Incompatibilities

Kh Sadique Faisal
Asst. Lecturer
Northern University Bangladesh


Incompatibilities

It is the result of prescribing or mixing two
or more substances which are antagonist
in nature and an undesirable product is
formed which may affect the safety,
purpose or appearance of the preparation.
Incompatibility may be :
-Pharmaceutical
-Therapeutic
Pharmaceutical incompatibilities
- Physical or
- Chemical incompatibilities.
- Are usually unintentional
- Occur in vitro between drugs and other
components during preparation, storage
or administration.

Physical Incompatibility

A visible physical change takes place
An unacceptable, non-uniform, unsighty,
unpalatable product product is formed.
Difficult to measure an accurate dose.

Result of insolubility and immiscibility,
precipitation, liquefaction, Adsorption and
complexation of solid materials.
Can be corrected by applying pharmaceutical
skill
Correction(Physical
incompatibilities )
By one or more methods:
Order of mixing
alteration of solvents
change in the form of ingredients
alteration of volume
Emulsification and addition of suspending agent,
addition, substitution or omission of
therapeutically inactive substances.
1. Insolubility and immiscibility
It is the result of the mixture of two or more immiscible
liquid or an immiscible solid with a liquid

-Acceptable liquid product can be obtained by
emulsification or solubilization
(a)
Rx
Olive oil 30ml
Water up to 120ml
make an emulsion
use a suitable emulsifying agent
b. Liquid preparation with Indiffusible solids (
Sulphamethoxasole, phenacetin, Zinc oxide,
calamine etc.) + a suspending agent = a
uniform distribution of the solids in the liquid
phase for sufficiently long time so as to facilitate
accurate measurement of dose.
Rx,
Sulphamethoxazole 4.0g
Trimethoprim 0.8g
Na- CMC 0.5g
Purified water qs to 100ml
Sulphamethoxazole &Trimethoprim are
indiffusible in water. To make them diffusible a
suspending agent is used
c. Insoluble Powders (Sulpher, certain
Corticosteroids and Antibiotic) + Water =
Non-wetted, non distributed liquid powder
Product.

Insoluble non-wetted drug Powders + Water +
wetting Agent (Saponins for sulpher drug
containing lotions and Polysorbate for
corticosteroids and Antibiotic = uniformly
dispersed Powder product in water
.



2. Precipitation
a. A solubilised substance may precipitate
from it solution if a non solvent for the
substance is added to the solution.
i. Alcohlic solution of Resins + water =
precipitated Resins
ii. Aqueous dispersion of Hydrophillic
colloids (polysaccharide mucilage + high
conc. of Alcohol or salts = Precipitated
colloids.


But significant amount are tolerated if well diluted and added in small
amount with vigorous stirring
b. High concentration of electrolytes cause Cracking of
soap emulsion by salting out the emulsifying agents.

c.Vehicles (one or more organic liquids) use to dissolve
medicaments of low solubility, water soluble adjuncts
particularly inorganic salts may be precipitated in such
vehicles.


3. Liquefaction

Certain low melting point solids sometimes liquefy when mixed
together due to the formation of eutectic mixture or liberation of
water .
For example, if any two of the following medicaments are combined
together, they form a eutectic mixture: Menthol, Thymol, Camphor,
Phenol, Salol, Naphthol and chloral hydrate. Also Sodium salicylate
or asprin with Phenazone

In order to overcome such incompatibility, the eutectic forming
ingredient may either be dispensed separately or these may be
mixed separately with enough quantity of adsorbent powder like
magnesium carbonate or Kaolin to form free flowing product.
Alternately, if liquefaction has already occurred, the liquid may be
adsorbed on a surface of sufficient quantity of powder , filled into
capsule and dispensed
Example:
Menthol 2.0g
Camphor 2.0g
Ammonium carbonate 20.0g
Make a powder.
In this case, if the ingredients are mixed together, they
shall liquefy due to formation of a eutectic mixture.
Hence, to dispense them in the form of a powder, it is
necessary to mix them separately with sufficient quantity
of a suitable adsorbent like magnesium carbonate. The
three mixture then mix together to obtain a powder.
d. Adsorption and Complexation

Certain substances including drugs and excipients may
interact to form physical complex which may alter the
appearance or activity of the medicament,

For example, mixtures containing clays such as Kaolin,
Attapulgite or suspended antacids may pose
incompatibility problems due to adsorption

Adsorption of Cyanocobalamin by Talc, a tablet lubricant
may decrease the absorption from GIT.

Similarly Adsorption of antimicrobial preservatives such
as parabens on to the drugs or excipients may lead to
loss of their antimicrobial activity.
-
Chemical Incompatibilities

Chemical Incompatibilities is usually a
result of chemical interaction taking place
among the ingredients of a prescription.
Such interactions may take place
immediately upon compounding when
these are termed as immediate in
compatibilities and are evident as
effervescence, precipitation or colour
change.
More often the interaction are not evident
immediately on compounding but take
place over a period of time. Such
interaction are termed delayed
incompatibilities.
Provided the product is harmless
the interaction fall into:
a. Tolerated-: the reaction is minimised 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 of the preparation (substitution
of caffeine citrate wih caffeine in sodiun
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 proceed 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.

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 morter 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.

