Incompatibilities

By
Prof. Dr. Gamal Zayed
Definition

Incompatibility refers to interactions between two or more

substances which lead to changes in chemical, physical,
therapeutic properties of the pharmaceutical dosage form.
Incompatibility occurs as a result of mixing of two or more
Substances & an undesirable product is formed which may affect
the safety, efficacy & appearance of the pharmaceutical
preparation.

Pharmaceutical incompatibility may occur not only during

compounding and dispensing but also at any stage during
formulation, manufacturing, packing or administration of drugs.
The major function of the of pharmacist is to recognize and
overcome incompatibilities so as to make elegant and effective
combinations of the drugs which the physician prescribes.
Several changes may take place to give an indication of
incompatibility, the most important are:

 Decomposition of the ingredients with formation of new compounds

 Precipitation either chemical or physical
 Explosion
 Eutaxia which mean liquefaction when ingredients are prescribed in
powder from
 Deterioration or destruction of one or more of the ingredients
 Types of Incompatibility
1. Therapeutic incompatibility
2. Physical incompatibility
3. Chemical incompatibility 

I) Physical incompatibility
When two or more substances are combined together, physical
changes take place and an unacceptable product is formed. These
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,
substance to help in compounding of the prescription.
II) Chemical incompatibility
Are those in which two or more ingredients react to give new
compounds. These may or may not be subjected to simple correction and in
extreme cases it is necessary to eliminate one of the reactants or change it
to a non reactive form.

III) Therapeutic incompatibility

It is the modification of the therapeutic effect of one drug by the prior
concomitant administration of another. (It is also called drug interactions)
Intentional and unintentional incompatibility
Incompatibilities of any of these three types may be intentional or
unintentional.
In some cases, the incompatibilities may be intended by the physician
(intentional)
e.g. in white precipitate of zinc polysulphides which occurs when solutions of
zinc sulphate and sulfuarted potash are combined in an expected or intentional
incompatibilities.

R/  

Zinc sulfate 4g
Sulfurated Potash 4g
Water ad. 100 ml
 In prescribing morphine as analgesic, a physician may use atropine to
prevent an excessive depressant effect of morphine on the respiratory
center. In these cases, it is common for the drugs which are used to
neutralize the side effects to be prescribed in partial doses.
 Caffeine is intended to overcome the cerebral depressant action of
antihistaminic.

In other cases, a precipitate may form which the physician did not
anticipate of (unintentional)
Example: The precipitation of free phenobarbital due to the acidity of the
elixir of lactated pepsin is an unintended incompatibility.

R/  

Sodium phenobarbital gr vi
Elixir lactated pepsin ad. fl ᶚ
I) Physical Incompatibilities (pharmaceutical incompatibility)
Physical incompatibilities are often called pharmaceutical incompatibilities
and are evidenced by the failure of the drugs to combine properly.

Types of physical incompatibilities

1) Immiscibility
2) Insolubility
3) Precipitation
4) Liquefactions
I,1) Immiscibility (separation of immiscible liquids)
Sometimes when certain substances are mixed together and immiscible
liquid floats on the surface. Ethyl nitrite spirit floats on the surface of when
a substantial proportion of potassium citrate is present in the prescription.

Oils and water are immiscible with each other. They can be made miscible
with water by emulsification.
R/  
Castor oil ml 15
Water ml 60

Make 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.
Another example, phenol will be salted out by sodium sulfate. A clear
solution can be obtained if the phenol is dissolved in 10 ml of glycerin and
the sodium sulfate is added as dilute aqueous solution.
I,2) Insolubility or incomplete solution
Insolubility means the inability of material to dissolve in a particular
system. This could happen when two or more substances are combined,
they may not give a homogenous product owing to immiscibility or
insolubility.
1) Oils and silicones are immiscible in water.
2) Gums and resins are insoluble in alcohol.
3) Sometimes the physician may prescribe the wrong solvent and in
other cases the amount of the liquid may be insufficient to dissolve all of
soluble substances.
 The terpin hydrate is not-soluble in this vehicle

R/  

Terpin hydrate 3g
Simple syrup ad 120 ml
Correction: Half of the syrup may be replaced by alcohol.

