Incompatibilities Kh Sadique Faisal Asst. Lecturer Northern University Bangladesh Incompatibilities It is the result of prescribing or mixing two or more substances which are antagonist in nature and an undesirable product is formed which may affect the safety, purpose or appearance of the preparation. Incompatibility may be : -Pharmaceutical -Therapeutic Pharmaceutical incompatibilities Physical or - Chemical incompatibilities. - Are usually unintentional - Occur in vitro between drugs and other components during preparation, storage or administration. - Physical Incompatibility A visible physical change takes place An unacceptable, non-uniform, unsighty, unpalatable product product is formed. Difficult to measure an accurate dose. Result of insolubility and immiscibility, precipitation, liquefaction, Adsorption and complexation of solid materials. Can be corrected by applying pharmaceutical skill Correction(Physical incompatibilities ) By one or more methods: Order of mixing alteration of solvents change in the form of ingredients alteration of volume Emulsification and addition of suspending agent, addition, substitution or omission of therapeutically inactive substances. 1. Insolubility and immiscibility It is the result of the mixture of two or more immiscible liquid or an immiscible solid with a liquid -Acceptable liquid product can be obtained by emulsification or solubilization (a) Rx Olive oil 30ml Water up to 120ml make an emulsion use a suitable emulsifying agent b. Liquid preparation with Indiffusible solids ( Sulphamethoxasole, phenacetin, Zinc oxide, calamine etc.) + a suspending agent = a uniform distribution of the solids in the liquid phase for sufficiently long time so as to facilitate accurate measurement of dose. Rx, Sulphamethoxazole 4.0g Trimethoprim 0.8g Na- CMC 0.5g Purified water qs to 100ml Sulphamethoxazole &Trimethoprim are indiffusible in water. To make them diffusible a suspending agent is used c. Insoluble Powders (Sulpher, certain Corticosteroids and Antibiotic) + Water = Non-wetted, non – distributed liquid powder Product. Insoluble non-wetted drug Powders + Water + wetting Agent (Saponins for sulpher drug containing lotions and Polysorbate for corticosteroids and Antibiotic = uniformly dispersed Powder product in water . 2. Precipitation a. A solubilised substance may precipitate from it solution if a non solvent for the substance is added to the solution. i. Alcohlic solution of Resins + water = precipitated Resins ii. Aqueous dispersion of Hydrophillic colloids (polysaccharide mucilage + high conc. of Alcohol or salts = Precipitated colloids. But significant amount are tolerated if well diluted and added in small amount with vigorous stirring b. High concentration of electrolytes cause Cracking of soap emulsion by salting out the emulsifying agents. c.Vehicles (one or more organic liquids) use to dissolve medicaments of low solubility, water soluble adjuncts particularly inorganic salts may be precipitated in such vehicles. 3. Liquefaction Certain low melting point solids sometimes liquefy when mixed together due to the formation of eutectic mixture or liberation of water . For example, if any two of the following medicaments are combined together, they form a eutectic mixture: Menthol, Thymol, Camphor, Phenol, Salol, Naphthol and chloral hydrate. Also Sodium salicylate or asprin with Phenazone In order to overcome such incompatibility, the eutectic forming ingredient may either be dispensed separately or these may be mixed separately with enough quantity of adsorbent powder like magnesium carbonate or Kaolin to form free flowing product. Alternately, if liquefaction has already occurred, the liquid may be adsorbed on a surface of sufficient quantity of powder , filled into capsule and dispensed Example: Menthol 2.0g Camphor 2.0g Ammonium carbonate 20.0g Make a powder. In this case, if the ingredients are mixed together, they shall liquefy due to formation of a eutectic mixture. Hence, to dispense them in the form of a powder, it is necessary to mix them separately with sufficient quantity of a suitable adsorbent like magnesium carbonate. The three mixture then mix together to obtain a powder. d. Adsorption and Complexation Certain substances including drugs and excipients may interact to form physical complex which may alter the appearance or activity of the medicament, For example, mixtures containing clays such as Kaolin, Attapulgite or suspended antacids may pose incompatibility problems due to adsorption Adsorption of Cyanocobalamin by Talc, a tablet lubricant may decrease the absorption from GIT. Similarly Adsorption of antimicrobial preservatives such as parabens on to the drugs or excipients may lead to loss of their antimicrobial activity. - Chemical Incompatibilities Chemical Incompatibilities is usually a result of chemical interaction taking place among the ingredients of a prescription. Such interactions may take place immediately upon compounding when these are termed as immediate in compatibilities and are evident as effervescence, precipitation or colour change. More often the interaction are not evident immediately on compounding but take place over a period of time. Such interaction are termed delayed incompatibilities. Provided the product is harmless the interaction fall into: a. Tolerated-: the reaction is minimised by applying some suitable order of mixing or mixing the solution in dilute form but no alteration is made in the active ingredients of the preparation. b. Adjusted-: the reaction is prevented by addition or substitution of one of the reacting substances with another of equal therapeutic value but does not affect the medicinal of the preparation (substitution of