Question

Discuss Incompatibility. Discuss the types and classification and methods to overcome incompatibility.

Answer 1

Incompatibility is defined as a change resulting and an undesirable product is formed, which may affect the safety, efficacy, appearance and stability of the pharmaceutical product. It is of three types. It includes physical, chemical and therapeutic incompatibilities.

TYPES OF INCOMPATIBILITIES:-

The incompatibilities occur when the components of a medicine interact in such a way that properties of that medicine are adversely affected

1. Physical incompatibilities

2. Chemical incompatibilities

3. Therapeutic incompatibilities

PHYSICAL INCOMPATIBILITIES:-

When two or more than two substances are combined together, a physical change takes place and an unacceptable product is formed.

Interaction between two or more substances which may lead to change in color, odor, taste, viscosity and morphology. It is also called as pharmaceutical incompatibility

Manifestations of physical incompatibility:-

The following list outlines the various ways incompatibility between or among drug agents may be

manifested.

A. Insolubility:-insolubility of prescribed agents in vehicle

B. Immiscibility:-Immiscibility of two or more liquids

C. Precipitation:-It occurs due to solvent is insoluble when it is added to solution

D. Liquefaction:-Liquefaction of solids mixed in a dry state (called eutexia)

INSOLUBILITY

It means the inability of material to dissolve in a particular solvent system. The majority of

incompatibilities is due to insolubility of the inorganic as well as organic compounds in particular solvents.

The following factors affect the solubility of prescribed

agent in vehicle and may render it less soluble.

 Change in PH

 Milling

 Surfactant

 Chemical reaction

 Complex formation

 Co-solvent

 Any change in previous factors may lead to precipitation of drugs and change in their properties.

Rx

Chalk powder –2g

Tincture catechu – 2ml

Cinnamon water – 2ml

Causes: - Chalk powder is not soluble in water.It gets

precipitated when added to aqueous medium.These

precipitates are found in diffusible in nature which results

in physical incompatibility.

Remedy: - Use of suspending agents is necessary to

suspend the precipitated chalk particles.

Generally 2% W/V of compound tragacanth powder is

recommended as suspending agent.

The corrected prescription is

Mixture of prepared chalk

Rx

Chalk powder –2g

Tragacanth – 0.4g

Tincture catechu – 2ml

Cinnamon water up to 30ml

IMMISCIBILITY

When two suchingredients are combined resulting in a

non- homogenous product, such ingredients are called

immiscible to each other and the phenomenon is called

immiscibility.This manifestation appears clearly in

emulsions, creams, lotions, some types of ointments.

Separation in two phases is noticed in this pharmaceutical

dosage form.Storage must be in room temperature to

prevent separation9, 10.

The following factors lead to immiscibility11

 Incomplete mixing

 Addition of surfactant with

 Unsuitable concentration

 False time of addition

 Unsuitable for the type of emulsion

 Presence of micro – organisms

 Some bacteria grow on constituents of mixture.

E.g.:- Gelatin Arabic gum

 Others produce enzymes which oxidize the

surfactant.

 Temperature

 Oils and water are immiscible with each other which

shows physical incompatibility

E.g.:- Castor oil emulsion

Rx

Castor oil – 15ml

Water – 60ml

Causes: -In this prescription castor oil is immiscible with

water due to high interfacial tensions, which is a sign of

incompatibility.

Remedy:-To overcome this type of incompatibility

emulsification is necessary with the help of an

emulsifying agent. The corrected prescription is

Castor oil emulsion

Rx

Castor oil – 15ml

Acacia – 2% W/V

Water– upto 60ml

LIQUIFACTION

When certain low melting point solids are mixed

together, a liquid or soft mass know as eutectic mixture is

produced.This occurs due to the lowering of the melting

point of the mixture to below room temperature and

liberation of hydrates12.

If such conditions take place, compounding such powders

becomes difficult since the ultimate mixture turns to

liquid. The medicaments showing this type of behavior

are camphor, menthol, phenol, thymol, chloral hydrate,

aspirin, sodium salicylates, etc……

E.g.:-Insufflations

Rx

Menthol – 5g

Camphor – 5g

Water – 60ml

Causes: - This mixture is a physical incompatibility

because both the ingredients in the prescription are

liquefiable of mixed together.

Remedy:-These substances can be dispensed by any one

of the following method.Triturate together to form liquid

and mixed with an absorbent (light kaolin, magnesium

carbonate) to produce the following powder.The

individual medicaments is powdered separately and

mixed with an adsorbent and then combined together

tightly and filled in a suitable container12.

Hence the corrected prescription is

Rx

Menthol – 5g

Camphor – 5g

Light kaolin– 0.2g

Begum et al Asian Journal of Pharmaceutical Research and Development. 2018; 6(6): 56-61

ISSN: 2320-4850 [58] CODEN (USA): AJPRHS

PRECIPITATION

Solubilized substances may precipitate from it solution if

a non-solvent for the substances is added to the solution.