 Ephedrine sulphate in liquid paraffin

R/  

Ephedrine sulphate 0.25 g

Menthol 0.02 ml
Liquid paraffin ad. 30 ml
The ephedrine sulphate is an alkaloidal salt and is not soluble in
liquid paraffin, but anhydrous ephedrine is soluble in it.
Correction: Ephedrine sulphate is substituted with anhydrous
ephedrine to make a clear solution.
 Phenacetin in water

R/  

Phenacetin 3g
Caffeine 1g
Orange syrup 12 ml
Water 90 ml
In this prescription, phenacetin is an indiffusible (poorly wettable)
substance.
Correction: compound powder of tragacanth or mucilage of tragacanth
is used as a suspending agent to make a suitable suspension.
I,3) Precipitation where there is no chemical reaction
A drug in solution is generally precipitated from its solution if another
solvent in which it is insoluble is added to the solution.
Examples:
1- The 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.
2- Camphor and volatile oils are salted out of aromatic water when salts or
metals are dissolved in the liquid.
3- Gums are insoluble in alcohol (acacia and tragacanth)
I,4) Eutaxia i.e. Liquefaction of solid ingredients
When certain 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 room temperature and
liberation of water of hydration. Many chemicals form hydrates compounds
with water of hydration.

The medicaments showing this type of behavior are camphor, menthol,

thymol, phenol, chloral hydrate and aspirin. This type of substance creates
problems when they are dispensed in powder form.
 R/  
Menthol 5g
Camphor 5g
Ammonium chloride 30 g
Light magnesium carbonate 60 g

Correction: Remove either menthol or camphor.

Methods for Correcting Physical incompatibilities:
There are different methods can be applied to correct (overcome) the
physical incompatibilities these methods are:
 Modify the Order of Mixing
 Alteration of Solvent
 Changing the form of ingredients
 Alteration of Volume
1- Modify the order of mixing
 This will overcome certain physical incompatibilities and should always
be considered first.
 The manner as well as the order of mixing should receive consideration
from the pharmacist.

R/
Mg. Carbonate 7.5 g
Sod. Bicarbonate 7.5 g
Citric Acid 7.5 g
Distilled water 250 ml (Make solution)
There is insufficient citric acid to neutralize and solubilize both of carbonate. If citric
acid is reacted first with the sodium bicarbonate, some magnesium carbonate will be
insoluble, and a suspension will result.
Correction: if the magnesium carbonate is solubilized with citric acid first, and the
sodium bicarbonate is added to the mixture, a solution is obtained. The sequences
selected in such cases will depend on the directions given in the prescription.
2- Alteration of Solvent
Solvents can be altered to a limited extent depending on the nature of the
medication and the use for which it is intended. An alcohol soluble drug
may be prescribed in elixir which doesn’t have enough concentration of
alcohol to hold it in solution. It then impossible to increase the alcoholic
concentration within reasonable limits as long as the volume of the
prescription is not changed.
Example 1:  
R/
Terpin hydrate 2g
Alcohol 10 ml
glycerin 20 ml

Fiat: solution, send 60 ml

The alcohol content is not high enough to hold all the terpin hydrate and
crystals will settle at the bottom. This can be corrected by increasing the
alcohol content to 40% to obtain a clear solution.
Example 2:

R/  
Ephedrine sulfate 0.18 g
Terpin hydrate 3g
Elixir phenobarbital to 60 ml

The concentration of alcohol in the elixir (12-15%) is insufficient to dissolve

the terpin hydrate (concentration of alcohol must not be less than 40%).
Correction:
1) To obtain clear solution, replace most of the elixir with alcohol and add
sufficient phenobarbital to give the prescribed dose.
2) When a solution is prescribed for external use, the solvent may be
altered more completely.
 Example 3:
R/  
Mercuric iodide gr. iii
Thymol gr. v
Water Q.S fƷ x

Fiat solution
Sig.: to be applied to the knee

Mercuric iodide is insoluble in water, thymol is sparingly soluble in water, and

both of them are soluble in alcohol. In such a case, the physician should be
called and permission is requested to replace the water with alcohol so that a
clear solution can be made.
Correction:
1) If an alcoholic solution is required, a permission is requested to replace the
water with alcohol so that a clear solution can be made.
2) If non alcoholic solution is required, then mercuric iodide may be in
solution by adding a small amount of KI or NaI.
3- Changing the Form of Ingredients
This enables the pharmacist to obtain better preparation. It should be
clearly understood that the change is applicable only when the therapeutic
action of the ingredient is not changed.
If an alkaloid is prescribed in an aqueous solution the soluble salt of
alkaloid may be used. If alkaloidal salt is prescribed in an oily solution, the
alkaloid would be used instead.

