Swat College of Pharmaceutical Sciences
Chapter # 3
Incompatibility
PHARMACY PRACTICE-II (DISPENSING, COMMUNITY, SOCIAL & ADMNISTRATIVE
PHARMACY)
3rd professional Notes
Composed by Sajadullah Reviewed by Dr. Irfan
Incompatibilities
Chapter # 3
INCOMPATIBILITY
Definition
When two or more ingredients of a prescription are mixed together, the undesirable
change that may take place in the physical, chemical or therapeutic properties of the
medicament is termed as incompatibility. It may affect the safety, efficacy and
appearance of a medicine.
Types
A. PHYSICAL INCOMPATIBILITY
A visible physical change takes place in this type of incompatibility. Usually, this is due
to immiscibility or insolubility. It can cause unsightly, non-uniform products from
which removal of an accurate dose is very difficult.
Physical incompatibilities are often called pharmaceutical incompatibilities and are
evidenced by the failure of the drugs to combine properly.
These types of incompatibilities can be corrected by one or more methods,
• Alteration in the order of mixing
• Alteration of solvents
Incompatibilities
• Alteration of volume
• Change in the form of ingredients
• Emulsification and addition of suspending agent,
• Addition, substitution or omission of therapeutically inactive substances.
Classification
(A) Immiscibility
(B) Insolubility
(C) Liquefaction
(A) Immiscibility:
1) Oils are immiscible with water and hence combination of oily drugs with water
produces a product possessing two separate layers.
Remedy:
This problem can be overcome by emulsification or solubilization (eg. Emulsion and
creams).
Incompatibilities
Example # 1:
RX
Olive oil 30ml
Water up to 120ml
Remedy:
Make an emulsion using a suitable emulsifying agent.
2) Care must be taken when concentrated hydro-alcoholic solutions of volatile
oils, such as spirits and concentrated water are used as adjuncts (e.g. as
flavouring agents) in aqueous preparations. Large globules of oils may be
separated.
Remedy:
To prevent the formation of large globules, the hydroalcoholic solution should either
be gradually diluted with the vehicle before admixture with the remaining ingredients
or poured into the vehicle with constant stirring.
3) Addition of high concentrations of electrolytes to mixture in which the vehicle
is a saturated aqueous solution of a volatile oil causes the oil to separate and
collect as a surface layer.
Incompatibilities
e.g. This happens in Potassium Citrate Mixture B.P.C in which large quantity of soluble
solid salts out the lemon oil.
Remedy:
To disperse the droplets evenly, quillaia tincture is added as a wetting agent.
(B) INSOLUBILITY
1) Liquid preparations containing indiffusible solids such as chalk, aromatic chalk
powder, Sulphamethoxazole, Phenacitin, calamine and zinc oxide (in lotions)- a
thickening agent isnecessary to obtain a uniform product from which uniform
doses can be removed.
Example # 1
RX
Sulpha-methoxazole 4.0g
Trimethoprim 0.8g
Na-CMC 0.5g
Purified water qs to make 100ml
Incompatibilities
Remedy:
A uniform distribution of the solids in the liquid phase can be achieved with
thickening agents.
2) Some insoluble powders such as Sulphur and certain corticosteroids
(hydrocortisone acetate) and antibiotics are difficult to wet with water.
Remedy: Wetting agents
e.g. saponins for Sulphur containing lotions and polysorbates in parenteral
suspensions of corticosteroids and antibiotics are used to distribute the powder and
prevent formation of a slowly dispersing, solid stabilized foam on shaking.
3) Sometimes excess of surface-active agent leading to deflocculation in a
suspension may result in claying.
Remedy: Reduce the concentration of surface-active agent.
4) When a resinous tincture is added to water, the water insoluble resin
agglomerate forming indiffusible clots.
Remedy:
This is prevented by slowly adding the undiluted tincture, with vigorous stirring, to a
diluted dispersion of protective colloid (Tragacanth mucilage or compound
tragacanth powder). This will produce a stable preparation.
Incompatibilities
5) Aqueous dispersion of Hydrophilic colloids i.e., polysaccharide mucilage is
precipitated by high concentration of alcohol or salts.
Remedy:
Well dilute and add small amounts with vigorous shaking.
6) High concentrations of electrolytes cause cracking of soap emulsions (ionic) by
salting out the emulsifiers.
