Pharmaceutical Incompatibilities

Dr.Gaurav Tiwari BP 103T

Definition

• Pharmaceutical incompatibility occurs as a result of mixing of two or more pharmaceutical substances which results in an undesirable product which may affect the safety, efficacy and appearance of pharmaceutical preparation.
• Pharmaceutical incompatibility may occur not only during compounding and dispensing but also at any stage during formulation, manufacturing, packing or administration of drugs.

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Importance Of Determining Incompatibility

Incompatible products may effect:

• Safety of medicament.
• Efficacy of product.
• Appearance of a medicine.
• Purpose of medication

TYPE OF INCOMPATIBILITIES

1. Physical incompatibility
2. Chemical incompatibility
3. Therapeutic incompatibility

PHYSICAL INCOMPATIBILITY

• When two or more than two substances are combined together, physical changes take place and an unacceptable product is formed. These changes which occurs as a result of physical incompatibility are usually visible and can be easily corrected by applying the pharmaceutical skill to obtain a product of uniform dosage.

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Physical incompatibilities may be corrected by using any one or more of the following method.

• Change the order or mixing of the prescription
• Emulsification
• Adding of suspending agent
• Change in the form of ingredients
• By adding, substitution or omission of therapeutically inactive
• Examples of physical incompatibilities
• IMMISCIBILITY
• INSOLUBILITY
• PRECIPITATION
• LIQUEFACTION

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IMMISCIBILITY

Oils and water immiscible with each other. They can be made miscible with water by emulsification.

Example:

• Castor oil…………………15ml
• Water………………………60ml
• Make an emulsion.

In this prescription castor oil is immiscible with water. To overcome this incompatibility an emulsifying agent is used to make a good emulsion

INSOLUBILITY

Insolubility means the inability of material to dissolve in a particular system. The major of incompatibilities are due to insolubility of the inorganic as well as organic compounds in a particular solvent. Example: 1

• Ephedrine sulphate…………0.25gm
• Menthol…………………………..0.02ml
• Liquid paraffin (sufficient to make)………….30ml

The ephedrine sulphate is an alkaloidal salt and is not soluble in liquid paraffin, but anhydrous ephedrine is soluble in it. Hence ephedrine sulphate is substituted with anhydrous ephedrine to make a clear solution.

Example: 2

• Phenacetin……………3g
• Caffeine………………..1g
• Orange syrup…………12 ml
• Water ……………………up to 90ml

In this prescription Phenacetin is an in-diffusible substance. Compound powder of tragacanth or mucilage of tragacanth is used as a suspending agent to make a suitable suspension

PRECIPITATION

A drug in solution may be precipitated, if the solvent in which it is insoluble is added to the solution.

• Example:
• The resins are insoluble in water. When the tincture containing resins is added in water, resin agglomerates forming indiffusible precipitates. This can be prevented by slowly adding the undiluted tincture with vigorous stirring to the diluted suspension Or By adding some suitable thickening agent

LIQUEFACTION

• When certain low melting point solids are mixed together, a liquid or soft mass known as “eutectic mixture” is produced. This occurs due to the lowering of the melting point of mixture to below room temperature and liberation of water of hydration. Many chemicals form hydrates, compounds with water of hydration. The medicaments showing this type of behavior are camphor, menthol, thymol, phenol, chloral hydrate and aspirin. This type of substance create problem when they are dispensed in powder form.

Example

• Menthol……………5g
• Camphor…………...5g
• Ammonium chloride…….30g
• Light magnesium carbonate…….60g
• In this prescription menthol, camphor and ammonia chloride get liquefied on mixing with each other. To dispense this prescription, menthol camphor and ammonium chloride are triturated together to form liquid. Add light magnesium carbonate and mix it thoroughly to make free flowing powder.

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CHEMICAL INCOMPATIBILITY

• Chemical incompatibility may be as a result of chemical interactions between the ingredients of a prescription and a toxic or inactive product may be formed. Chemical incompatibilities often occur due to oxidation –reduction. Acid base hydrolysis or combination reaction. These reactions may be noticed by precipitation effervescences, decomposition, colour change or by explosion.

CHEMICAL INCOMPATIBILITY IS TWO TYPES

1. Tolerated:

In tolerated incompatibilities, the chemical interaction can be minimized by changing the order of mixing or mixing the solutions in dilute forms but no alteration is made in the formulation.

• Adjusted:

In adjusted incompatibilities the chemical interaction can be prevented by addition or substitution of one of the reacting ingredients of a prescription with another of equal therapeutic value. Example: Caffeine citrate can be substituted with caffeine in sodium salicylate and caffeine citrate mixture

CHEMICAL INCOMPATIBILITY MAY BE

• INTENTIONAL: When the prescriber knowingly prescribes the incompatibility drugs.
• UNINTENTIONAL: When the prescriber prescribes the drugs without knowing that there is incompatibility between the prescribed drugs.

PRECIPITATE YIELDING INTERACTIONS

The precipitate form through the chemical incompatibility may be diffusible or indiffusible. The method A and B is followed in dispensing the prescription yielding diffusible and indiffusible precipitates respectively.