Example:
R/  
Ephedrine sulphate 0.25 g
Menthol 0.02 g
Light mineral oil to 30 ml

The alkaloid salt is not oil soluble; substitution of anhydrous

ephedrine base will permit preparation of clear solution. The dose be
adjusted to 0.33 gr.
4- Alteration of Volume
This is usually applied to in cases where a mixture contains substance which
will be thrown out of the solution or damaged by high concentration of one
or more of the other ingredients.
Example 1:
R/  
Strychnine hydrochloride 0.15 g
Sodium bromide 5g
Syrup 40 ml

Strychnine is precipitated in presence of bromide or iodide unless the

mixture contains 12% alcohol or more. When no alcohol or when the
alcoholic liquid is insufficient, it is better to reduce the amount of the
vehicle (syrup) used to produce half of the volume to reach the desired
ratio of alcohol. The dose in such case must be halved.
In some prescriptions, a drug may be present in too large quantity to be
dissolved by the prescribed amount of vehicle. In such cases, solution may
be affected by increasing the volume.

R
/
 
Sodium bicarbonate g 10
Sodium citrate g5
Peppermint water to g 60
Fiat solution  

Both sodium bicarbonate and sodium citrate are water soluble but sodium
bicarbonate is not soluble enough for 10 g to be dissolved in 60 ml of
peppermint water. The solubility of sodium bicarbonate is 1/10 hence it
requires 100 ml of vehicle. The solubility of sodium citrate is 1/1.5, hence
it requires 7.5 ml, so, the volume of the vehicle must be increased to
dissolve both salts.
II) Chemical Incompatibilities
Chemical incompatibility occurs when the combination of two or more
drugs undergoes a chemical reactions and undesired chemical compound
results. Chemical incompatibility may be as a result of chemical
interactions between the ingredients of a prescription and a toxic or
inactive product may be formed.
Chemical incompatibilities often occur due to:
 oxidation–reduction.
 acid base hydrolysis.
 Combination reaction.
These reactions may be noticed by:
1) Precipitation
2) Effervescences
3) Decomposition
4) Color change and some times 5) Explosion.
Chemical incompatibilities may be:
Unintentional:
When the prescriber prescribes drugs without knowing there is
incompatibility between them.

Intentional:
When the prescriber know and prescribes the incompatibility drugs.

Example for the intentional chemical incomp.:

The ordering of citric acid and tartaric acid with carbonates and
bicarbonates is intended with the purpose to liberate carbon dioxide which
lessens the bitter and salty taste of medicaments by causing numbness of
the tongue (CO2 acts as masking agent).
Example:

R/  
Ammonium chloride 30 ml
Codeine sulfate gr v
Syrup wild cherry to 60 ml
Fiat solution  

If codeine sulfate and ammonium chloride are dissolved in small portion of

water and mixed with the syrup, there is a precipitate of codeine tannate
because of a reaction between the codeine sulfate and the wild cherry.
Correction: A clear product may be obtained by dissolving the solid drugs in
separate portions of the syrup, pour both of these solutions into 30 ml of
glycerin and then adding sufficient syrup to make the required volume.
 R/  
Strychnine hydrochloride solution 6 ml
Aromatic spirit of ammonia 4 ml
Water make up to 1200 ml

Strychnine hydrochloride is an alkaloidal salt were as aromatic spirit of

ammonia is an alkaline substance. When they react together, the
strychnine gets precipitated because the quantity of strychnine
hydrochloride prescribed in the prescription is much more than its solubility
in water (1 in 7000). The aromatic spirit of ammonia contains negligible
amount of alcohol which cannot dissolve the strychnine.