7) Some medicaments are soluble in organic solvents but water-soluble adjuncts
(inorganic salts) may be precipitated in such solvents.
(C) LIQUEFACTION
When certain low melting point solids are powdered together a liquid or soft mass is
produced due to lowering of the melting point of the mixture to below room
temperature. Thus an eutectic mixture is formed.
Any two of the following exhibits this type of behavior:
Camphor, menthol, phenol, thymol and chloral hydrate, also sodium salicylate or
Aspirin with phenazone.
Incompatibilities
Example # 1:
RX
Camphor 2gm
Menthol 2gm
Talc q.s to make 100gm
Make powder
Comments: If these ingredients are triturated together, they will form an eutectic
mixture.
Remedy
Method- I:
When all the ingredients are triturated and an eutectic mixture (liquid) is formed, the
liquid is then triturated with enough absorbent powder e.g. light kaolin, light
magnesium carbonate or Talc, to give a free flowing powder.
Method-II:
Each ingredient is triturated separately with small amount of adsorbent or diluent and
then these powders are lightly mixed by tumbling action and packed.
The diluent largely prevents contact between the ingredients and adsorbs any liquid
that may be produced.
Incompatibilities
Example # 2:
Rx
Aminopyrine 0.3 g
Acetyl salicylic acid 0.2g
Codeine sulphate 0.015g
Belladonna extract 0.010g
Prepare capsules
Comment: In this prescription aminopyrine and acetyl salicylic acid form eutectic
mixture and wetting of belladonna extract give green colour.
Remedy
Light magnesium oxide (approximately 65 mg) may be added. The half quantity of
magnesium oxide is mixed with aminopyrine and the other half with acetyl salicylic
acid separately. The two are mixed gently and then other ingredients are added and
mixed gently.
(B) CHEMICAL INCOMPATIBILITY
Chemical incompatibility occurs when a reaction between two or more substances
lead to a change in chemical properties of pharmaceutical dosage form.
Incompatibilities
CAUSES
Chemically incompatibility is generally caused by pH change, a double decomposition
reaction or complex formation.
Provided the product is harmless the interaction falls into:
(a) Tolerated: the reaction is minimized by applying some suitable order of mixing or
mixing the solution in dilute form but no alteration is made in the active ingredients
of the preparation.
(b) Adjusted: the reaction is prevented by addition or substitution of one of the
reacting substances with another of equal therapeutic value but does not affect the
medicinal activity of the preparation (substitution of caffeine citrate with caffeine, in
sodium salicylate and caffeine citrate mixture).
Precipitate yielding combination
Generally, reaction between strong solutions proceed at a faster rate and the
precipitates formed are thick and do not diffuse readily. Reaction between the dilute
solutions proceeds at a slow rate and the precipitates formed are light and diffuse
readily in the solution. Hence the reacting substances should be diluted as much as
possible before mixing. The preparation should contain a thickening agent, if the
precipitate is non-diffusible.
Incompatibilities
Method A
This is suitable for diffusible precipitates
• Divide all or most of the vehicle into two portions
• Dissolve the reactants in separate portions
• Mix the two portions by slowly adding one to the other with stirring rapidly.
(Sometimes a small volume must be reserved for dissolving other ingredients, rinsing
measures, and adjusting to volume.)
Method B
It is used for bulky indiffusible precipitates.
• Divide the vehicle into two equal portions as in A.
• Dissolve one reacting substance in one portion.
• Place the other portion in a mortar and Incorporate a suitable amount of
Tragacanth powder (2gm/100ml of the finished product) with constant
trituration untill a smooth mucilage is produced, then add and dissolve the
other reacting substances.
• Mix the two portions by slowly adding one portion to the other with rapid
stirring.
Incompatibilities
pH effects
Modern medicaments are often salts of weak acids and bases. These salts are usually
soluble in water while most of the unionized acids and bases are practically insoluble.
Consequently, if a solution of weakly basic drug is made alkaline, the free base may
be precipitated, while precipitation of free acid may occur if a solution of a weakly
acidic drug is acidified.
