INCOMPATIBILITIES

Syllabus:

Physical and chemical incompatibilities, inorganic incompatibilities including incompatibilities of metals and their salts, non-metals, acids, alkalis, organic incompatibilities. Purine bases, alkaloids, pyrazolone derivatives, amino acids quaternary ammonium compounds, carbohydrates, glycosides, anaesthetics, dyes, surface-active agents, correction of incompatibilities. Therapeutic incompatibilities.

Definition of incompatibility

When two or more ingredients of a prescription are mixed together, the undesired change that may take place in the physical, chemical or therapeutic properties of the medicament is termed as incompatibility.

Classification

Incompatibilities are of three types:

1. Therapeutic incompatibility

2. Physical incompatibility

3. Chemical incompatibility

PHYSICO-CHEMICAL INCOMPATIBILITIES

Physical imcompatibilities: Where the inmcompatibility is caused by immiscibility, solubility or liquefaction or solubilization.

Chemical incompatibilities: Where incompatibility is due to a chemical reaction or complexation.

PHYSICAL INCOMPATIBILITY

It may cause unsightly, non-uniform products from which removal of an accurate dose is very difficult.

Immiscibility

1. Problem: Oils are immiscible with water.

Remedy: Emulsification or solubilization.

e.g. Preparation of castor oil emulsion.

Castor oil is not soluble in water. Hence, a third agent (gum acacia) is added to prepare a stable emulsion. This third agent is called emulsifier.

e.g. Preparation of cresol soap solution

Soap in high concentration in water forms micelles. The over all preparation is transparent.

e.g. Oil-soluble vitamins A, D are solubilized by polysorbates (non-ionic surfactants)

2. Problem: Concentrated hydroalcoholic solutions of volatile oils, such as spirits (e.g. lemon spirits) and concentrated aromatic water (e.g. concentrated cinnamon water), when used as adjunct (i.e. additive), e.g. as flavoring agents in aqueous preparations.

Consequence :Large globules of oils separate out.

Remedy:

(i) The hydroalcoholic solution should be gradually diluted with the vehicle before mixing with the remaining ingredients.

(ii) The hydroalcoholic solution should be poured slowly into the vehicle with constant stirring.

(iii) Addition of high concentrations of electrolytes (e.g. salts) in which the vehicle is a saturated aqueous solution of a volatile oil.

Consequence: Oil separates and collects as an unsightly (looking bad) surface layer.

e.g. Potassium Citrate Mixture B.P.C.

Potassium citrate (electrolyte)

Citric acid

Lemon spirit

Syrup

Chloroform water D.S.

Water

** Quillaia Tincture 1%

When the lemon spirit, used for flavoring, is added the lemon oil is thrown out of the solution, party by the change of solvent and partly by the salting out effect of the high concentration of soluble salt (potassium citrate).

To prevent separation of this oil as surface layer quillaia tincture is included as an emulsifier.

Insolubility

1. Problem: Liquid preparations containing diffusible solids.

Consequence : Indiffusible solids will produce suspensions those will settle quickly, from which uniform doses cannot be poured out.

Remedy: A thickening agent is necessary to increase the viscosity and reduce the rate of settling of particles.

Indiffusible solids

e.g. chalk, aromatic chalk powder, succinyl sulfathiazole and sulphadimidine (in mixture)

e.g. calamine and zinc-oxide (in lotion)

Thickening agents e.g. gum acacia, gum tragacanth, methylcellulose etc.

2. Problem: Wetting problem with insoluble powders.

Some insoluble powders like sulphur and certain corticosteroids and antibiotics are difficult to wet with water.

Consequence: When water is added to this powders a slowly dispersing foam is formed on shaking. This foam is stabilized by fine solid particles.

Remedy: Wetting agents like saponins or polysorbates are incorporated.

Preparation	Wetting agents used
Sulphur containing lotion Corticosteroid injections Antibiotic injections	Saponin Polysorbate Polysorbate

3. Problem: Claying of suspensions.

When large amount of wetting agents are used, a deflocculated suspension will be produced where all he particles will settle individually and will produce tightly packed sediment. This is called ‘claying’.

Consequence: This tightly packed suspension is difficult to redisperse upon shaking.

Remedy: Reducing the amount of wetting agent will solve the problem. It will form smaller agglomerates of particles that will settle quickly but will be easily redispersed upon shaking.

4. Problem: When a resinous tincture is added to water the water insoluble resin agglomerates forming indiffusible clots.