Correction: Divide the vehicle into two equal portions. Dissolve one of the
reacting substances in one of the portion and the other in the other portion.
Mix the two portions by slowly adding one portion to the other by rapid
stirring.
 R/  
Cocaine hydrochloride 0.3 g
Boric acid 1.2 g
Sodium borate 1.2 g
Purified water to 60 ml
Fiat solution  

The alkalinity imparted to the solution by sodium borate causes

precipitation of water insoluble cocaine base.
Correction: Elimination of sodium borate prevents this incompatibility.
 R/  
Sodium citrate Ʒ iv
Calcium bromide Ʒ iii
Syrup ƺi
Peppermint water to ƺ iii
Fiat solution  

Both sodium citrate and calcium bromide are soluble in water. But
when mixed together, an exchange reaction of the calcium and
sodium ions form calcium citrate which is insoluble.
Correction: This incompatibility is prevented by substituting sodium
bromide for calcium bromide and the dose is adjusted to be 2 g
2. Soluble salicylate with ferric salt:
Ferric salt reacts with sodium salicylate to liberate indiffusible precipitates
of ferric salicylate therefore gum tragacanth has to be added.

   
R/
Ferric chloride solution 2 ml
Sodium salicylate 3g
Water make up to 90 ml
   
3. Soluble salicylate with acidic vehicle
The acidic vehicle results in formation and precipitation of salicylic acid. This
incompatibility can be overcome by a change to neutral or alkaline vehicle
or the addition of sufficient alcohol to dissolve salicylic acid.
Correction: It is best to use elixir pepsin instead of lactated pepsin.

R/  
Sodium salicylate 15 g
Elixir lactated pepsin 120 ml
4. Soluble iodide incompatibilities:
Iodides undergo oxidation forming iodine which is an undesirable
product. For example, oxidation of iodides with potassium chlorate.
When soluble iodides react with potassium chloride, free iodine is
liberated.
KClO3 + 3FeI2 → 3FeOI +3I+KCl
To prevent the incompatibility, the two reacting substances must be
dispensed separately.
2) Chemical incompatibilities causing evolution of gas
Prescriptions containing carbonates or bicarbonates and acids such as citric
acid, acetic acid and tartaric acid usually effervesce on mixing.

R/  

Ammonium carbonate Ʒi
Ammonium chloride Ʒ ii
Dilute acetic acid flƺ i
Syrup wild cherry flƺ iv

Correction: This incompatibility doesn’t cause much inconvenience; it

can be overcome by letting the reaction to go completion in open mouth
bottle.
In a wide mouthed bottle, add ammonium carbonate and acetic acid, mix
till effervescence ceases. Add ammonium chloride and complete the
volume with syrup cherry.
3) Chemical incompatibilities causing color change
 The color change is usually evidenced by a chemical reaction.
 Sometimes the color change is very important as in the case epinephrine
solution, which turns brown by oxidation, becomes inactive and must be
rejected.
 On the other hand, salicylate mixture acquires reddish or pinkish color on
keeping. The color change is of no significance from the therapeutic point
of view R/  
Sodium salicyate 8g
Sodium bicarbonate 16 g
Peppermint water to 60 ml

This solution slowly darkens in color and becomes almost black in 2-3 days.
The change is attributed to an oxidation of the salicylate to quiniode
structure. The reaction is promoted by alkaline medium. The therapeutic
value of the preparation is not appreciably affected.
Correction: A number of antioxidants can be used for retarding the color
development. In the above formula, sodium bisulphite can serve this function.
Sometimes, color change may be modified or prevented by the addition of
inhibiting agents such as citrates or citric acid. Only small amount of
inhibitors are enough to control the color.
Example:
R/  
Liquid phenol 8 ml
Tincture of ferric chloride 3 ml
Water to 90 ml

If the preparation is prepared as it is, dark inky color is obtained.