caffeine citrate wih caffeine in sodiun salicylate and caffeine citrate mixture) Precipitate yielding combination Generally reaction between strong solutions proceed at a faster rate and the precipitates formed are thick and do not diffuse readily. Reaction between the dilute solutions proceed 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 mixing. The preparation should contain a thickening agent if the precipitate is non-diffusible. Method A This is suitable for diffusible precipitates Divide all or most of the vehicle into two portions Dissolve the reactants in separate portions Mix the two portions by slowly adding one to the other with stirring rapidly. (Sometimes a small volume must be reserved for dissolving other ingredients, rinsing measures, and adjusting to volume.) Method B It is used for bulky indiffusible precipitates. Divide the vehicle into two equal portions as in A Dissolve one reacting substance in one portion Place the other portion in a morter and Incorporate a suitable amount of Tragacanth powder (2gm/100ml of the finished product) with constant trituration untill a smooth mucilage is produced, then add and dissolve the other reacting substances Mix the two portions by slowly adding one portion to the other with rapid stirring. Chemically incompatibility is generally caused by pH change, a double decomposition reaction or complex formation. pH effects Modern medicament are often salts of weak acids and bases. These salts are usually soluble in water while most of the unionized acids and bases are practically insoluble. Consequently if a salt of weakly basic drug is made alkaline , the free base may be precipitated, while precipitation of free acid may occur if a solution of a weakly acidic drug is acidified. Whether precipitation occur or not depends on a) The solubility of the unionized acid or base. b) The pH of the solution. c) The dissociation exponent (pKa) of the acid or base Solubility of the Unionized Acid or Base 1. Alkaloids Most alkaloidal salts are soluble in water but alkaloidal bases practically insoluble in water and are freely soluble in organic solvents. When an alkaline substance like aromatic spirit of ammonia, solution of ammonia, ammonium bicarbonate, Sodium bicarbonate, Borax, etc., is added to an alkaloidal salt solution the free alkaloid may be precipitated. However they are not always precipitated, because all alkaloids are slightly soluble in water and other added substances, for examples a) Strychnine Strychnine is a constituent of Nux Vomica Tincture which is used in some official mixtures as a bitter to stimulate the appetite. The amount of strychnine present is 0.125 gm per 100ml of tincture nux vomica and the solubility of strychnine is about 1 in 7000, i. e., 100 ml of water will dissolve 1 x 100 / 7000 = 0.143 gm of Strychnine Hence the amount of strychnine in 10 ml of tincture will dissolve easily in 100 ml of water and therefore, 10 % of the tincture in water will not precipitate in alkaline conditions. Further , tinctures contain certain amount of alcohol due to which the precipitation is further prevented. Moreover the solubility of strychnine is much more in alcohol (i. e. 1 in 150) than in water. Therefore it follows that in mixtures sufficient amount of alcohol strychnine will not be precipitated even when more than 10 ml of tincture per 100 ml is present in the prescription. Generally Chemical incompatibilities results from: 1. Acid- Base reactions Acid base reactions often result into precipitation, gas formation, breaking of structure of disperse systems or colour change. a. Precipitation Most medicaments in use are often salts of weak acids or bases. These salts have a very good water solubility whereas their corresponding unionised acids or bases are practically insoluble in water. if a solution of a salt of a weakly acidic drug is acidified,, the free acid may be precipitated. Similarly, precipitation of free base may occur if a solution of a salt of weakly basic drug is made alkaline. Example 1 Sodium salicylate 4g Lemon syrup 20ml Purified water to 100ml make a mixture Since Lemon syrup contains citric acid, it will acidify the solution and cause precipitation of the free acid (salicylic acid). In order to overcome this incompatibility, it is necessary to use other sweetening and flavouring agent instead of lemon syrup. Example II Strychnine hydrochloride solution 5ml Aromatic spirit of ammonia 3ml purified water to 100 ml make a mixture Strychnine HCl used in the mixture is an alkaloidal salt whereas aromatic spirit of ammonia is an alkaline substance. On reaction between the two, insoluble strychnine is precipitated. since the precipitate formed is diffusible, the incompatibility may be taken care by suitable formulation. In this case, strychnine HCl solution should be dissolved in half the required quantity of water while aromatic spirit of ammonia should dissolved in the remaining portion of water. The two portion should be mixed slowly. b. Gas formation Gas may be evolved due to chemical reaction between the ingredients of a formulation. Example: carbonates or bicarbonates with an acid or acidic drug resulting in the evolution of carbon dioxide Example 1: Reaction of sodium bicarbonate, borax and glycerol Rx Sodium bicarbonate 1.5g Borax 1.5g Phenol 0.75g glycerin 25 ml water to 100ml Prepare a spray In this case , borax decomposes in presence of glycerin to form sodium metaborate and boric acid Na2B4O7 Borax + 3H2O = Na2B2O4 + Sodium metaborate 2H3BO3 Boric acid Boric acid thus formed further reacts with glycerin to form Glyceryl boric acid 2C3H5(OH)3 + 3H3BO3 ---- (C3H3)2(HBO3) + 6H2O Glycerin Boric acid Glyceryl boric acid For compounding of such preparation, the ingredients should be allowed to react in an open vessel and only when the reaction is complete, should the preparation be transferred to the final container, otherwise there may be a chances of explosion. The reaction may be hastened by the use of hot water Example II Reaction of alkali bicarbonates with soluble calcium and magnesium salts, l When alkali bicarbonate are combined with soluble calcium and magnesium salts, double decomposition reaction occurs resulting in the formation of corresponding insoluble carbonate and carbon dioxide 2NaHCO3 + CaSO4 ----------- Ca(HCO3)2 + Na2SO4 4Ca(HCO3)3 ----------------- 3CaCO3 + Ca(OH)2 +5CO2 +3H2O Since the reaction proceeds slowly at room temperature, it should be accelerated by using a hot vehicle and the resulting mixture should not be pocked until reaction is complete. 