Pharmaceutical
Incompatibility
Dr. Murtaza
Introduction
Incompatibles are substances which have opposite medicinal properties, or
substances when mixed together, react chemically to produce other
substances.
Incompatibility is defined as 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.
An understanding of incompatibilities can save the pharmacist valuable time
in compounding as well as ensure the therapeutic efficiency of the products.
Incompatibilities range from minor to dangerous.
Incompatible products may effect
Safety of medicament
Efficacy of product
Appearance of a medicine
Purpose of medication
Classification of Incompatibility
3 classes of drug incompatibility
Physical incompatibility
Chemical incompatibility
Therapeutic incompatibility
Physical Incompatibility/ Pharmaceutical Incompatibility
It is an evidence of failure of the drug to combine properly.
In physical incompatibility involves interaction between two
or more substance which leads to change in colour, odour,
taste, viscosity & morphology.
It is a result of insolubility & immiscibility, precipitation,
liquefaction, adsorption & complexation of solid materials.
These incompatibilities produce a mixture which is
unacceptable in appearance and taste and may
result in non-uniform dosage form.
E.g.Gums are insoluble in alcohol. resins are
insoluble in water
Physical incompatibilities can be corrected by
one or more methods viz.
Order of mixing
Alteration of solvents
Changes in the form of ingredients
Alteration of volume
Accurate choice of emulgent & suspending agent
Addition
Examples of physical incompatibilities
1. Immiscibility
Immiscibility is the result of the mixture of two or more immiscible liquids or an
immiscible solids with liquid. e.g. oil & water
Oils and water immiscible with each other . They can be made miscible with water
by emulsification.
Example
Castor oil…………………15ml
Water………………………60ml
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
Rectifying method
Vigorous shaking
By using emulsifying or Solubilizing agents..
Cont….
2. Insolubility
Changes in pH, milling, surfactant, chemical reaction, co-solvent are the factors that affect the
solubility.
Insolubility means the inability of material to dissolve in a particular system. The major of
incompatibilities are due to insolubility of the inorganic as well as organic compounds in a
particular solvent.
Example
Ephedrine sulphate …………0.25 gm
Menthol…………………………..0.02 ml
Liquid paraffin (sufficient to make)………….30 ml
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.
Cont….
3. Precipitation
For instance, if mucilage of acacia & alcohol are put together they
form precipitation of acacia by the alcohol. For that reason acacia not
be used with alcohol for mucilage preparation.
A drug in solution may be precipitated, if the solvent in which it
is insoluble is added to the solution.
Example
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
Cont….
4. Liquefaction
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 create problem when they are dispensed in powder form.
Example
Menthol……………5g
Camphor…………...5g
Ammonium chloride…….30g
Light magnesium carbonate…….60g
In 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 and mix it thoroughly to make free flowing powder.
In the suspension contains diffusible solids in that type of the suspension uses the thickening agents. If thickening
agents are not used then particles settle quickly & dose cannot be maintained.
Chemical incompatibility/ immediate incompatibility
After compounding, it may occur immediately.
Itoccurs due to chemical reactions (oxidation-
reduction, acid base hydrolysis or combination
reactions) between the prescribed ingredients & are
noticed by effervescence, decomposition (altering
the composition of one or more of the
constituents), colour change.
Chemical interaction occurs between the ingredients
& a toxic & inactive product will be formed.
CHEMICAL INCOMPATIBILITY IS TWO
TYPES
Tolerated
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.
Adjusted
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
CHEMICAL INCOMPATIBILITY IS TWO
TYPES
INTENTIONAL
When the prescriber knowingly prescribes the incompatibility
drugs.
UNINTENTIONAL
When the prescriber prescribes the drugs without knowing
that there is incompatibility between the prescribed drugs.
Examples of Chemical Incompatibility
Formation of precipitate - Most alkaloid salts are soluble in water but
alkaloidal bases practically insoluble in water & are freely soluble in
organic solvents.
e.g. strychnine HCl aromatic spirit of ammonia purified water to 100ml.
In that case, strychnine HCl is an alkaloid salt & aromatic spirit of ammonia
is an alkaline substance.
Those, two insoluble mixture combine with each other that time forms the
precipitate of strychnine.
Inthis case, strychnine HCl solution should be dissolved in half quty. of
water & aromatic spirit of ammonia dissolved in the remaining quty. of
water.
Then mix both the mixture slowly.
Cont….
Gas formation
e.g. carbonates or bicarbonates with an acid or acidic drug resulting in
the evolution of carbon dioxide.
Ammonium carbonate
Ammonium Chloride
Acetic acid
syrup of cherry
Amm. Carb. + acetic acid CO2
So those compounds compounded in open container to avoid explosion.
Colour Changes
Colour changes due to changes in pH.
It can be prevented by properly buffering the vehicle.
Ionic Reaction
Many organic compounds associated with a large cation or
anions.