Remedy: The undiluted tincture is added slowly to a diluted dispersion of a protective colloid with vigorous stirring.

e.g. Preparation containing either Compound Benzoin tincture

Benzoin Tincture

Lobelia Ethereal Tincture

Myrrh Tincture]

Tolu Tincture

When these tinctures are diluted with aqueous vehicle the resins precipitate and adheres to the side of the container and forms non-dispersable clots in the liquid. To prevent this the tincture is mixed in a slow stream into the centre of Tragacanth Suspension and stirring rapidly.]

The hydrocolloids (acacia, tragacanth, and starch) are adsorbed over the surface of the resin particles and confer hydrophilic properties and prevent aggregation into clots.

4. Problem: Dispersions of hydrophilic colloids such as acacia or tragacanth mucilage are precipitated by high concentrations of alcohols or salts.

Remedy: Alcohols or salts are well diluted in the vehicle and then the electrolyte or alcohol solution is added slowly into mucilage (hydrophilic colloid) with constant stirring to avoid local high concentration that might neutralize the effect of the protective colloid.

e.g. Lobelia and Stramonium Mixture, Compound B.P.C.

Lobelia Ethereal Tincture Resin solutions

Stramonium Tincture

Tragacanth Mucilage Hydrophilic colloid

Potassium iodide Electrolyte

Chloroform Water D.S. Vehicle

Water

Method – I

1. Half of the vehicle + Tragacanth power

® Triturated in a mortar and pestle.

® Tragacanth mucilage is formed.

2. Tincture is poured slowly into the centre of the mucilage with constant stirring.

3. Dissolve the electrolyte into half of the remaining vehicle.

® Added slowly and stirred to prevent local concentration.

4. The remaining vehicle is added to make up the volume.

Liquefaction

When certain low melting point solids are powdered (triturated in a mortar & pestle) together, a liquid or soft mass is produced due to lowering of melting point of the mixture to below room temperature.

The medicaments those exhibits this behaviours are:

(i) any pair among the following compounds:

camphor, menthol, phenol, thymol, chloral hydrate.

(ii) Sodium salicylate and phenazone

(iii) Aspirin and phenazone

Method-I

If menthol and thymol are required to be dispensed as powder, they are triturated in a mortar to form the liquid mixture. The the liquid is triturated with enough adsorbent powder e.g. light kaolin or light magnesium carbonate to give a free flowing product.

N.B. Kaolin and magnesium carbonate are efficient absorbent and the light

category of the powder has a very large specific surface area.

Method-II

If the final bulk volume of powder is very small then menthol and thymol are triturated separately with small amount of adsorbent powder. Then the two powders are combined lightly and packing the resultant powder in capsules.

The absorbent powders coat the particles and prevent contact between the medicaments and absorb any liquid that may be produced while triturating.

CHEMICAL INCOMPATIBILITY

Chemical incompatibilities are generally caused by pH change, a double decomposition reaction or complex formation.

Precipitate yielding interactions

Two ingredients may produce precipitation after reaction in a solution.

Method – A

All or most of the vehicles are divided into two portions. The reactants are dissolved in separate portions of vehicles. One portion is mixed with the other while stirring rapidly. This method will produce generally, lighter, more difussible precipitate.

Portion –I Dissolve

50 ml reactant ‘A’

Vehicle Final

100 ml preparation

Portion-II Dissolve

50ml reactant ‘B’

Method-B

This method is used for bulky indiffusible precipitates. In this case bulky precipitates will be suspended and stabilized by adding thickening agents.

The vehicle is derived into two portions. In one portion one of the reactant is dissolved.

The other portion is used to prepare tragacanth mucilage (2 g per 100ml final preparation). The second reactant is dissolved in the tragacanth mucilage.

The first solution is then added to the mucilage.

Portion –I Add Final

50 ml reactant ‘A’ Product

Vehicle

100 ml

Portion-II Prepare tragacanth mucilage Add reactant B

50ml with the vehicle in the mucilage

pH EFFECT

· Modern drugs are often salts of weak acids and weak bases.

· These salts are usually soluble in water while free bases are practically insoluble.

· Consequently, if a solution of a salt of weak acid is acidified the free weak acid may precipitate out.

· Similarly, if a solution of a salt of weak base is made alkaline the free weak base may precipitate out.

