Such incompatibilities
are due to insolubility of the inorganic as well as
organic compounds in a particular solvent.
 Insolubility

Amount Of Solvent Require to Dissolve 1 Part Of Solute
 Examples
Some indiffusible solids such as Chalk, Aspirin, Phenobarbitone, Succinyl
sulphathiazole etc

Some Antibiotics and Cortisone Acetate, Hydrocortisone Acetate, Procaine

benzyl penicillin.

Constituents of alcoholic vegetable drugs may precipitate when the solvent

is changed (On addition of water). For e.g. tinctures of Belladonna and
hyoscyamus.

 
 Example 1

 E p h e d r i n e sulphate…………0.25gm
Menthol…………………………..0.02ml
 L i q u i d paraffin (sufficient to make)………….30ml
The ephedrine sulphate is an alkaloidal salt and is not soluble in
liquid paraffin, but anhydrous ephedrine is soluble in it. Hence
ephedrine sulphate is substituted with anhydrous ephedrine to
make a clear solution.
 Example 2

Phenacetin……………3g
Caffeine……………….. 1g
 O r a n g e syrup…………12 ml
 D . W a t e r ……………………up to 90ml
In this prescription Phenacetin is an in-diffusible substance.
Compound powder of tragacanth or mucilage of tragacanth is
used as a suspending agent to make a suitable suspension
 Precipitation

 A drug in solution may be precipitated, if the solvent in
which it is insoluble is added to the solution.
Example:
 T h e resins are insoluble in water. When the tincture
containing resins is added in water, resin agglomerates
forming indiffusible precipitates. This can be prevented by
slowly adding the undiluted tincture with vigorous stirring to
the diluted suspension Or By adding some suitable thickening
agent
 Liquefaction

 W h e n certain low melting point solids are mixed together, a
liquid or soft mass known as “eutectic mixture” is produced.
 T h i s occurs due to the lowering of the melting point of
mixture to below room temperature and liberation of water of
hydration. Many chemicals form hydrates, compounds with
water of hydration.
 T h e medicaments showing this type of behavior are camphor,
menthol, thymol, phenol, chloral hydrate and aspirin. This
type of substance create problem when they are dispensed in
powder form.
 Example

 M e nt hol … … … … … 5g
Cam phor…………. . .5g
 A m m o n i u m chloride…….30g
 L i g h t magnesium carbonate…….60g
 I n this prescription menthol, camphor and ammonia
chloride get liquefied on mixing with each other. To dispense
this prescription, menthol, camphor and ammonium chloride
are triturated together to form liquid. Add light magnesium
carbonate (acts as absorbent) and mix it thoroughly to make
free flowing powder.
 Chemical Incompatibilities

 C h e m i c a l incompatibility may occur as a result of chemical
interactions between the ingredients of a prescription and a
toxic or inactive product may be formed.
Reaction between two or more substances which lead to change
in chemical properties of pharmaceutical dosage form
 Possible Reasons

Chemical incompatibilities often occur due to;
Oxidation
Reduction
 A c i d base hydrolysis or
 C o m b i n a t i o n reaction.
 How you can notice?

 T h e s e reactions may be noticed
by;
Precipitation
Ef fe rves c enc es
Decomposition
 C o l o u r change
 Explosion
 Types

 To l e r a t e d :
In tolerated incompatibilities, the chemical interaction
can be minimized by changing the order of mixing or
mixing the solutions in dilute forms but no alteration is
made in the formulation.
 
 Adjuste
d:
In adjusted incompatibilities the chemical interaction
can be prevented by addition or substitution of one of
the reacting ingredients of a prescription with another
of equal therapeutic value.
Example: Caffeine citrate can be substituted with
caffeine in sodium salicylate and caffeine citrate mixture
 It may be…..