Interaction of such ions of opposing types may yield compound
which may totally lack the useful properties of the interacting
molecules.
e.g. cream prepared using cationic emulgent may crack if mixed
with a cream prepared using an anionic emulgent.
Therapeutic Incompatibility
Therapeutic incompatibility is also called as drug
interactions.
Itcauses modification of the therapeutic effect of
one drug by the prior concomitant administration
of another.
Itoccurs due to when drug or excipients, which
are antagonist to one another & are prescribed
together.
Therapeutic incompatibility occurs due to
following reasons viz…
Antagonistic combinations
Synergistic (or additive) combination
Contraindicated drug
Drug interaction
Wrong dosage form
Overdose
Therapeutic incompatibility
1. Synergistic (or additive) combination
When certain drugs having the same pharmacologic action are prescribed
together, the combined action they produce is greater than the sum of their
individual actions.
Such combinations should be in reduced amount.
Thesynergistic action will sometimes be desired to decrease toxicity or reduce
cost of prescription
Examples of useful synergistic effect
Combinations of sulfonamides show less nephrotoxicity than a single
sulfonamide.
Neomycin – erythromycin combination has a broader spectrum than either
antibiotic alone.
Aspirin – codeine combination reduces the amount of expensive codeine required.
Therapeutic incompatibility
2. Antagonistic combinations
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 tanninsAcidifiers
with alkalinizers e.g. aspirin with AL(OH)3.
Therapeutic incompatibility
Contraindicating Drugs
ContraindicatingDrugs are drugs when
prescribed together may lead to increased
toxicity or decrease activity.
Some drugs are not prescribed for lactating
mother because it will excrete into milk.
E.g.Phenytoin, Phenobarbitone,
Chloramphenicol etc.
Therapeutic incompatibility
Drug Interaction
Definition
e.g.tetracycline is inactivated by the milk due to
the presence of calcium and drugs containing
Ca+2. It forms insoluble, non-absorbable complex
with milk and not show any effect on systemic
circulation.
Therapeutic incompatibility
Wrong dosage form
There are some drugs which have similar names.
Digitoxin is a cardiac glycoside. It is a phytosteroid and
is similar in structure and effects to digoxin(though the
effects are longer-lasting). Unlike digoxin(which is
eliminated from the body via the kidneys), it is
eliminated via the liver, so could be used in patients
with poor or erratic kidney function.
Therapeutic incompatibility
Overdose (Dosage Error)
It can result from the administration of a single high dose, or
the too frequent administration.
It could be due to unclear prescription.
Example 1
R/Atropine sulphate 6 mg
Phenobarbital 360 mg
mgFt. caps, i mitte xiisig. caps, i t.d.s
Example 2
Codeine phosphate 15 mg
Ammonium chloride 500 mg
Ft. caps, i mitte xx
sig; caps, ii q.h.
Manifestations of Incompatibility
Insolubility of prescribed agent in vehicle (physical)
Immiscibility of two or more liquids (physical)
Precipitation due to change in menstrum that results in decreased solubility
(physical)
Eutexia-the liquefaction of solids mixed in dry state (physical)
Cementation of insoluble ingredients in liquid mixtures (physical)
Change in color (chemical)
Oxidation-reduction or explosive reaction (chemical)
Precipitation due to chemical reaction (chemical)
Inactivation of sulfa drugs by procaine HCI (therapeutic)
Inactivation of tetracycline by calcium ions (therapeutic)
Corrective Measures
Addition of an ingredient that does not alter the
therapeutic value.
Change of an ingredient. Minor changes such as a
soluble form of an ingredient for an insoluble form are
included.
Change of a solvent.
The utilization of special techniques in compounding,
such as treating each ingredient separately.
Omission of an agent that has no therapeutic value, or
that may be dispensed separately.
Utilization of special techniques in com- pounding
Intentional Therapeutic incompatibilities
Such circumstances rarely occur, but when they do it does not necessarily
indicate a moment of forgetfulness on the part of the physician. Such agents
may have been used together in order for one agent to modify the activity of
the other.
Examples: Atropine should antagonize the depressant effect of morphine to
the respiratory tract.
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.
Intentional Chemical Incompatibility
Strong iodine solution U.S.P. (Lugol’s solution)
R/
Iodine 50 gm
Potassium iodide 100 gm
purified water ad 1000 ml
Iodine dissolves in potassium iodide to form the
water soluble I3 complex.
Intentional chemical incompatibles
Carbonaeous mixture (Postion Revier Mixture)
Solution A:
R/
Sodium bicarbonate 3.5 gm
Simple syrup 30 ml
Water to 150 ml
Solution B:
R/
Citric acid 4 gm
Syrup lemon 30 ml
Water to 150 ml
Fait Mist. A and B, Mitte 50 ml of each
Sig.: one tablespoonful from solution A is mixed with an equal volume of solution B and the mixture
is taken when effervescence is about to cease
Intentional Physical incompatibilities
Tincture myrh is diluted with water to
give a precipitate which is used as a gargle
in the treatment of tonsillitis.
Take care