Whether precipitation occurs or not depends on:
a) The solubility of the unionized acid or base.
b) The pH of the solution.
c) The dissociation exponent (pKa) of the acid or base
Solubility of the Unionized Acid or Base
Alkaloids
Most of salts are soluble in water but alkaloidal bases practically insoluble in water
and are freely soluble in organic solvents. When an alkaline substance like aromatic
spirit of ammonia, solution of ammonia, ammonium bicarbonate, Sodium
bicarbonate, Borax, etc., is added to an alkaloidal salt solution the free alkaloid may
be precipitated. However, they are not always precipitated, because all alkaloids are
slightly soluble in water. e.g., Strychnine, morphine, cocaine etc.
Incompatibilities
Other weak bases
Certain other organic bases (e.g., local anesthetics, methadone etc.) of low solubility
may precipitate under alkaline conditions.
Barbiturates
Barbiturates i.e. Phenobarbitone, pentobarbitone etc. are insoluble in water but their
salts are soluble in water. There salts make the solution alkaline and hence are
incompatible with acids, acidic salts (ammonium bromide) and acidic syrups (Lemon
syrup), which may precipitate the corresponding insoluble barbiturate.
Other weak acids
Certain other organic acids (e.g., sulphonamides) of low solubility may precipitate
under acidic conditions.
Generally Chemical incompatibilities results from:
1. ACID-BASE REACTIONS:
Acid base reactions often result into precipitation, gas formation, breaking of
structure of disperse systems or colour change.
(a) Precipitation
Most medicaments in use are often salts of weak acids or bases. These salts have very
good water solubility,whereas their corresponding unionized acids or bases are
Incompatibilities
practically insoluble in water. If a solution of a salt of a weakly acidic drug is acidified,
the free acid may be precipitated. Similarly, precipitation of free base may occur if a
solution of a salt of weakly basic drug is made alkaline.
Example # 1:
RX
Sodium salicylate 4g
Lemon syrup 20ml
Purified water q.s to make 100 ml
Make a mixture
Since Lemon syrup contains citric acid, it will acidify the solution and cause
precipitation of the free acid (salicylic acid).
Remedy: Use other sweetening and flavouring agent instead of lemon syrup.
This is an adjusted treatment not tolerated treatment because we substitute one
flavoring agent by another.
Incompatibilities
Example # 2
RX
Strychnine hydrochloride solution 5ml
Aromatic spirit of ammonia 3ml
Purified water q.s to make 100 ml
Make a mixture
Strychnine HCI used in the mixture is an alkaloidal salt, whereas aromatic spirit of
ammonia is an alkaline substance. On reaction between the two, insoluble strychnine
is precipitated.
Remedy: Strychnine HCl solution should be dissolved in half the required quantity of
water, while aromatic spirit of ammonia should dissolve in the remaining portion of
water. The two portions should be mixed slowly. (It is tolerated treatment).
(b) Gas Formation
Gas (e.g. CO₂) may be evolved due to chemical reaction between the
ingredients of a formulation. For compounding such preparations, the
ingredients should be allowed to react in an open vessel and only when the
reaction is complete, should the preparation be transferred to the final
Incompatibilities
container, otherwise there may be chances of explosion. The reaction may be
hastened by the use of hot water. Example: carbonates or bicarbonates with an
acid or acidic drug resulting in the evolution of carbon dioxide.
Example #1:
RX
Sodium bicarbonate 1.5g
Borax 1.5g
Phenol 0.75g
Glycerin 25ml
Water q.s to make 100ml
Prepare a spray
In this case, borax decomposes in presence of glycerin to form sodium metaborate
and boric acid. The resultant boric acid reacts with glycerin to form Glyceryl boric acid
which upon reaction with bicarbonates yield CO₂.
Incompatibilities
Example # 2
Reaction of alkali Bicarbonates with soluble calcium and magnesium salts
When alkali bicarbonates are combined with soluble calcium and magnesium salts,
double decomposition reaction occurs resulting in the formation of corresponding
insoluble carbonate and carbon dioxide. Since the reaction proceeds slowly at room
temperature, it should be accelerated by using a hot vehicle and the resulting mixture
should not he packed until reaction is complete.
3. Breaking of structure of disperse system
Gelling agent such as carbomers, sodium carboxymethyl cellulose etc. very rapidly
lose viscosity by change in pH outside an optimum range.
• Carbomer dispersion liquify by decreasing their pH below 5 or increasing it
above 10.
• Alginic acid is precipitated from dispersion of sodium alginate at pH below 3.0.