Chemically incompatibility is generally caused by pH change, a
double decomposition reaction or complex formation.

pH effects
Modern medicament 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 salt 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 occur 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

1. Alkaloids
Most alkaloidal 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
and other added substances, for examples
a) Strychnine
Strychnine is a constituent of Nux Vomica Tincture which
is used in some official mixtures as a bitter to stimulate
the appetite.
The amount of strychnine present is 0.125 gm per
100ml of tincture nux vomica and the solubility of
strychnine is about 1 in 7000, i. e., 100 ml of water will
dissolve
1 x 100 / 7000 = 0.143 gm of Strychnine
Hence the amount of strychnine in 10 ml of tincture will
dissolve easily in 100 ml of water and therefore, 10 % of
the tincture in water will not precipitate in alkaline
conditions.
Further , tinctures contain certain amount of
alcohol due to which the precipitation is further
prevented.
Moreover the solubility of strychnine is much
more in alcohol (i. e. 1 in 150) than in water.
Therefore it follows that in mixtures sufficient
amount of alcohol strychnine will not be
precipitated even when more than 10 ml of
tincture per 100 ml is present in the
prescription.
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 a very good water solubility
whereas their corresponding unionised acids or
bases are 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

Sodium salicylate 4g
Lemon syrup 20ml
Purified water to 100ml
make a mixture
Since Lemon syrup contains citric acid, it
will acidify the solution and cause
precipitation of the free acid (salicylic
acid).
In order to overcome this incompatibility,
it is necessary to use other sweetening
and flavouring agent instead of lemon
syrup.
Example II

Strychnine hydrochloride solution 5ml
Aromatic spirit of ammonia 3ml
purified water to 100 ml
make a mixture
Strychnine HCl 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.
since the precipitate formed is diffusible, the
incompatibility may be taken care by suitable formulation.
In this case, strychnine HCl solution should be dissolved in
half the required quantity of water while aromatic spirit of
ammonia should dissolved in the remaining portion of
water. The two portion should be mixed slowly.
b. Gas formation


Gas may be evolved due to chemical reaction
between the ingredients of a formulation.
Example: carbonates or bicarbonates with an acid
or acidic drug resulting in the evolution of carbon
dioxide

Example 1:
Reaction of sodium bicarbonate, borax and
glycerol
Rx
Sodium bicarbonate 1.5g
Borax 1.5g
Phenol 0.75g
glycerin 25 ml
water to 100ml
Prepare a spray

In this case , borax decomposes in
presence of glycerin to form sodium
metaborate and boric acid
Na2B4O7 + 3H2O = Na2B2O4 + 2H3BO3
Borax Sodium metaborate Boric acid
Boric acid thus formed further reacts with
glycerin to form Glyceryl boric acid
2C3H5(OH)3 + 3H3BO3 ---- (C3H3)2(HBO3) + 6H2O
Glycerin Boric acid Glyceryl boric acid
For compounding of such preparation, 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 container,
otherwise there may be a chances of
explosion. The reaction may be hastened
by the use of hot water
Example II
Reaction of alkali bicarbonates with soluble calcium and
magnesium salts, l
When alkali bicarbonate are combined with
soluble calcium and magnesium salts, double
decomposition reaction occurs resulting in the
formation of corresponding insoluble carbonate
and carbon dioxide
2NaHCO3 + CaSO4 ----------- Ca(HCO
3
)
2
+
Na2SO4
4Ca(HCO3)
3
----------------- 3CaCO3 + Ca(OH)2
+5CO2 +3H2O
Since the reaction proceeds slowly at room temperature, it
should be accelerated by using a hot vehicle and the
resulting mixture should not be pocked 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 P
H
below
5 or increasing it above 10.
Similarly, below a P
H
3, alginic acid is precipitated from
dispersion of sodium alginate and carboxy methyl
cellulose is precipitated from its sodium derivatives.
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
d. Colour change

d. 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 phenolphthelin
(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 oxidise 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.
Oxidation due to trace metal ions can be
prevented by the use of chelating agents like
Disodium EDTA.
Example I
RX,
Potassium Chlorate 4g
Ferric iodide syrup 10 ml
Purified water to 60 ml
Make a mixture
In this case potassium chlorate react with ferric iodide.
Initially the mixture is quite clear but on standing,
crystals of iodine is deposited. It is therefore essential to
dispense the two compounds separately with instructions
to mix the two before administration.

Example II

RX,
Sodium salicylate 4g
Sodium biocarbonate 4g
Peppermint water to 60mi
make a mixture
Sodium salicylate gets oxidized in presence of
sodium biocarbonate 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.
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 complex 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
(macrogel esters and ethers) and solubilisers
(polysorbates) exhibit this phenomenon.
Complexation may sometimes be useful specially when it
is reversible. In such case a large amount of drug is
available in the unbound form and when this drug is
utilised, it is replaced from the complex.
Thus the complex provides a reservoir of drug from
which a safe but sufficient concentration is available to
the tissue over a prolonged 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 Iodine 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 an anionic solubilizers may lower the
antimicrobial activity of a cationic medicament or
preservative.
Ionic incompatibilities may however be
prevented by carefully selecting the
medicaments and adjuvents in a proposed
formulation so as to exclude combination of
anionic and cationic ingredients in a single
formulation.
In case of emulsified system containing an ionic
medicament or preservative, it may be
advantageous to use a non-ionic emulsifier.

5. Explosive combination

Oxidising agents are chemically in compatible 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
oxidisable 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.