This document discusses pharmaceutical incompatibilities, specifically physical incompatibilities. It defines pharmaceutical incompatibilities as undesired changes in safety, appearance, or therapeutic purpose that occur when mixing substances or drugs with antagonistic chemical, physical, or therapeutic properties. Physical incompatibilities are caused by insolubility, precipitation, immiscibility, liquefaction of solids, evaporation, adsorption, absorption, or physical complexation. Remedies include changing the order of mixing, altering solvents, modifying ingredient forms or dosage forms, adding emulsifiers or suspending agents, and adjusting therapeutically inactive substances. Common examples like insoluble solids in suspensions and eutectic mixtures that liquefy are described.

1. SHITAL TRIVEDI
ASSISTANT PROFESSOR,
Department of pharmaceutical technology,
L.J.INSTITUTE OF PHARMACY
Subject: Pharmaceutics
SEMESTER 1
Pharmaceutical Incompatibilities-
Physical Incompatibilities

2. Pharmaceutical Incompatibilities
• Definition:
Pharmaceutical Incompatibilities refer to the undesired changes (in terms of safety,
appearance &/or therapeutic purpose) which occur by prescribing or mixing of the
formulation substances or drugs which are antagonistic in nature because of their
chemical, physical or therapeutic properties.

3. Types of Pharmaceutical Incompatibility
1. Physical incompatibilities
2. Chemical incompatibilities
3. Therapeutic incompatibilities
1. Physical Incompatibility
• Definition:
• Physical Incompatibilities refer to the undesired changes (in terms of safety,
appearance &/or therapeutic purpose) which occur on mixing of the substances
or drugs which are antagonistic in nature because of their physical properties.

4. 2. Chemical Incompatibility
• Definition:
• Chemical Incompatibilities refer to the undesired changes (in terms of safety,
appearance &/or therapeutic purpose) which occur on mixing of the substances
or drugs which are antagonistic in nature because of their chemical properties.
3. Therapeutic incompatibility
• Definition:
• Change in therapeutic response or intensity of response of one or more drugs,
which is not intended by the prescriber, is called therapeutic incompatibity. (It is
also called drug interactions).

5. Physical Incompatibility
• Reasons for Physical Incompatibilities:
1. Insolubility
2. Precipitation
3. Immiscibility
4. Liquefaction of solid
5. Evaporation, Adsorption, Absorption and physical complexation.
• Physical appearance like clarity, color, viscosity, may get changed. Product may
become non uniform &/or unpalatable and may result into unacceptable product.
• Therapeutic effect may or may not be affected.

6. Insolubility:-
• Liquid dosage form (Suspension) containing Insoluble solid dug in vehicle.
• Sedimentation of solid drug particles, may result into dosage inaccuracy.
• Solid can be Diffusible “ SHAKE WELL BEFORE USE” on label
to ensure dosage uniformity
Indiffusible 1) Addition of suspending agents.
e.g.. 2 % w/v CPT (Compound
powder of tragacanth )
2) “SHAKE WELL BEFORE USE”
3) Change in dosage form.
• Diffusible solids: e.g. Bismuth carbonate, Light Kaolin, Magnesium carbonate etc.
• Indiffusible solids: e.g. Aspirin, Zinc oxide, Calamine, Phenacetin.
• CPT as per B.P.: Tragacanth, 1; gum acacia, 1; starch, 1; refined sugar, 3.

7. Immiscibility:-
• Liquid dosage form contains two immiscible liquids.
• Product will be non uniform and inelegant. Sedimentation of heavy liquid or
creaming of low density liquid, may result into dosage inaccuracy.
• E.g. Castor oil…… 30 ml
Purified water q.s. to 100 ml
Remedy: 1.) Addition of suitable emulsifiers.
2.) “ Shake well before use”
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8. Precipitation:-
• Solubilized substance /drug may get precipitated out from its solution because of
change in solubility due to change in solvent system.
• E.g. Alcoholic solution of Resin + water Precipitation of Resin
• Aqueous dispersion of hydrocolloids + Alcohol/Excess salt Precipitated
colloids.
• Precipitate can be Diffusible “ SHAKE WELL BEFORE USE” to
ensure dosage uniformity
Indiffusible 1) Addition of suspending agents.
e.g.. 2 % w/v CPT (Compound
powder of tragacanth )
2) “ Shake well before use”
3) Change in dosage form.

