Incompatibility

Nahla S Barakat, PhD

Professor of Pharmaceutics
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 Introduction:

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.
The term incompatibility may be applied to the pharmaceuticals
when problem arises during their compounding, dispensing or
administration. Incompatibilities were frequent in earlier days when
the prescription contains multiple ingredients.
Types of Incompatibility:
There are three types of incompatibility:
1. Therapeutically incompatibility
2. Chemical incompatibility
3. Pharmaceutical or physical incompatibility
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 Importance of Determining Incompatibility:

Incompatible products may effect:

Safety of medicament.
Efficacy of product.
Appearance of a medicine.
Purpose of medication.

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 The most important step in dealing with incompatibility is

recognizing by noting an incompatibility before aprescription

is filled. The pharmacist can take corrective measures that
save both time and material. It is easier to prevent an
incompatibility rather than to correct it. An incompatibility is
not recognized until after the prescription has been
compounded. The prescription should not be dispensed until
the incompatibility has been corrected.

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 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.

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 Unintentional

incompatibility may be tolerated i.e.

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.

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Chemical incompatibilities may be classified as follows:

A. Oxidation-reduction:
Oxidation refers to the loss of electrons and reduction to the

gain of electrons. Prescription mixtures are usually oxidized

on exposure to air, higher storage temperatures, light, over
dilution, incorrect pH adjustment or in presence of catalysis.
Use of antioxidants such as ascorbic acid, sodium sulphite or
sodium metabisulphite is often helpful.

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 Trace metal ion catalysis may be counteracted by complexing

agents such as disodium edetate and sodium calcium edetate.

Auto-oxidation in fats and oils, phenolic substances,
aldehydes and vitamins is controlled by agents such as propyl
gallate, thymol, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), and hydroquinone etc. Silver,
mercury and gold salts may be reduced by light to the
metallic form although such reactions are rare in
prescriptions.

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 B. Acid-base reactions:
Such reactions result into precipitation, gas formation,

colour development or colour change.

Change in or Development of Colour:
Most of the dyes employed in pharmaceutical practice and
their colour are influenced by their ionization depending on
pH of the solution. Laxative phenolphthalein is colourless in
acid solution but red in alkaline mixtures.

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 Gentian violet is a basic purple compound but on addition of

acid, the compound changes the colour through green to

yellow. Such incompatibilities are corrected by the addition
of a buffer or change of the vehicle to prevent formation of
free acid or base from the salt.

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 C. Hydrolysis:
Many substances hydrolyse in water and their reaction may

be facilitated by heat catalysts, hydrogen ions and hydroxyl

ions. Esters, amides and metals like Zn and Fe etc., are
common examples. Soluble salts of barbituric acid derivatives
and sulphonamides hydrolyze in water and yield insoluble
free acids. Phenyl salicylate hydrolyses in basic media to
salicylic acid and phenol.

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 Addition of any of the species formed as a result of hydrolysis

is a common method employed to prevent or reverse the

ionic hydrolysis. Examples of drug substances which may
undergo hydrolytic decomposition include procaine,
sulphonamides, chlorothiazide, barbituric acid derivatives,
aspirin, some alkaloids, and penicillin.
Similarly gelatin, sucrose, sodium acetate, flavouring oils and
chlorobutanol; some of the common ingredients in
prescriptions; are also liable to decomposition by hydrolysis.

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 E. Racemization:
It is the conversion of an optically active form of a drug

substance to an optically inactive form without a change in

chemical constitution but is usually associated with a
reduction in pharmacological activity.
Examples of substances undergoing racemization are
adrenaline, ephedrine, norephedrine etc. In alkaline solution
but not in acid solutions, 1-hyoscyamine may undergo
racemization to form atropine.

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 Physical Incompatibility
Physical incompatibilities are often called pharmaceutical

incompatibilities.
This type of incompatibility results by the slow or immediate formation
of decomposed solutions or precipitates, when the drugs are combined
in a pharmacy setup or laboratory.
Def.: Interaction between two or more substances which lead to change

in color, odor, taste, viscosity and morphology.

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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 ( When 2 or
more substances are combined they don not give
homogenous product due to immiscibility or insolubility.
2. Immiscibility of two or more liquids
3. Liquification of solids mixed in a dry state (called
eutexia

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 1. Insolubility:
The following factors affect the solubility of prescribed agent in

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vehicle and may render it less soluble:

1. Change in pH
2. Milling
3. Surfactant
4. Chemical reaction
5. Complex formation
6. Co-solvent
Any change in previous factors may lead to precipitation of drugs
and change in their properties.

