Physical and Chemical Incompatibilities

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PHARMACEUTICAL INCOMPATIBILITYPHYSICAL AND CHEMICAL INCOMPATIBILITYBYK.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allianze college of medical sciences

1

pharmaceutical

incompatibility

occurs

as

a

result of mixing of two or more antagonistic substances and an undesirable product is formed 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 compounding and dispensing but also at any stage during formulation, manufacturing, packing or administration of drugs.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 2 Allian

TYPE OF INCOMPATIBILITIES:

A) Physical incompatibility B) Chemical incompatibility C) Therapeutic incompatibility

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 3 Allian

A)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 obtain a product of uniform dosage, substance to help in compounding of the prescription.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 4 Allian

An attractive 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 vIMMISCIBILITY vINSOLUBILITY vPRECIPITATION vLIQUEFACTION

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 5 Allian

IMMISCIBILITY Oils and water immiscible with each other. They can be made miscible with water by emulsification. Example: Castor oil 15ml Water 60ml Make on emulsion. In this prescription castor oil is immiscible with water . To overcome this incompatibility an emulsifying agent is used to make a good emulsion

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 6 Allian

INSOLUBILITYInsolubility 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 Menthol 0.25gm 0.02ml 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.

Liquid paraffin (sufficient to make)

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 7 Allian

Example: 2 Phenacetin Caffeine Orange syrup Water up to In this prescription indiffusible substance. 1g 12 ml 90ml Phenacetin is an of Compound powder 3g

tragacanth or mucilage of tragacanth is used as a suspending agent to make a suitable suspension

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 8 Allian

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

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) 9 Allian

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 10

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 11

CHEMICAL INCOMPATIBILITYChemical 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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 12

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. 2) 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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 13

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 14

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 15

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 16

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.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 17

Example: Strychnine hydrochloride solution Aromatic spirit of ammonia Water make up to 1200 ml 6 ml 4 ml

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 it gets precipitated as diffusible precipitates. Hence precipitate yielding combination.

follow method A for

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 18

2. SOLUBLE SALICYLATE INCOMPATIBILITIES: Soluble 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 to 90 ml

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 19

3. SOLUBLE IODIDES INCOMPATIBILITIES: Iodides undergo oxidation forming iodine which is an undesirable product. Hence, following steps may be taken to avoid this chemical change. Example: Oxidation of iodides with potassium chlorate: When soluble iodides react with potassium chloride, free iodine is liberated. KCIO3 + 3FeI2 3FeOI +3I+KCI To prevent the incompatibility, the two reacting substances must be dispensed separately.

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 20

4. CHEMICAL INCOMPATIBILITY CAUSING EVALUTION OF CARBONDIOXIDE GAS. Bismuth sub nitrate when combined with sodium bicarbonate when combined with sodium bicarbonate in the presence of water, carbon dioxide gas is liberated due to the following reaction. 2BiONO3 +2NaHCO3 (BiO) 2 CO3 + 2NaNO3 +CO2 +H2O

K.SAMINATHAN. M.pharm, M.B.A,( P.hD) Allian 21

5.INCOMPATIBILITY OF EMULSIFYING AGENTS: Emulsion prepared with alkali metal, ammonia and triethanoamine soaps are incompatible with salts producing polyvalent cations. Due to double decomp