Salt of weak acid + acid ® Free acid ¯

Salt of weak base + alkali ® Free base ¯

Whether precipitation occurs or not depends on –

(a) The solubility of the unionized acid or base,

(b) The pH of the solution

Solubility of the unionized acid or base

1. Alkaloids

2. Other weak bases

3. Barbiturates

4. Other weak acids

1. ALKALOIDS

· Alkaloids are weak bases. They are almost insoluble in water.

· Salts of alkaloids are soluble in water.

· If these salts are dispensed with alkaline preparations or substances then free alkaloid may be precipitated.

The alkaline preparations those are generally incorporated with alkaloidal salt solutions are

(i) Aromatic Ammonia Solution

(ii) Strong Ammonium Acetate Solution

(iii) Ammonium bicarbonate

(iv) Sodium bicarbonate

However, if the alkaloidal salts are taken in low concentration then this problem does not occur because all alkaloids (free base) are slightly soluble in water.

e.g. Nux vomica and Alkali Mixture

This preparation contains Nux vomica Tincture

and Sodium bicarbonate (NaHCO₃)

Remedy: If small amount of nux vomica tincture is taken then amount of free alkaloid base in the final preparation will remain within the solubility limit of the alkaloid. In this preparation contains only 5% Nux-vomica Tincture.

Given below are some of the alkaloid solutions used as source to some alkaline preparations:

Alkaloidal preparation	Alkaloids present (solubility in water)	Maximum volume (in %) of alkaloidal preparation that can be added to alkaline preparation (without any precipitation)
NuxVomica Tincture BPC	Strychnine (1 in 7000parts)	10
(i)Morphine hydrochloride solution (ii)Opium Tincture (iii)Camphorated Opium Tincture (iv)Chloroform and Morphine Tincture	Morphine (1 in 5000 parts) Morphine Morphine Morphine	2.5 1.8 37.5 10.0
Belladonna, Hyoscyamus and Stramonium Tinctures	Solanaceous alkaloids Atropine (1 in 400) Hyoscyamine (1 in 280)	Unlimited
Ipecacuanha Tincture	Emetine (1 in 1000 parts)	66.7
Cocaine hydrochloride preparations	Cocaine	Very small amount

2. OTHER WEAK ALKALOIDS

Other organic weak bases of low solubility, which may be precipitated under alkaline conditions, include the

Local anaesthetics – amethocaine and cinchocaine

Analgesic – methadone

3. BARBITURATES

The derivatives of barbituric acid are almost insoluble in water, but their sodium salts are soluble. These soluble salts are occasionally prescribed in mixture (liquid).

Incompatibility Solutions of the salts are very alkaline and are incompatible with

acids,

acidic salts (e.g. ammonium bromide) and

acidic syrups (e.g.. lemon syrup)

In presence of these acidic ingredients the insoluble barbituric acid derivative will precipitate. This precipitate can neither be re-dispersed nor suspended satisfactorily with thickening agents.

Remedy When precipitation is likely, it is preferable to substitute the chemically equivalent amount of the corresponding insoluble barbituric acid derivative which can be suspended easily with thickening agent.

4. OTHER WEAK ACIDS

Sulfonamides are weak acids in unionized form and their solubility is less.

Incompatibility In presence of acid or acidic salts the unionized form may be precipitated.

Remedy Sulfonamide salts and the acidic ingredients are dissolved in separate amount of vehicle. With one portion tragacanth mucilage is prepared and the other portion is suspended in it.

Double decomposition

1. ALKALOIDAL SALTS WITH SOLUBLE IODIDES

Alkaloidal salts will react with soluble iodides and may precipitate insoluble iodide salts of alkaloids.

Alklaoidal salts	Soluble iodide
Emetine hydrochloride Methadome hydrochloride Strychnine hydrochloride Papaverine hydrochloride	Potassium iodide

Incompatibility

Emetine-HCl + KI ® Emetine-HI + KCl

Solubility of Emetine-HI is less hence may precipitate.

Example: Potassium iodide is used as expectorant in some alkaloid containing cough mixtures.

Remedy: If the alkaloid concentration is very low then precipitation does not occur.

2. ALKALOIDAL SALTS WITH TANNINS

Incompatibility:

Alkaloidal salts + tannins ® Alkaloidal tannates¯

N.B. One advantage of this reaction is in case of alkaloidal poisoning strong tea (or tannic acid solution) is used to precipitate the alkaloids.

Remedy: Method-B (suspended with the help of tyragacanth mucilage) is used to suspend the precipitate.

3. SOLUBLE BARBITURATES WITH AMMONIUM BROMIDE

Incompatibility

e.g. Phenobarbitone-Na + NH₄Br ® Phenobarbitone¯ + NaBr + NH₃.

