Incompatibilities in Prescription Mr Chechare D D PRESs
Incompatibilities in Prescription Mr. Chechare. D. D. PRES's College of Pharmacy (D. Pharm), Nashik.
Incompatibility 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 formulation, manufacturing, packing or administration of drugs.
A ) P h y s i c a l I n TYPE OF INCOMPATIBILITIES
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 to a product of uniform dosage, an attractive apperance & having satisfactory therapeutic activity.
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 substance. • Examples of physical incompatibilities 1)IMMISCIBILITY 2)INSOLUBILITY 3)PRECIPITATION 4)LIQUEFACTION
1. IMMISCIBILITY Oils and water are immiscible with each other. They can be made miscible with water by emulsification. Example: Castor oil-15 ml Water-60 ml 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.
2. 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: Phenacetin-3 g Caffeine-1 g Orange syrup-12 ml Water up to -90 ml In this prescription Phenacetin is an indiffusible substance. Compound powder of tragacanth or mucilage of tragacanth is used as a suspending agent to make a suitable suspension.
3. 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
4. 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 crystallisation. 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-5 g Camphor-5 g Ammonium chloride-30 g Light magnesium carbonate -60 g 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.
B. 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. 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.
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 there acting substances in one portion. Weigh a suitable quantity of compound tragacanth powder (2 g 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 WELL BEFORE USE”should be fixed on the container whenever USE method A or method B is followed in dispensing the prescription.
1)Alkaloidal Incompatibility 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 6 ml Aromatic spirit of ammonia 4 ml & Water make up to 120 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 not dissolves the strychnine. Hence it gets precipitated as diffusible precipitates. Hence follow method A for precipitate yielding combination.
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 -2 ml Sodium salicylate- 3 g Water make up to 90 ml
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: i)Oxidation of iodides with potassium chlorate: When soluble iodides react with potassium chloride, free iodine is liberated. KCIO 3+ 3 Fe. I 2 ------>3 Fe. OI +3 I+KCI. To prevent this incompatibility, the two reacting substances must be dispensed separately.
ii) Oxidation of iodides with quinine sulphate: Quinine sulphate is not freely soluble in water. It is made soluble in the presence of dil. Sulphuric acid. The sulphuric acid liberates hydriodic acid from the potassium iodide, & hydriodic acid is partly oxidised by the sulphuric acid , yielding iodine. the iodine , hydriodic acid & quinine sulphate then combine to form a compound called herapathite or Iodosulphites of Quinine. The Compound has following chemical formula: (C 20 H 24 O 4 N 2). 3 H 2 SO 4. 2 HI. 2 I 2. 6 H 2 O This incompatibility can be removed by any one of following method: a)Patient should be supplied with a mixture for 3 days only. b) In case the patient requires a mixture for more than 3 days both the solutions are prepared in half the volume of water and supplied in a separate bottle.
4 CHEMICAL INCOMPATIBILITY CAUSING EVALUTIONOF CARBONDIOXIDE GAS. Bismuth subnitrate when combined with sodium bicarbonate in the presence of water, carbon dioxide gas is liberated due to thefollowing reaction. 2 Bi. ONO 3+2 Na. HCO 3 ----> (Bi. O)2 CO 3+ 2 Na. NO 3+CO 2+H 2 O
5. MISCELLANEOS CHEMICAL INCOMPATIBILITY : I)Potassium Chorate with oxidisable substances: When potassium chlorate is prescribed along with charcoal. sulphuror any oxidisable substance, during dispensing if heating /trituration is done there are chances of explosion. Mixing of potassium chlorate with any dey substance is not advisable but is essential, then ingredients should be powdered separately in dry mortar & mix gently with clean spatula on ointment tile, without any friction.
ii)COLOUR STABILITY OF DYES: The colour of the most of the dyes used in pharmaceutical formulation is influenced by their ionization which depends on p. H of the solution. The phenolphthalein dye is colorless in acid solution but red in alkaline mixture.
1) Error in dosage 2) Wrong dose or dosage form 3) Contra-indicated drugs 4) Synergistic & antagonistic drugs 5) Drug Interaction.
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