• METHOD (A):

The method is followed when diffusible precipitates are formed in very small quantity. Divide the vehicle into two equal portions. Dissolve one of the reacting substances in one of the portion and the other in the other portion. Mix the two portions by slowly adding one portion to the other by rapid stirring.

• METHOD (B)

The method is followed when indiffusible precipitates are formed in large quantity. Divide the vehicle into two portions. Dissolve one of the reacting substances in one portion. Weigh a suitable quantity of compound tragacanth powder (2g per 100 ml of finished product) and transfer in a mortar and use part of second portion of vehicle to produce smooth mucilage. Then add other reacting substances. Mix the two portions by slowly adding one portion to the other with rapid 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.

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1.Alkaloidal salts with alkaline substances

• Alkaloids are weak bases. They are almost insoluble in water but alkaloidal salts are soluble in water. If these salts are dispensed with alkaline preparations, such as, strong solution of ammonium acetate, aromatic spirit of ammonia, solution of ammonia. Ammonium bicarbonate, the free alkaloid may be precipitated.

Example

• Strychnine hydrochloride solution……….6ml
• Aromatic spirit of ammonia……………....4ml
• Water……………………………………...make up to 1200ml

Strychnine hydrochloride is an alkaloidal salt were as aromatic spirit of ammonia is an alkaline substance. When they react together, the strychnine get precipitated because the quantity of strychnine hydrochloride prescribed in the prescription is much more than its solubility in water (1 in 7000). The aromatic spirit of ammonia contains negligible amount of alcohol which can nor dissolves the strychnine. Hence it gets precipitated as diffusible precipitates.

• Hence follow method A for precipitate yielding combination.

2.Sodium Salicylate Incompatibilities:

• Sodium salicylate with ferric salt:

Ferric salt reacts with sodium salicylate to liberate indiffusible precipitates of ferric salicylate therefore follow method B for precipitate yielding interactions.

Example:

Ferric chloride solution………..2ml

Sodium salicylate……………...3g

Water…………………………..make up to90 ml

3.SOLUBLE IODIDES INCOMPATIBILITIES

Iodides undergo oxidation forming iodine which is an undesirable product.

• Example: Oxidation of iodides with potassium chlorate: When soluble iodides react with potassium chloride, free iodine is liberated.
• KCIO3 + 3FeI2 3FeOI +3I+KCI

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To prevent the incompatibility, the two reacting substances must be dispensed separately.

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4.Chemical incompatibility causing evolution of carbon dioxide gas�

• Bismuth sub-nitrate when combined with sodium bicarbonate in the presence of water, carbon dioxide gas is liberated due to the following reaction.

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• 2BiONO3 + 2NaHCO3 (BiO)2CO3 + 2NaNO3 + CO2 + H2O

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5.Incompatibility of emulsifying agents

Emulsion prepared with alkali metal, ammonia and triethanoamine soaps are incompatible with salts producing polyvalent cations. Due to double decomposition, a polyvalent soap is formed which inverts the emulsion.

• 6.COLOUR STABILITY OF DYES:

The colour of the most of the dyes used in pharmaceutical formulation is influenced by their ionization which depends on pH of the solution. The phenolphthalein dye is colorless in acid solution but red in alkaline mixture.

Therapeutic incompatibility

It may be the result of prescribing certain drugs to the patient with the intention to produce a specific degree of action but the nature or the intensity of the action produced is different from that intended by the prescriber.

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CAUSES:

It may be due to the administration of :

• Overdose or improper dose of a single drug.
• Improper Dosage form.
• Contraindicated drug.
• Synergistic and antagonistic drugs

Rx

Codeine phosphate……………0.5 gms

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Directions for Pharmacist:

Make powders.

Send such 10 powders.

1 dose to be taken at bed time

Comments:

• This is an example of over dosage. Probably, the physician intended to write 5mg and yet prescribed 500mg of codeine phosphate. The prescription must be referred back to prescriber.

Rx

Tetracycline Hydrochloride 250 gms

Directions for Pharmacist:

Make Capsules.

Send 10 such capsules.

Label:

Take 10 capsules every six hours with milk.

Comments:

Therapeutic incompatibility.

• In this prescription the dose is alright but the direction is wrong. Tetracycline is inactivated by calcium present in milk. Water replaces milk

Rx

Amphetamine Sulphate 20 mg

Ephedrine Sulphate 100 mg

Simple syrup up to 100 ml.

Label: Take 25ml every 4 hours

Directions for Pharmacist:

Make a mixture.

Therapeutic incompatibility:

In this prescription there is a combination of two sympathomimetic drugs with additive effects and there is a need to reduce the dose of each. Refer the prescription back to prescriber.

Rx

• Acetophenatidine 150 mg
• Acetyl Salicylic Acid 200 mg
• Caffeine 40 mg

Directions for Pharmacist:

Make Capsules. Send such 10 capsules.

Comments:

Correct prescription. Therapeutic incompatibility but Intentional.

Acetaphenatidin is an analgesic and so is aspirin. Acetophenatidin supresses the CNS. This side effect is undesireable. Caffeine, a central stimulant is included to overcome the side effect of acetophenetidin. Dispense as such

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