Remedy: NH₄Br is an acidic salt; i.e. it is providing the necessary H⁺ to phenobarbitone-Na. So NH₄Br is replaced with sodiumbromide (NaBr).

N.B. Phenobarbitone is barbituric acid derivative. Bromide ion (Br^–) has sedative action.

4. GAS PRODUCTION

Incompatibility

Carbonates + Acid or ® CO₂

Or, bicarbonates acidic drugs

Remedy:

The ingredients are mixed in a wide mouthed mortar and left until effervescence has ceased. If the rate of reaction is slow it is hastened by using hot vehicle.

e.g.(a)

Ammonium carbonate Squill Syrup or

Or + Squill oxymel or ® CO₂

Ammonium bicarbonate Vinegar Squill

All of these squill preparations contain acetic acid. This acetic acid reacts with NH₄CO₃ or NH₄(HCO₃) to produce CO₂.

Remedy:

(i) Substitution of Squill preparation with neutral squill tincture or,

(ii) Wait for effervescence to complete then poured in an container.

e.g.(b) Borax, sodium bicarbonate and glycerol

Incompatibility

Borax is hydrolysed to boric acid.

Boric acid reacts with glycerol to produce glycerol-boric acid, which liberates CO₂ from bicarbonate.

Remedy: The reaction is hastened by addition of hot water.

e.g. (c) Alkali bicarbonates with soluble calcium and magnesium salts.

CaCl₂ + 2NaHCO₃ ® CaCO₃¯ + CO₂ + 2NaCl + H₂O

Remedy: These carbonates are readily diffusible hence Method A is followed.

i.e. (i) CaCl2 is dissolved in ½ portion of the hot vehicle.

(ii) NaHCO₃ is dissolved in ½ portion of the hot vehicle.

(iv) NaHCO₃ solution is added to CaCl₂ solution. So the reaction will be fast, CO₂ release will be rapid. CaCO₃ will be diffusible.

5. LIQUORICE LIQUID EXTRACT IN ACID MEDIA

This extract (Yastimadhu) contains glycyrrhizin, a sweet substance, consisting of potassium and sodium salts of glycyrrhizinic acid.

Incompatibility

K salt of glycyrrhizinic acid + acid media ® Free glycyrrhizinic acid

Free glycyrrihizininc acid forms a sticky, blask sediment that is difficult to diffuse. Further the insoluble substances are tasteless, hence the flavor is lost.

Remedy: The extract should be prescribed in neutral or alkaline solutions only.

6. POTASSIUM CHLORATE AND OXIDIZABLE SUBSTANCES

Incompatibility :

Potassium chlorate + sulfur or

organic compounds or Explosion

readily oxidizable substances Triturated or heated

in dry condition

in contact with charcoal

N.B. Potassium chlorate, sulfur and charcoal are the common ingredients of fire crackers.

Remedy:

1. Mixing of dry substances is inadvisable but, if essential, the ingredients should be powdered separately in a mortar, and then all the ingredients are taken on an ointment plate and mixed gently with a spatula. Any type of friction is avoided. Potassium chlorate is powdered in a scrupulously clean mortar.

2. The tablets should be supplied in rigid containers with a warning to the patient not to carry them loose in a pocket or handbag, because of the risk of catching fire from contact with matches or surfaces containing phosphorous compounds.

pH and pKa

Unionized form of a weakly acidic or weakly basic compound is less soluble in water than its ionized form. How much amount of the compound will remain in ionized or unionized state depends on Handerson-Hasselbach equation:

If the compound is a weak acid:

e.g. HA + H₂O = A^– + H₃O⁺ .

Acid Corresponding base

(Unionized) (Ionized)

So the Handerson Hasselbach equation will be :

THERAPEUTIC INCOMPATIBILITY

Usually this incompatibility arises when one or more drugs produce response or intensity different from that intended in the patients.

Classification

A) Over doses

B) Under doses

C) Improper consumption by the patient

D) Contra-indicated drugs

A) Over doses: This can be subgrouped as follows:

Excessive single dose

Sometimes a single dose may become overdose depending on the health of the patient e.g. a normal dose (taking body weight as 70 kg for an adult male) may be overdose for a lowly built person. However it should not be more than 2 to 3 normal dose.

Remedy: The pharmacist should consult the physician and clarify the dose.

e.g. 1 Rx

Atropine sulphate 6 mg

Phenobarbital 360 mg

Make capsules.