INTENTIONAL:
 W h e n the prescriber knowingly prescribes
h
te incompatible drugs.
UNINTENTIONAL:
 W h e n the prescriber prescribes the drugs without
knowing that there is incompatibility between the
prescribed drugs.
 Precipitate Yielding Interactions

The precipitate form through the chemical incompatibility may
be diffusible or indiffusible. The method A and B is followed in
dispensing the prescription yielding diffusible and indiffusible
precipitates respectively.
Method A
Method B
 Method A

1. The method is followed when diffusible precipitates are
formed in very small quantity.
2. Divide the vehicle into two equal portions.
3. Dissolve one of the reacting substances in one of the portion
and the other in the other portion.
4. Mix the two portions by slowly adding one portion to the
other by rapid stirring.
 Method B

 T h e method is followed when indiffusible precipitates are
formed in large quantity. Divide the vehicle into two portions.
 Dissolve one of the reacting substances in one portion.
 Weigh a suitable quantity of compound tragacanth powder
(2g per 100 ml of finished product) and transfer in a mortar
and use part of second portion of vehicle to produce smooth
mucilage.
 T h e n add other reacting substances.
 Method B

 M i x the two portions by slowly adding one portion to the
other with rapid 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.
 1.Alkaloidal salts with alkaline substances

 A l k a l o i d s are weak bases.
 T h e y are almost insoluble in water but alkaloidal salts
soluble in water.
 If these salts are dispensed with alkaline preparations,
such as, strong solution of ammonium acetate, aromatic spirit
of ammonia, solution of ammonia. Ammonium bicarbonate,
the free alkaloid may be precipitated.
 Example

 Strychnine hydrochloride solution……….6ml
 Aromatic spirit of ammonia……………....4ml
 D. Water……………………………………...make up to 1200ml
Strychnine hydrochloride is an alkaloidal salt whereas aromatic spirit of
ammonia is an alkaline substance. When they react together, the strychnine
get precipitated because the quantity of strychnine hydrochloride prescribed
in the prescription is much more than its solubility in water. The aromatic
spirit of ammonia contains negligible amount of alcohol which can not
dissolves the strychnine. Hence it gets precipitated as diffusible
precipitates.
 Hence follow method A for precipitate yielding combination.
Sodium salicylate with ferric salt

Ferric salt reacts with sodium salicylate to liberate indiffusible
precipitates of ferric salicylate therefore follow method B for
precipitate yielding interactions.
Example:
 Ferric chloride solution………..2ml
 Sodium salicylate……………...3g
 D. Water…………………………..make
up to90 ml
 Soluble Salicylates with Acids

 M o s t acids and acid syrups decompose sodium
salicylate. Ppts of salicylic acid are formed as a result of
this.
 I t is difficult to suspend such ppts due to needle
shaped crystals.
 D o not dispense such prescription.
 Example

Rx
 L e m o n Syrup (Citric Acid) B.P.C
 S o d i u m Salicylate
 D i s p e n s e to the patient.
If prescribed, It can be replaced with the prescriber's permission
by mixture of lemon tincture and plain syrup to avoid any
problem
 Therapeutic Incompatibility

 I t is result of prescribing certain drugs to a patient
with the intention to produce a specific degree of
p’cological action, but nature or intensity of the action
produced is different from that intended by the
prescriber.
 Reasons

It may be due to the administration of :
 O v e r d o s e or improper dose of a single
drug.
 I m p r o p e r Dosage form.
 Cont raindi cat e d drug.
 S y n e r g i s t i c and antagonistic drugs.
 Example

 Rx
 Codeine phosphate……………0.5 gms
 Directions for Pharmacist:
 Make powders.
 Send such 10 powders.
 1 dose to be taken at bed time
 Comments:
 This is an example of over dosage. Probably, the physician intended
to write 5mg and yet prescribed 500mg of codeine phosphate. The
prescription must be referred back to prescriber.
 Example

Rx
 Acetophenetidi 150mg
n 200mg
 A c e t y l salicylic 30mg
ad
ci
Caffeine
 A c e t o p h e n e t i d i n & acetyl salicylic acid are analgesic.
 S e n d 10 capsules.
 A c e t o p h e n e t i d i n depresses the CNS & this effect is
undesirable.
 C a f f e i n e is CNS stimulant to neutralise the side effect
of acetophenetidin.
 General Methods used to remove
incompatibilities

Modify the order of mixing
™Dispense with labels like Shake well before use
™Recommend storage condition.
™Add physical stabilizer. (Suspending or emulsifying agent)
™Add chemical stabilizer. (Antioxidant/Buffer)
™Add preservative.
™Select soluble , compatible or stable form of dosage form.
Health Related Project
Assignment of Dispensing Pharmacy
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