• Carboxy methyl cellulose is precipitated from its sodium derivatives at pH
below 3.0.
Incompatibilities
Emulsion prepared using soap as emulsifying agent are liable to break in presence of
mineral acids which destroy the emulsifying activity of soap by precipitating the acids.
When a dispersion system e.g. cream is diluted with another of different PH,
precipitation and or degradation of active ingredients may occur.
4. Colour change
The colour of most of the dyes used in formulations is influenced by their ionization
which in turn depends on the pH of the solution, thus crystal violet which is also used
as antiseptic is a purple coloured compound but changes colour through green to
yellow on acidification. Similarly, phenolphthalein (used as laxative) is colourless in
acidic solution but becomes pink in alkaline media. Colour change due to change in
pH can be prevented by properly buffering the vehicle or by preventing reaction that
cause formation of free acid or base in the medium.
(2) OXIDATION-REDUCTION REACTION
Certain prescription mixtures may oxidize on exposure to air, heat, light or due to
change in pH or reaction with trace metal ions. Use of antioxidants like ascorbic acid,
Sodium metabisulphite etc, is often helpful in each cases.
Incompatibilities
Oxidation due to trace metal ions can be prevented by the use of chelating agents like
Disodium EDTA.
Example # 1
RX
Potassium Chlorate 4g
Ferric Iodide syrup 10ml
Purified water q.s. to make 60ml
Make a mixture
In this case potassium chlorate react with ferric iodide, Initially the mixture is quite
clear but on standing, crystals of iodine are deposited. It is therefore essential to
dispense the two compounds separately with instructions to mix the two before
administration.
Example # 2:
RX
Sodium salicylate 4g
Sodium bicarbonate 4g
Peppermint water 60ml
Incompatibilities
Make a mixture
Sodium salicylate gets oxidized in presence of sodium bicarbonate and the mixture
darkens on storage. This alkaline catalyzed oxidation may however be prevented by
the use of a suitable antioxidants like 0.1% sodium metabisulphate.
(3) COMPLEXATION
Many macromolecular adjuncts used in formulation form complexes in which
medicaments and preservatives are bound to the macromolecules or trapped within
micelles. This behavior is most common with non-ionic macromolecules. Because
these complexes are too large to penetrate cell membranes, the activity of the
medicament or preservatives may be greatly reduced. A number of medicaments and
excipients like suspending agent (polysaccharides), emulgents (macrogol esters and
ethers) and solubilisers (polysorbates) exhibit this phenomenon.
Complexation may sometimes be useful especially when it is reversible. In such case
a large amount of drug is available in the unbound form and when this drug is utilized,
it is replaced from the complex. Thus the complex provides a reservoir of drug from
which a sate but sufficient concentration is available to the tissue over a prolonged
Incompatibilities
period. A 10 to 15 % aqueous: solution of Povidone has been found suitable for this
purpose.
Complex Formation may also reduce the irritancy and improve the stability of a drug
as in Iodophores, which are complexes of lodine in which the Halogen is bound to a
water-soluble polymer (Povidone) or solubilised in the micelles of surfactants.
(4). IONIC REACTIONS
The therapeutic or pharmaceutical properties of many organic compounds are
usually associated with a large cation or anion. Interaction of such ions of opposing
types may yield compounds which may totally lack the useful properties of the
interacting molecules.
• For instances, Cream prepared using cationic emulgent may crack if mixed with
a cream prepared using an anionic emulgent.
• Similarly, anionic solubilizers may lower the antimicrobial activity of a cationic
medicament or preservative.
• lonic incompatibilities may however be prevented by carefully selecting the
medicaments and adjuvants in a proposed formulation so as to exclude
combination of anionic and cationic ingredients in a single formulation.
Incompatibilities
• In case of emulsified system containing an ionic medicament or preservative, it
may be advantageous to use a non-ionic emulsifier.
(5). EXPLOSIVE COMBINATION
Oxidizing agents are chemically incompatible with reducing agent and a combination
of the two in a formulation may lead to an explosive reaction.
For example, if Potassium chlorate is prescribed with an oxidizable substance like
Sulphur, tannic acid, etc. and the two are triturated or heated together, there is a fair
chance of an explosive reaction taking place. In such case, it is better to dispense the
components separately or if it is necessary to mix them together, the mixing should
be done very lightly.