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 Example of prescription:

Terpine hydrate 3g
Simple syrup q.s tomake

120ml
MFT solution.
Terpine hydrate is insoluble in simple syrup then how we
make solution? So in this case of the syrup may be replace
by alcohol or iso-alcohlic elixirs or the drug may be
suspended with accasia tragacanth and dispense with a shake
label.

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 Example of prescription:

Magnesium carbonate .. 3.75g

Citric acid . 7.5g
Sodium bicarbonate . 7.5g
Boiled water q.s to make

250ml
MFT solution or MFT citrate solution.

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 Magnesium carbonate is insoluble and will react with citric acid to from

magnesium citrate in solution. Sodium bicarbonate is soluble in liquid. If citric

acid is dissolved first in water and then sodium bicarbonateis added to this
solution and after that magnesium carbonate is added. A clean and complete
solution is not produced, since some of the magnesium carbonate will remain
unchanged. On the other hand a perfectly clean solution can be obtained by
adding the magnesium carbonate to the solution of citric acid first and allow
these 2 compounds to react completely to form solution of magnesium citrate
and then adding the sodium bicarbonate. The reason for this order of mixing is
that both magnesium carbonate and sodium bicarbonate will react with citric
acid in solution. When bicarbonate ion is added first it uses some of citric acid
so that not enough is left to convert all the magnesium carbonate to solubilize
magnesium citrate.
As a result the carbonate that is left will not dissolve by reacting the magnesium
carbonate and citric acid. First all of the carbonate is converted to the citrate
then the sodium bicarbonate which is water soluble is added to give a clean
solution.

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 2. Immiscibility of two or more liquids

This manifestation appears clearly in emulsion, creams, lotions, some types of

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ointments.
Separation in two phases is noticed in these pharmaceutical dosage forms.
The following factors lead to immiscibility:
1. Incomplete mixing
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. gelatin Arabic gum
- Others produce enzymes which oxidize the surfactant
4. Temperature
Storage must be in room temperature to prevent separation
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 3. Liquification of solids mixed in a dry state (eutexia)

Def.: 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.
When the substances with low melting points such as camphor, menthol and thymol are

mixed together, a liquid mixture i.e. eutectic mixture is formed and this process is
known as liquefaction.
2. Exit of crystalline water: By mixing hydrated crystals and dry crystals, crystalline

water diffuse to dry crystals.

Examples:
Camphor ,menthol, phenol, thymol ,chloral hydrate, sodium salicylate,Aspirin ,

phenazone.
Methods Of Rectifying Liquefaction:

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By the use of absorbent like kaolin, light magnesium carbonate.

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 4. Precipitation
Precipitation can result when the solvent in which the solute

is insoluble is added to the solution. Resins are normally not

soluble in water. So, the tinctures of resins may form
precipitate on addition to water.

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5. Immiscibility
This can be corrected by using one or more of the following
methods:

1. Addition of suspending agents or thickening agents:

In the following prescription tragacanth (mucilage or

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compound powder) is used as a suspending agent.

Phenacetin 3g
Caffeine 1g
Orange Syrup 12ml
Water upto 90ml
As Phenacetin is an indiffusible substance.

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

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addition of some thickening agents or with vigorous stirring and shaking.

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.

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 Examples of Incompatibility:
1. Acids are incompatible with alkaline salts, carbonates and

oxides. They causes the precipitation of albumin. So, acids are

prescribed alone.
2. Bases and alkaline carbonates must not be prescribed
alongwith other drugs in solution. They may precipitate
metallic and alkaloidal salts.

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 Methods for correction/prevention of physical incompatibility

Modified order of mixing:
This method will vary often to overcome certain type of physical

incompatibility. So this should be considered first.

Example if salt is not soluble in alcohol, prescribed in hydro alcoholic
liquids. So we dissolve salt first in water and then this solution should
be mixed with the liquid prescribed.
Example:
alcohol soluble substances to be dispensed in hydro alcoholic liquids.
First dissolve in small amount of alcohol, then mixed with the
prescribed solution. A general rule is to dissolve the prescribed
substance first in the solvent in which it is most soluble and then add
to this solution slowly with constant stirring so as to effect the gradual
dilution in the liquid in which it is least soluble.
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 Example of prescription:

Magnesium carbonate .. 3.75g

Citric acid . 7.5g
Sodium bicarbonate . 7.5g
Boiled water q.s to make

250ml
MFT solution or MFT citrate solution.