9. Liquefaction of solids
• Eutectic solids: Certain low melting points solids when mixed together liquefy due
to formation of eutectic mixtures.
• They form a soft mass/liquid when mixed together.
• Ex- Menthol, Thymol, Camphor, Phenol, Aspirin.
• Remedy:
1) Eutectic forming ingredients may be dispensed separately.
2) Addition of adsorbent:
A) Ingredients may be mixed separately with sufficient quantity of adsorbent like
Kaolin or Magnesium carbonate and then gently mixed together.
B) If Liquefaction of solids observed, then liquid may be adsorbed over the surface
of adsorbent to make it free flowing powder.
• Deliquescent solids may turn into liquid. E.g. Table Salt. Calcium Chloride, NaOH,
KOH, Ammonium Chloride.

10. • Evaporation of water Increase the concentration of drug.
Crystallization (e.g. Syrups)
• Adsorption: Adsorption of antimicrobial preservatives such as parabens on to the
drugs or excipients may lead to loss of their antimicrobial activity.
• Absorption: Hygroscopic substances absorb atmospheric moisture, may form
lump.
• Complexation:
Certain substances including drugs and excipients may interact to form physical
complex which may alter the appearance or activity of the medicament.
e.g. β-cyclodextrin complexation.

11. Remedy-Physical incompatibilities
• By one or more methods:
• Order of mixing
• Alteration of solvents
• Change in the form of ingredients (More soluble form)
• Change in the dosage form.
• Emulsification and addition of suspending agent,
• Addition, substitution or omission of therapeutically inactive substances.

12. FAQs
1. Define Pharmaceutical incompatibilities. Explain physical incompatibilities.
2. Explain physical incompatibility due to liquefaction with remedy.

13. Chemical Incompatibility
• Definition:
Chemical Incompatibilities refer to the undesired changes (in
terms of safety, appearance &/or therapeutic purpose) which
occur on mixing of the substances or drugs which are
antagonistic in nature because of their chemical properties.

14. Chemical incompatibility: Chemical reactions
Chemical incompatibilities occur, due to the chemical
properties of drugs and additive like,
• PH change
• Oxidation-reduction reactions
• Acid-base hydrolysis ( E.g. Aspirin hydrolysis to Salicylic and
acetic acid.)
• Double decomposition
• Isomerisation
• Polymerisation
• Decarboxylation
• Carbon dioxide Absorption
• Complex formation (E.g. Heavy metals inactivate tetracycline)

15. Chemical incompatibility may result into….
• Precipitation
• Effervescence
• Decomposition/degradation
• Color change
• Explosion

16. Correction of incompatibility due to oxidation
• Addition of antioxidants.
• Addition of chelating agents to reduce the effect of metals.
(Presence of metal potentiate oxidation)
• Change in dosage form….liquid to solid.
• Addition of buffer to maintain pH.
• Storage at low temperature.
• Replacement of oxygen with nitrogen.
• Protection of drug product from light (if photo-oxidation)
– Storing in amber color container
– Storage in dark place
– Packing with light absorbing substances

17. Correction of incompatibility due to Hydrolysis
• Addition of moisture absorbents.
• Change in solvent system to replace aqueous system.
• Change in dosage form….solution to suspension to solid.
• Addition of buffer to maintain pH.
• Storage at low temperature.
• Addition of complexing agent to reduce free drug.
• Protection of drug product from air humidity
– Storing in moisture proof container
– Storage in dry place

18. Types of Chemical Incompatibilities
• Based on method of rectification.
1. Tolerated incompatibility: -
In this type of incompatibility, the chemical reaction can be
minimized by way of applying suitable order of mixing or any
modification in the process without any alteration in the active
ingredients of the prescription.
2. Adjusted incompatibilities: -
In this type of incompatibility, preparation is prepared either
by some addition or substitution or deletion of any of the
ingredient in the prescription to prevent the harmful reaction
without altering its therapeutic value.