Therapeutic Incompatibility
Therapeutic incompatibility occurs when an undesirable pharmacological reaction
occurs within the patient as a result of two or more incompatible medications
prescribed concurrently (also called Drug Interactions). These medications do not
necessarily have to be given via the same route. They exist when the response to one
or more drug is of different nature or intensity than that intended by the prescriber.
Incompatibilities
(In cases of doubts on the part of the pharmacist, the prescribing physician should be
consulted).
Mechanisms of therapeutic incompatibility
They are divided into two groups:
(1) Pharmacokinetics:
One drug affects the absorption, distribution, metabolism and excretion of another
drug.
(2) Pharmacodynamics:
One drug affects the pharmacological activity of another drug. e.g. synergism,
antagonism etc.
Pharmacokinetic interactions
1. Altered GIT absorption
(a) Altered pH
The non-ionized form of a drug is more lipid soluble and more readily absorbed
from GIT than the ionized form.
Example: Antacid increases pH and lowers absorption of acidic drugs (i.e.
Ketoconazole). Therefore, these drugs must be separated by at least 2 hours in
the time of administration of both.
Incompatibilities
(b) Altered intestinal bacterial flora
Certain drugs activity is influenced by normal intestinal bacterial flora which
in turn is affected by antibiotics administration.
Example: 40% or more of the administered dose of digoxin is metabolized by
the intestinal flora. Therefore, antibiotics cause high concentrations of digoxin
by killing these bacteria. (Toxicity will occur)
(c) Complexation or chelation.
Example: Tetracycline forms complexes with calcium and iron containing
preparations. Similarly, antacid (aluminium and magnesium hydroxide)
chelates ciprofloxacin and decrease its absorption by 85%. (Absorption
decreases)
(d) Drug-induced mucosal damage
Example: anticancer drugs i.e., Vincristine, cyclophosphamide inhibit
absorption of certain other drugs. Le., digoxin.
(e) Altered motility
Example: Metoclopramide (antiemetic) enhance stomach emptying and
increase absorption of certain other drugs i.e. Cyclosporine.
Incompatibilities
(2) Altered protein binding (Distribution)
Certain high affinity drugs displace other plasma protein bound drugs and thereby
increases its concentration.
Example: Phenytoin (90% bound) and warfarin (99% bound) are displaced by
Aspirin and Sulfonamides.
(3) Altered Metabolism
Majority of drugs are metabolized by CYP450 family, Certain drugs either
induce or inhibit these enzymes and thereby affecting the metabolism of co-
prescribed drugs (substrates).
(a) Enzyme induction
Example: Phenytoin increases hepatic metabolism of theophylline leading to
its decreased levels and reduced action.
(b) Enzyme inhibition
Example: Verapamil inhibits carbamazepine metabolism and increases its
concentrations. Omeprazole Inhibits oxidative metabolism of diazepam.
(4). Altered Renal Excretion
(a) Inhibition of renal tubular secretion
Incompatibilities
When a drug has a competitive reactivity to the protein that is responsible for
active transport of another drug. This will reduce such a drug excretion
increasing its concentration and hence its toxicity.
Example: Probenecid... Decreases tubular secretion of methotrexate.
(b) Alteration of urine pH
Iionized drugs are reabsorbed lower than non-ionized ones. Making the pH of
urine acidic will make weakly basic drugs ionized and hence enhance their
excretion.
These are useful in some clinical situations such as poisoning treatment. For
example, amphetamine poisoning can be reversed by enhancing its excretion via
urine acidification.
Pharmacodynamic interactions
(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. The synergistic action will
sometimes be desired to decrease toxicity or reduce cost of prescription.
Incompatibilities
Examples
• Neomycin-erythromycin combination has a broader spectrum than either
antibiotic alone.
• Aspirin-codeine combination reduces the amount of expensive codeine
required.
• Sulphonamides-trimethoprim combination (broader spectrum).
(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 tannins.
• Acidifiers with alkalinizers e.g. aspirin with AL(OH)3.
• B-adrenoceptor antagonists ie., Propranolol diminishes the effectiveness
of B-receptor agonists, i.e., salbutamol or terbutaline.
Sometime this antagonistic affect is desirable e.g. Protamine is administered as an
antidote to anticoagulant action of heparin (toxicity).