E.g.:- Resins are insoluble in water

Alcoholic solution of resins + water =precipitated resins.

Aqueous dispersions of hydrophilic colloids

(polysaccharide mucilage + high concentration of alcohol

or salts) =precipitated colloids.

a) High concentration of electrolytes causes cracking of

soap emulsion by salting out the emulsifying agents.

Vehicles (one or more organic liquids) use to dissolve

medicaments of low solubility; water soluble adjuvant

practically inorganic salts may be precipitated in such

vehicles. Whentinctures containing resinous matter are

added in water, resin agglomerates forms in diffusible

precipitates. This can be prevented by slowly adding the

undiluted tincture with vigorous shake.Suspension or by

adding some suitable thickening agent13,14.

E.g.:- Lotion of compound tincture of benzoin

Rx

Tincture benzoin compound – 5g

Glycerin – 10ml

Rose water upto 100ml

Causes: - Tincture benzoin compound contain

resins.This change in solvent system results in an

unavoidable precipitate.

Remedy: - Addition of tincture with rapid stirring yields

a fine colloidal dispersion. So there is no need of any

suspending agents.

CHEMICAL INCOMPATIBILITIES

Reaction between two or more substances which lead to

change in chemical properties of pharmaceutical dosage

form. As aresult of this a toxic or inactive or product may

be formed15.

Occurrence:-

Chemical incompatibilities occur, due to the chemical

properties of drugs and additive like16,

 PH change

 Oxidation-reduction reactions

 Acid-base hydrolysis

 Double decomposition

 Complex formation

These reactions may be noticed by

 Precipitation

 Effervescence

 Decomposition

 Color change

 Explosion

TYPES OF CHEMICAL INCOMPATIBILITIES

Based on chemical interactions

Tolerated incompatibility: - In this type incompatibility,

the chemical interactions can be changing the order of

mixing the solutions indilute forms, without or by

changing the order of mixing.

Adjusted incompatibilities: - In adjusted incompatibility

change in the formulation is needed with a compound

having equal therapeutic value17.

E.g.: substitution of caffeine citrate with caffeine in

sodium salicylate and caffeine citrate mixture.

Based on natureof chemical reaction

Immediate incompatibilities: - If the chemical reaction

takes place, immediately after combining the prescription

ingredients, they are called immediate incompatibilities.

Hence, they should be dispensed only after correction.

Delayed incompatibility: - When the chemical reaction

proceeds at a very slow rate and no appreciable visible

change occurs which may develop on keeping the product

for along time are called delayed incompatibility18.

Based on the prescriber

Intentional:- When the prescriber knowingly prescribes

the incompatible drugs.

Unidirectional:- When the prescriber prescribes the drugs

without knowing that there is incompatibility between the

prescribed drugs19.

Generally reaction between strong solution proceed at a

faster rate and the precipitates are 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 mixing20.

Precipitate yielding interactions

The precipitates so formed may be diffusible or

indiffusible. The method A or B is followed in dispensing

the prescription yielding diffusible and indiffusible

precipitates respectively.The preparation should contain a

thickening agent if the precipitate is non-diffusible21.

Method A:

This method is suitable for diffusible precipitates

following steps are carried out22.

Divide the vehicle into two portions.

Dissolve the reactants in separate portions and mix the

two portions by slowly by adding one into other with

constant stirring.

Method B:

This method is suitable for in diffusible precipitates

following steps are carried out23.

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 other reacting substance to the

mucilage.

Add the solution of first reactant to the mucilage slowly

with constant stirring.

A secondary label ―SHAKE THE BOTTLE BEFORE

USE‖ should be fixed on the container whenever method

A or method B is followed in dispensing the prescription.

Examples of chemical incompatibilities and their

correction24

Begum et al Asian Journal of Pharmaceutical Research and Development. 2018; 6(6): 56-61

ISSN: 2320-4850 [59] CODEN (USA): AJPRHS

 Alkaloid incompatibility:-

1. Alkaloidal salts with alkaloid substances

2. Alkaloidal salts with soluble iodides

3. Alkaloidal salts with tannins

4. Alkaloid salts with salicylates

5. Alkaloid with soluble iodides and bromides.

 Soluble salicylates incompatibility:-

1.Soluble salicylates with ferric salts

2.Soluble salicylates with alkali bicarbonates

3.Soluble salicylates and benzoates with acids.

 Soluble iodides incompatibility:-

1.Oxidation of iodides with potassium chlorate

2.Oxidation of iodides with quinine sulphate.

 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.

 Miscellaneous incompatibilities:-

1.Soluble barbiturates with ammonium bromide

2.Potassium chlorate with oxdisible substances

3. Incompatibility of emulsifying agent

4. Color stability of dyes

5. Incompatibilities of liquorices liquid extract

Eg-1: strychnine hydrochloride mixture

Rx

Strychnine hydrochloride solution -6ml

Aromatic spirit of ammonia -4ml

Water up to - 120ml

Causes:-

 The quantity of strychnine hydrochloride is more

than its solubility in water (1:30).

