Pharos University

Faculty of Pharmacy & Drug Manufacturing

Principles and kinetics of Drug Stability Practical-PHR 416

Lab-8
Incompatibilities in Pharmaceutical Preparations
The term incompatibility may be applied to pharmaceuticals when a problem arises during
the pharmaceutical compounding of more substances because of their therapeutic,, physical
or chemical properties, the substances are said to be incompatible. A preparation is
considered to posses an incompatibility when combination of its ingredients adversely affects
its appearance, elegance or therapeutic efficacy.
Incompatibility may be classified into three main groups: therapeutic, physical and chemical.

1. Incompatibility involving Surface active agents

Types of surfactants:
a-Anionic (-)
Ex: SLS, sodium stearate, potassium stearate.
b-Cationic (+)
Ex: cetrimide.
c- Amphoteric (+&-)
Ex: Betaines.
d-Non ionic
Ex: span & tween.
a. Interaction between oppositely charged surfactants
The interaction occurs upon mixing anionic surfactants with cationic surfactants. This may be
manifested, visually, as turbidity or formation of a precipitate. The surface activity of both
materials will be drastically reduced.
This occurs upon mixing sodium lauryl sulphate with cetrimide.

Procedure:
1-add 2 ml of 0.1% w/v sodium lauryl sulphate.
2-add cetrimide solution (0.1%) drop wise, and observe any change in the clarity of the
solution.
3-add excess of cetrimide solution (about 5 ml )to the turbid solution and record any change.
b. Interaction between surfactants and drugs.
− Drugs may interact with surfactants carrying opposite charge.
The results of this type of interaction are:
I- reduction of the therapeutic effectiveness of the drug
II- reduction of the surface active property of the surfactant

1
 − SAA and acidic drug or excipient :
It occurs with soap surfactants which are salts of weak fatty acids easily displaced by
stronger acids.
e.g. Na Stearate + Salicylic acid stearic acid (ppt) + sodium salicylate
It results in loss of surface activity.
- SAA and Heavy metals
e.g. Na Stearate + Ca+2 Ca Stearate (insoluble in H2O)
It can occur by hard water which contains divalent ions.

Practical experiments
Interaction in soap emulsions
Emulsions made with monovalent soap may undergo craking or phase inversion, if the
medium contains polyvalent ions or if the medium is acidic.

2 C17 H35 C OO Na +MgCl2 (C17 H35 C OO)2 Mg+2 NaCl

C17 H35 C OO Na + H+ C17 H35 C OO H + Na+

− Turpentine liniment:
R/
Soft soap 1.5 gm
Camphor 1g
Turpentine oil 13 ml
Distilled Water 4.5 ml
Prepare 20 ml of turpentine liniment.

Procedure:
1. Dissolve the soft soap in water in a casserole by soaking soft soap in specified amount
of water for 10 min on a water bath.
2. Dissolve camphor in turpentine oil.
3. Add oil phase to soap solution with constant stirring in one and the same direction.
4. Take 10 ml liniment in test tube & add 2 ml of 5 % CaCl2 solution, shake and observe
the stability of the emulsion cracking
5. Add 3ml of dilute hydrochloric acid to 10 ml of liniment shake and observe the
stability of the emulsion cracking

Comment on your observation.

What will happen if amount of CaCl2 solution added is increase

2
 − Cleansing lotion:

R/
Beeswax 1g
Liquid paraffin 8.2ml
Stearic acid 260 mg
Triethanolamine 2.8 ml
Salicylic acid 5g
Water 9 ml

The lotion is in the form of emulsion.

Emulsifier is Triethanolamine Stearate which is formed in-situ emulsifier.
TEA + Stearic acid TEA Stearate

1. Melt Stearic acid, beeswax in a casserole on a water bath; add liquid paraffin after
melting other ingredients.
2. Mix TEA in calculated amount of water in a beaker and warm them on water bath.
3. Add content of beaker to the casserole on the water bath and mix vigoursly in one
direction till formation of milky emulsion.
4. Continue stirring outside the water bath till cold.
5. Add the lotion on salicylic acid in a mortar and mix well.
6. Comment on what happened.
2. Incompatibility of soluble salicylates and benzoates with acidic drugs
Salicylic and benzoic acids are poorly soluble in water. In acid medium, soluble salicylates
and benzoates precipitate the free insoluble acids.

C6H5-COO Na + H+ C6H5 COO H + Na+

Free acids or acidic drugs or adjuvants imparting acidic pH values will precipitate the free
acid.

For example:
Lemon syrup contains citric acid and, therefore is unsuitable for flavouring sodium salicylate
or benzoate containing preparations. If prescribed, it can be replaced by a mixture of lemon
tincture and simple syrup.

A) Prepare 3% of sodium salicylate solution containing 30 % V/V lemon syrup, B.P.C.

R/
3
 Sodium salicylate 3 gm
Lemon syrup 30 ml
Water to 100 gm
Send 25 ml
Procedure:
1. Dissolve Na salicylate (or benzoate) in 15 ml water in a beaker.
2. Add lemon syrup and transfer to cylinder.
3. Complete volume to 25 ml and transfer to bottle.
4. Observe the clarity of this product.
5. Comment on your observation.

− Repeat the above preparation, but using 30 % V/V of Lemon tincture in simple
syrup (10% V/V).
− Compare the clarity of this preparation with previous one.
3. Incompatibility of phenolic drugs with ferric ions
Phenolic drugs as salicylates, resorcinol, adrenaline and oxyphenbutazone, react with ferric
ions to give a violet green colour.

Source of ferric ions

1. As impurities in other chemicals or ingredients used in the formulation.
2. From metallic containers e.g. tanks, mixers, spautals.
3. Water if not distilled, may contain heavy metal impurities as ferric.
The discolouration may occur immediately or after storage of the formula.
Treatment
1. It is better corrected by avoiding the source of this interaction.
2. It is prevented by the addition of ions such as tartrate or citrate which complex with ferric
ions.

A) prepare 25 ml of sodium salicylate mixture B.P.C. 25 %

R/
Sodium salicylate 50 gm
Chloroform water (double strength) 500 ml
Water to 1000 ml

B) Repeat the above prescription by using water containing 100 ppm of iron and observe the
colour of the mixture.

C) Repeat the mixture B but using water containing 100 ppm of iron and 2 % Sodium citrate.