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 Alternate of solvents:

Solvents can be altered but to a limited extent.

Example:
an alcohol soluble drug may be prescribed in elixir that does not

have sufficient concentration of the alcohol to hold it insolution. It

is then allowed to increase alcoholic concentration with in
reasonable limit. So long as the volume of the prescription is not
changed.
Alcohol: it is a good solvent for many organic compounds such as
alkaloid, camphor, phenol, tannins, balsams, resins and some other
organic acids.
Glycerin: it has solvent properties between those of alcohol and
water. It is particularly good for dissolving tannins, boric acid,
phenols,codeine and certain metallic salts.
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 Example of alternate solvents to prepare clear solution is

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given by following prescription.

Alcohol .. 15ml
Terpine hydrate . 2gm
Glycerin 20ml
Wild cherry syrup . Q.s to make 60ml
MFT solution.

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 The prescription if filled as written will not give a clear

solution. The alcohol concentration is not high enough to

hold all the terpinehydrate in solution and small crystal settle
out. This condition can be corrected by adjusting the alcohol
concentration to 40%, which is same as that of the official
terpine hydrate elixir.

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 Changing the form of ingredients:

A change in the form of the ingredients is

often unable to obtain a better preparation. However it should be clearly

understand that this action is applicable only when the therapeutic action
of ingredientis not altered.

Example of prescription:

Phenobarbital .. gr vii (7 gran)

Sodium salicylate z I (1dram)

Aqua mentha preparata ... q.s to make z ii (2 ounce)

Phenobarbital is insoluble in aqueous solution. Sodium slat of

Phenobarbital, which has the same action and the same dose, may be
used inits place to obtain a clear solution.

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 2. Chemical incompatibility:
This type of incompatibility is resulted due to the formation of

undesirable new product when two or more drugs are combined.

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Examples of Chemical incompatibility:

1. Precipitation
2. Colour change
3. Effervescences
4. Decomposition
Types of Chemical Incompatibility:
Chemical incompatibility can be intentional i.e. a prescriber
knowingly gives incompatible drugs, or unintentional i.e.
prescriber does not know that the drugs are incompatible.

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 There are two types of 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.

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 Methods Of Rectifying Insolubility:

Co solvency : for e.g. we may use alcohol, propylene glycol,

syrups.
Complexation: for e.g. formation of tri iodide complex
, complexation of caffeine with Sodium Benzoate.
Hydro trophy: for e.g. Hyoscamine with tween .
Solubilization: for e.g. Fats soluble vitamins, certain
antibiotics.

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 Rx
Olive oil
Water

30 ml
up to 120 ml

Directions for Pharmacist:

Make an emulsion.
Comments:
Physical incompatibility.

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 Rx
Phenacetin
Caffeine
Orange syrup
Water

3 gm
1 gm
12 ml
up to 90 ml

Directions for Pharmacist:

Make a mixture. Send 25 ml

Comments:
Physical incompatibility.

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 Menthol
Camphor
Ammonium chloride
Light magnesium carbonate

5 gm
5 gm
30 gm
60 gm

Directions for Pharmacist:

Make an Insufflations. Send 40 gm.

Comments:
Correct prescription.

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 Therapeutic INCOMPATIBILITY

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It may be the result of prescribing certain drugs to the

patient with the intention to produce a specific degree of
action but the nature or the intensity of the action produced
is different from that intended by the prescriber.
CAUSES:
It may be due to the administration of :
Overdose or improper dose of a single drug.
Improper Dosage form.
Contraindicated drug.
Synergistic and antagonistic drugs.

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 Tetracycline Hydrochloride

250 gms

Directions for Pharmacist:

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Make Capsules.
Send 10 such capsules.
Label:
Take 10 capsules every six hours with milk.
Comments:
Therapeutic incompatibility.

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 Rx
Amphetamine Sulphate
Ephedrine Sulphate
Simple syrup

20 mg
100 mg
up to 100 ml.

Directions for Pharmacist:

Make a mixture.
Comments:
Therapeutic incompatibility.

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