 The aromatic spirit of ammonia contains negligible

amount alcohol.

Remedy: - Strychnine hydrochloride gets precipitated

yielding diffusible precipitate, hence follow method A.

E.g-2.:Quinine hydrochloride mixture

Rx

Quinine hydrochloride -0.12ml

Sodium salicylate -4g

Water -100ml

Causes: - When quinine hydrochloride combined with

the sodium salicylates it forms quinine salicylates which

is an in diffusible precipitate.

Remedy: - Hence follow method B for precipitate

yielding interactions.

THERAPEUTIC INCOMPATIBILITY

It is the modification of the therapeutic effect of one drug

by the prior concomitant administration of another. It

may be as a result of prescribing certain drugs to a patient

with the intention to produce a specific degree of

pharmacological action, but have restore or intensity of

the action produced is different room that intended by the

prescriber25.

MECHANISM:

It is divided into two groups. They are

Pharmacokinetic: It involves the effect of a drug on

another from the point of view that includes absorption,

distribution, metabolism and excretion.

Pharmacodynamics: These are related to the

pharmacological activity of the inter-acing drugs.

E.g., Synergism, antagonism, altered cellular transport,

effect on the receptor site.

Therapeutic incompatibilities occurs due to following

reasons

a. Error in dosage

b. Wrong dose or dosage form

c. Contra-indicated drugs

d. Synergistic and antagonistic drugs

e. Drug interactions

ERROR IN DOSAGE

Many therapeutic incompatibilities result from errors in

writing or interpreting the prescription order. The most

serious type of the dosage error in the dispensing is

overdose of a medication26.

E.g., Atropine sulphate capsules

Rx

Atropine sulphate - 0.005g

Phenobarbitone - 0.015g

Aspirin - 0.300g

Causes:- In this prescription, the quantity of the atropine

sulphate in each capsule is more than its recommended

dose.

Remedy:- The prescription is referred back to the

prescriber to correct the overdose of the atropine

sulphate. The recommended dose of atropine for a single

capsule is 0.25 to 2mg.

WRONFG DOSE OR DOSAGE FORM

There are certain drugs which have quite similar names

and there is always a danger of dispensing the wrong

drug27.

E.g., Prednisone and Prednisolone

Digoxin and Dig toxin

Some times many drugs are available in the different

dosage forms and hence, if the dosage form is not clearly

mentioned on the prescription, it becomes necessary to

seek clarification from the prescriber.

The responsibility of the pharmacist becomes to check

the prescription intensively and if he finds these types of

errors he should immediately consult the prescriber for

the clarification.

PRESCRIBING CONTRA-INDICATED DRUGS

There are certain drugs which may be contra-indicated in

a particular disease or a particular patient who is allergic

to it28.

 Corticosteroids are contra-indicated in the patients

having peptic ulcers.

Begum et al Asian Journal of Pharmaceutical Research and Development. 2018; 6(6): 56-61

ISSN: 2320-4850 [60] CODEN (USA): AJPRHS

 The penicillin and sulphur drugs are contra-indicated

in the patients who are allergic.

 Vasoconstrictors are contra-indicated in hypertensive

patients.

 Barbiturates and morphine should not be given to the

asthmatic patients.

E.g., Sulphadiazine capsules

Causes:-Ammonium chloride is a urinary acidifier. It

causes the deposition of the

Sulphonamide crystals in the kidney.

Remedy: - Before prescribing such substances a doctor

must be careful. If he does not, a

Pharmacist shows his caliber to point out such type of the

doctor’s error. Such must

Immediately be referred back to the concerned doctor and

get corrected.

PRESCRIBING SYNERGISTIC OR

ANTAGONISTIC DRUGS

When two drugs are prescribed together, they tend to

increase the activity of each other which is known as

SYNERGISM. When two drugs are prescribed together,

they tend to decrease the activity of each other which is

known as ANTAGONISM29.

E.g.,

 A combination of aspirin and paracetamol increases

the analgesic activity.

 A combination of penicillin and streptomycin

increases the antibacterial activity.

 Amphetamines show its antagonists effect with the

barbiturates.

E.g., Amphetamine sulphate syrup

Causes:-In this prescription, there is a combination of

two sympathomimetic drugs

There by causing additive effect.

Remedy:- The prescription is referred back to the

prescriber for necessary corrections.

DRUG INTERACTIONS

The effect of one drug is altered by the prior or

simultaneous administration of another drug. The drug

interaction can usually be corrected by the proper

adjustment of dosage if the suspected interaction is

detected30.

E.g., Tetracycline capsule - 250mg capsules

Direction: Take one capsule every 6 hours with milk.

Causes:-Tetracycline is inactivated by calcium present in

milk. So, it should not be taken with milk.

Remedy: In this prescription, the therapeutic

incompatibility is unintentional. So, the prescription is

referred back to the prescriber to change the direction.