Correction: The addition of small amount of citrate or citric acid inhibits

the formation of such color.
4) Incompatibilities of emulsifying agents:
Emulsion prepared with alkali metal, ammonia and triethanolamine soaps
are incompatible with salts producing polyvalent cations. Due to double
decomposition, a polyvalent soap is formed which inverts the emulsion.
III) Therapeutic Incompatibilities
A therapeutic incompatibility, also known as physiological incompatibility, is
a type of incompatibility where the prescribed drugs produce undesirable
effects in vivo. Therapeutic Incompatibility occurs when the combined have
one of the following:
There are five types of therapeutic incompatibilities:
1. Overdose
2. Drug synergy
3. Wrong dosage form
4. Contraindication
5. Drug antagonism
1) Dosage error
 The dispensing of overdoes of medication is the most serious type of
dosage error. Overdoses can result from the administration of
excessive single dose or the too frequent administration of usual
doses.
 The pharmacist in evaluating the prescription order should consider how
much should be given in each dose, how frequent the medication is given,
age of the patient and the deterioration of the activity of the drug.
The problem in the following prescription is one that could cause serious
troubles if not recognized.

R/  

Atropine sulfate 0.006 g

Phenobarbital 0.360 g
Fait capsules, I mitte XII  
Sig. caps i t.d.s  

This represents 12 times the dose of atropine and Phenobarbital. The

physician undoubtedly intended that the prescription be divided into 12
doses but wrote the wrong direction.
Correction: It is necessary to call the prescriber and request permission
to correct the direction. (atropine sulfate 0.0005 g, Phenobarbital 0.03 g).
 R/  
Codeine phosphate 15 mg
Ammonium chloride 500 mg
Fait capsules, I mitte, XX  
Sig. caps ii q h for cough  

This represents an improper frequency of the dosage for codeine. It is

recommended the prescribed dose every 4 hours, not every hour.
Correction: The physician probably intended to write q 4 h and should be
consulted.
2) Additive and synergistic combinations
 If several drugs having the same pharmacological action are prescribed
together near their full or maximum individual dose, usually produce
undesirable effects. Drugs of such combinations usually should be
prescribed in reduced amounts since the sum of their therapeutic activity
may be too great. This is especially true if the combination is synergistic
i.e. the combined action is greater than would be expected from
the sum of their individual actions.

 Additive or synergistic action is desirable if the toxicity or side effects are

reduced by the lower doses used, the activity is increased or the
prescription becomes less expensive.
Examples of synergism
1) the combination of sulfonamides often shows less nephrotoxicity
than a single sulfonamide.
2) Bromide-barbiturate combinations reduce the bromide content;
hence the danger of bromoinsim is lessened.
3) The neomycin-erythromycin combinations have a broader spectrum
than either antibiotic alone.
4) Aspirin-codeine combination may reduce the amount of codeine
required.
5) Laxatives with anthelmintic.
3) Antagonistic combinations
Antagonistic combination of two or more drug prescribing the full doses of the
two antagonistic drugs may be an unintentional error. In such cases, it is
possible that the resulting prescription will have no therapeutic effect, if the
drug actions cancel each other. Demulcents with irritants (glycerin and
cantharidine), purgative with antidiarrhetics, acidifiers with alkalinizes will
oppose the action of each other.
A classical example of antagonism is when aspirin is prescribed together with
probencid in the treatment of gout.

R/   This prescription is an example of an

antagonistic combination. Although both
Probencid 500 mg
drugs are effective uricosuric agents
Aspirin 300 mg
separately, the combination is reported
Fait capsules, mitte, XX   ineffective due to the antagonism. The
Sig. cap i a day for gout   physician should be consulted
4) Contraindicated drugs
Sometimes combination increases the action and the toxicity of potent
drugs.
Examples:
 Santonin is more dangerous when administered together or closely
followed by castor oil or any fixed oil. The oils increase the solubility of
the active principles and thus increase their toxicity.

 Administration of tetracycline is prohibited with drugs containing calcium

ions or foods containing calcium such as milk because the calcium
causes precipitation of the antibiotic.
Sulfonamides are contraindicated with urinary acidifiers such as ammonium
chloride which may cause deposition of sulfonamide crystals in kidneys.

R/  
Sulfadiazine 250 mg
Sulfamerazine 250 mg
Ammonium chloride 500 mg
Fait capsule i, mitte, XXX  
Sig. caps ii q 4 h for cough  

This is contraindicated combination because ammonium chloride may

cause deposition of sulfonamide crystals in kidney, the physician should be
consulted.