3. Breaking of structure of disperse system Gelling agent such as carbomers, sodium carboxymethyl cellulose etc. very rapidly lose viscosity by change in PH outside an optimum range. Carbomer dispersion liquify by decreasing their PH below 5 or increasing it above 10. Similarly, below a PH 3, alginic acid is precipitated from dispersion of sodium alginate and carboxy methyl cellulose is precipitated from its sodium derivatives. Emulsion prepared using soap as emulsifying agent are liable to break in presence of mineral acids which destroy the emulsifying activity of soap by precipitating the acids d. Colour change d. Colour change The colour of most of the dyes used in formulations is influenced by their ionization which in turn depends on the PH of the solution, Thus crystal violet which is also used as antiseptic is a purple coloured compound but changes colour through green to yellow on acidification. similarly phenolphthelin (used as laxative) is colourless in acidic solution but becomes pink in alkaline media. Colour change due to change in PH can be prevented by properly buffering the vehicle or by preventing reaction that cause formation of free acid or base in the medium. 2.Oxidation - Reduction Reaction Certain prescription mixtures may oxidise on exposure to air, heat, light or due to change in PH or reaction with trace metal ions. Use of antioxidants like ascorbic acid, Sodium metabisulphite etc, is often helpful in each cases. Oxidation due to trace metal ions can be prevented by the use of chelating agents like Disodium EDTA. Example I RX, Potassium Chlorate 4g Ferric iodide syrup 10 ml Purified water to 60 ml Make a mixture In this case potassium chlorate react with ferric iodide. Initially the mixture is quite clear but on standing, crystals of iodine is deposited. It is therefore essential to dispense the two compounds separately with instructions to mix the two before administration. Example II RX, Sodium salicylate 4g Sodium biocarbonate 4g Peppermint water to 60mi make a mixture Sodium salicylate gets oxidized in presence of sodium biocarbonate and the mixture darkens on storage. This alkaline catalyzed oxidation may however be prevented by the use of a suitable antioxidants like 0.1% sodium metabisulphate. COMPLEXATION Many macromolecular adjuncts used in formulation form complexes in which medicaments and preservatives are bound to the macromolecules or trapped within micelles. This behavior is most common with non-ionic macromolecules. Because these complex are too large to penetrate cell membranes, the activity of the medicament or preservatives may be greatly reduced. A number of medicaments and excipients like suspending agent (polysaccharides), emulgents (macrogel esters and ethers) and solubilisers (polysorbates) exhibit this phenomenon. Complexation may sometimes be useful specially when it is reversible. In such case a large amount of drug is available in the unbound form and when this drug is utilised, it is replaced from the complex. Thus the complex provides a reservoir of drug from which a safe but sufficient concentration is available to the tissue over a prolonged period. A 10 to 15 % aqueous solution of Povidone has been found suitable for this purpose. Complex formation may also reduce the irritancy and improve the stability of a drug, as in Iodophores,which are complexes of Iodine in which the Halogen is bound to a water soluble polymer (Povidone) or solubilised in the micelles of surfactants . 4. Ionic Reactions The therapeutic or pharmaceutical properties of many organic compounds are usually associated with a large cation or anion. Interaction of such ions of opposing types may yield compounds which may totally lack the useful properties of the interacting molecules. For instances, Cream prepared using cationic emulgent may crack if mixed with a cream prepared using an anionic emulgent. Similarly an anionic solubilizers may lower the antimicrobial activity of a cationic medicament or preservative. Ionic incompatibilities may however be prevented by carefully selecting the medicaments and adjuvents in a proposed formulation so as to exclude combination of anionic and cationic ingredients in a single formulation. In case of emulsified system containing an ionic medicament or preservative, it may be advantageous to use a non-ionic emulsifier. 5. Explosive combination Oxidising agents are chemically in compatible with reducing agent and a combination of the two in a formulation may lead to an explosive reaction. For example, if Potassium chlorate is prescribed with an oxidisable substance like sulphur, tannic acid, etc and the two are triturated or heated together , there is a fair chance of an explosive reaction taking place. In such case, it is better to dispense the components separately or if it is necessary to mix them together, the mixing should be done very lightly.