Label: One capsule to be taken three times a day before meals.

Comments: In this prescription the doses of both atropine sulphate and phenobarbital are 12 times the normal doses. The physician intended for 12 capsules to be dispensed but he has mistaken or may be it is an incomplete prescription. Hence, before dispensing the pharmacist should consult the physician again.

Correct prescription

Atropine sulphate 6 mg

Phenobarbital 360 mg

Make capsules. Supply 12 capsules.

Label: One capsule to be taken three times a day before meals.

e.g. 2 Rx

Strychnine sulphate 20 mg

Iron and ammonium citrate 500 mg

Prepare capsules. Supply 12 capsules.

Label: One capsule to be taken three times a day after meals.

Comment: 10 times overdose of strychnine hydrochloride than that of normal. The pharmacist should consult the physician and obtain the permission to change the dose.

Corrected prescription

Strychnine sulphate 2 mg

Iron and ammonium citrate 500 mg

Prepare capsules. Supply 12 capsules.

Label: One capsule to be taken three times a day after meals.

Excessive daily dose

In this case the daily dose of drug is exceeded .

e.g.1 Rx

Codeine phosphate 15 mg

Ammonium chloride 500 mg

Prepare capsules and supply 24 capsules.

Label: Two capsules to be taken every hour for cough.

Comment: The U.S.P. recommends that the prescribed dose should be taken after every four hours and not every hour. Hence the physician should be consulted.

Additive and synergistic combinations:

There are certain drugs possessing similar pharmacological activity. If these drugs are combined together, they may produce additive or synergistic action. In such case advice of the physician is necessary.

e.g. Rx

Amphetamine sulphate 20 mg

Ephedrine sulphate 50 mg

Syrup q.s. 100 ml

Let a mixture be made

Label: Take 25 ml every four hours.

Comment: Both of the drugs are sympathetic stimulants and they are prescribed in their full dose. The formulation will produce additive overdose effect. Hence, The dose of individual drug should be reduced.

(B) Under dose In this type of incompatibility, effect of one drug is lessen or antagonised by the presence of another drug. This can be exemplified by combination of following types of drugs:

1. Stimulants like nux-vomica, strychnine sulphate, caffeine etc. with sedatives like barbiturates, paraldehyde etc.

2. Sympathomimetic or adrenergic like ephedrine, nor-adrenaline with sympatholytic drugs like ergotamine.

3. Sympathetic stimulants like methamphetamine with parasympathetic stimulants like pilocarpine.

4. Purgatives like castor oil, liquid paraffin etc with antidiarrheal agents like bismuth carbonates.

5. Acidifiers like dilute hydrochloric acid and alkalisers like sodium bicarbonate, magnesium carbonate.

e.g. Rx

Aspirin 300 mg

Probenecid 500 mg

Prepare capsules.

Label: One capsule a day for gout.

Aspirin is an NSAID given to reduce the pain and swelling in case of gout attack. Probenecid blocks the active reabsorption of uric acid from the lumen of nephron, but salicylates (aspirin) blocks this action of probenecid. Hence, both of the drugs are antagonistic to each other, so its combination is therapeutically useless.

(C) Improper consumption by the patient:

In certain prescription some special directions should be written. If the patients are nor advised the drugs may not produce the desired action due to low bioavailability.

e.g. Rx

Tetracycline hydrochloride 250 mg

Prepare capsules. Supply 10 capsules.

Label: Take one capsule every six hourly.

Comments: Calcium present in milk inactivates the tetracycline, hence a patient may not get any therapeutic effect if he/she takes the capsule with milk.

Remedy: The pharmacist should advise the patient to take the capsule with water and not with milk. The patient should not take antacid containing calcium salts.

(D) Contra-indicated drugs

Certain drugs should not be given in particular disease condition

e.g.

(i) corticosteroids are contraindicated in patients with peptic ulcer.

(ii) Vasoconstrictors are contraindicated in hypertensive patients

(iii) Some drugs should not be given in asthmatic patients e.g. barbiturates, morphine etc.

(iv) If a person is allergic to a drug (e.g. penicillin injection) then it should not be given to the patient.

(v) Certain combination of drugs are contraindicate:

Sulphadiazine 0.25 g

Sulphamerazine 0.25 g

Ammonium chloride 0.50 g

Prepare capsules

Label: Take two capsules six hourly for cough.

Comment: In this prescription ammonium chloride is a urinary acidifier and it could cause deposition of sulphonamide crystals in the kidney.

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