19. Types of Chemical Incompatibilities
• Based on chemical reaction rate.
1. Immediate incompatibility: -
• If the chemical reaction takes place, immediately after
combining the prescription ingredients, it is called
immediate incompatibility.
• Hence, product should be dispensed only after correction.
2. Delayed incompatibilities: -
• When the chemical reaction proceeds at a very slow rate
and no appreciable visible change occurs immediately but
which may develop on keeping the product for long time,
called delayed incompatibility.

20. Types of Chemical Incompatibilities
• Based on intention of the prescriber
1. Intentional incompatibility: -
When the prescriber knowingly prescribes the incompatible
drugs.
2. Unintentional incompatibilities: -
When the prescriber prescribes the drugs without knowing
that there is incompatibility between the prescribed drugs.

21. Precipitation yielding incompatibility
• E.g. of Precipitation yielding reaction:
Alkaloidal salt (Strychnine hydrochloride solution) + Alkaline
substance( Aromatic spirit of ammonia)
Alkaloidal base (Precipitated)….depends on solubility of
alkaloidal base.
• Precipitate can be diffusible or indiffusible.
If diffusible ppts., follow method A as remedy.
If indiffusible ppts., follow method B as remedy.

22. Remedy: Precipitation yielding incompatibility
• Method A:
• Divide the vehicle into two portions. Dissolve the reactants
in separate portions and mix the two portions by slowly
adding one into other with constant stirring.
• Method B:
• Divide the vehicle into two portions. Dissolve the one of the
reacting substance in one portion.
• Place second portion of vehicle in mortar and incorporate
suitable amount of compound Tragacanth powder
(2g/100ml of preparation) with constant trituration until a
smooth mucilage is produced.
• Add and dissolve the solution of first reactant to the
mucilage slowly with constant stirring.

23. Alkaloid incompatibility:-
• 1. Alkaloidal salts with alkaline substances
• 2. Alkaloidal salts with soluble iodides
• 3. Alkaloidal salts with tannins
• Advantage of this Incompatibility:
• Formation of tannates has been exploited in the treatment of
alkaloidal poisoning
• 4. Alkaloid salts with salicylates
E.g. (Adjusted incompatibility)
Rx
• Sodium salicylate 1.0 g
• Caffeine citrate 0.650 g
• Purified water q.s. to 30 ml
• Make a mixture.
• 5. Alkaloid with soluble iodides and bromides.

24. Soluble salicylates incompatibility:-
• 1.Soluble salicylates with ferric salts
• 2.Soluble salicylates with alkali bicarbonates
• 3.Soluble salicylates and benzoates with acids.

25. Soluble iodides incompatibility:-
• 1.Oxidation of iodides with potassium chlorate
• 2.Oxidation of iodides with quinine sulphate.
• E.g. (Colour changing reaction, Delayed type incompatibility)
Herapathite reaction ( Iodoquinine Sulphate)
Rx
Quinine Sulphate 1.5 g
Dilute Sulphuric acid 4 ml
Potassium Iodide 8 g
Water q. s. to 200 ml
Prepare mixture.
Initially clear solution but after 3 days bronze scale deposition on
surface of container of product.
This incompatible reaction used to test quinine in a product and to
obtain crystals of ‘Herapathite’.

26. Chemical incompatibility causing evolution of carbon
dioxide gas:-
• 1.Sodium bicarbonate with soluble calcium or magnesium
salts
• 2.Bismuthsubnitrate and sodium bicarbonate
• 3.Borax with sodium bicarbonate and glycerin.
• E.g. Acid + Carbonate/Bicarbonate CO2

27. Miscellaneous incompatibilities:-
• 1. Soluble barbiturates with ammonium bromide
• 2. Potassium chlorate with oxdisable substances
• 3. Incompatibility of emulsifying agent
• 4. Color stability of dyes
• 5. Incompatibilities of liquorice liquid extract

28. References :
• Text book of PHARMACEUTICS-II by Dr. A. K. Seth, PV books page no. 62-70.
• Pharmaceutics-I by Dr. D K Sharma, Dr. Shilpa Chaudhari, , dr. Santanu Mallik,
Thakur Publication Pvt. Ltd, Lucknow, page no. 199-203.
• “PHARMACEUTICAL INCOMPATIBILITES: A REVIEW” by S. Gousia Begu et al.,
Asian Journal of Pharmaceutical Research and Development. 2018; 6(6): 56-61
• https://doi.org/10.3109/10837450903397594