Dr.D.Panda – Pharmaceutical Aids
PHARMACEUTICAL AIDS Antioxidants And Preservatives An antioxidant is a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions produce free radicals and these radicals start chain reactions. When the chain reaction occurs in a cell, it causes damage or death of the cell. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions. [A Free Radical is an atom, molecule, or ion which has unpaired valence electrons or an open electron shell. A notable example of a free radical is the hydroxyl radical (HO•), a molecule that is one hydrogen atom short of a water molecule and thus has one bond "dangling" from the oxygen. Two other examples are the carbene molecule (:CH2), which has two dangling bonds; and the superoxide anion (•O2-), the oxygen molecule O2 with one extra electron, which has one dangling bond.] The antioxidants usually prevent oxidation of active compounds and they themselves get oxidised. There are many antioxidants which do have mild bactericidal or bacteriostatic activities, which are being termed as preservatives. The various anti-oxidants used in pharmaceutical products are Hypophosphorus acid (H3PO2), Sulphur dioxide (SO2), Sodium nitrite (NaNO2), Sodium thiosulphate (Na2S2O3), etc. The preservatives are added to the pharmaceutical preparations for preventing microbial growth and spoilage of the preparations. Both the antioxidants and preservatives are widely used in various pharmaceutical preparations like emulsions, ointments, injectables and sterile preparations. The various preservatives used in pharmaceutical products are Benzoic acid (C6H5COOH), Benzalkonium chloride/alkyldimethylbenzylammonium chloride { [C6H5CH2N(CH3)2R]Cl }, Ethyl paraben/ethyl para-hydroxybenzoate (HO - C6H4 – CO – O - CH2CH3), Methyl paraben {CH3(C6H4(OH)COO)}, Propyl paraben{C3H7(C6H4COO)O}, Butyl paraben {C4H9(C6H4(OH)COO)}, Chlorobutanol/trichloro-2-methyl-2-propanol (C4H7Cl3O), Chloro cresol, Cresol (methylphenols), Phenol (C6H5OH), Sodium benzoate (NaC7H5O2), Benzyl alcohol (C6H5CH2OH), Propylene glycol/Propane-1,2-diol (C3H8O2), Glycerol/Glycerin – sugar alcohol (C3H8O3), etc.
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Dr.D.Panda – Pharmaceutical Aids
Ideal Characteristics of Antioxidants : (A) Should not be toxic and harmful to the human body. (B) Should undergo a slow oxidation process but more readily than that of the drugs so as to protect the pharmaceutical product from oxidation and to attain a prolonged stability period. (C) Should be physiologically and chemically compatible. (D) Should not produce any solubility problemin in either oxidised or reduced form. Mechanism of action of antioxidants : The mechanism of action of inorganic antioxidants are similar to that of oxidation-reduction reactions where there is transfer of electrons from one compound to the other. The overall reaction can be shown as; OX + e
Red
When a substance acts as antioxidant (it being a reducing agent) it is oxidised itself and doesnot allow the oxidation of the pharmaceutical compound. Hypophosphorus acid H3PO2 Preparation : It is prepared by treating calcium hypophosphite [Ca(H2PO2)2] with H2SO4 in excess. After the treatment, the insoluble calcium salt is filtered out and the filtrate is concentrated in vacuum to get hypophosphorus acid. Ca(H2PO2)2 + H2SO4
CaSO4 + 2H3PO2
Properties : It is a clear yellowish liquid having slightly acidic odour and taste. Miscible in water and alcohol. It possesses both acidic and reducing properties. It acts as a monobasic acid because only one hydrogen is ionisable. HPH2O2 + H2O
H3 O
+ PH2O2 –
Also, it acts as a powerful reducing agent because it is able to reduce iodine to iodide ions HPH2O2 + 2I2 + 2H2O
4HI + H3PO4
Identification test : 1) 0.3ml of hypophosphorus acid when treated with 10ml of mercuric chloride solution yields a white precipitate that changes to grey on heating and finally deposits a globule of mercury. 2) 0.3ml of hypophosphorus acid when warmed with a 5ml solution of copper sulphate yields a reddish brown precipitate.
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Dr.D.Panda – Pharmaceutical Aids
Tests for purity : The compound is to be tested for presence of barium, calcium, oxalic acid, phosphoric acid, iron, chloride, arsenic, sulphate, heavy metals, etc. Assay : 5gm of accurately weighed sample is diluted with 50ml of water and then titrated with 0.5N sodium hydroxide solution using methyl orange as indicator. Each ml of 0.5N NaOH is equivalent to 0.033gm of H3PO2. Uses : It is used as an antioxidant in a concentration of 0.5 to 1% in pharmaceutical preparations. It is mainly used as a reducing agent in ferrous iodide syrup where it does not allow the formation of ferric ions. Sulphur dioxide (SO2 , Mol. Wt. – 64.06) Preparation : It is prepared by burning sulphur in the presence of air or oxygen. 2S + 2O2
2SO2
Properties : It is a colourless, non-inflammable gas with having pungent odour and it is soluble in water and alcohol. When SO2 gas is allowed to pass through iodine solution, sulphuric acid and hydroiodic acid are formed. SO2 + I2 + H2O
2HI + H2SO4
Uses : It is extensively used in the manufacture of sulphuric acid. It is selectively used as an antioxidant in some injectable preparations. Sodium Nitrite (NaNO2,
Mol. Wt. – 68.99)
Preparation : It is prepared by absorbing nitrogen oxide (NO) gas and oxygen in sodium carbonate solution. The solution is concentrated to crystallize the product. 2Na2CO3 + 4NO + O2
4NaNO2
+
2CO2
Properties : It occurs in the form of colourless to slightly yellow crystals or a white or slightly yellow granular powder; odourless; saline taste. Freely soluble in water but sparingly soluble in alcohol. When it is exposed to atmosphere, it gets oxidised to sodium nitrate. Its aqueous solution is alkaline. It is oxidised to nitrate in the acidic medium. 2NaNO2
+ H2SO4
Na2SO4
+
2HNO2.
Tests for purity : It is tested for presence of chloride, sulphate, heavy metals, etc. Assay : The method is based upon the oxidation of nitrite to nitrate. 1gm of sample is dissolved in 100ml of water. 10ml of this solution is pipetted out and slowly added to a mixture of 50ml of 0.1N KMnO4 solution, 100ml water and 5ml of H2SO4. In contact with acid, nitrous acid (HNO2) is formed which immediately gets oxidised to nitric acid (HNO3) by KMnO4 solution. Then, 25ml of oxalic acid is added to the mixture and heated to 80o C and then the excess qty. of oxalic acid is back titrated with the std. KMnO4 solution.
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Dr.D.Panda – Pharmaceutical Aids
NaNO2 + H2SO4 HNO2 + O
NaHSO4 + HNO2 HNO3
Each ml of 0.1N KMnO4 is equivalent to 0.00345gm of NaNO2. Uses : It acts as an antidote in cyanide poisoning and also as a smooth muscle relaxant as well as a vasodilator of coronary blood vessels. It is also being used as a food preservative.
Sodium thiosulphate (Na2S2O3 . 5H2O Mol. Wt. – 248.2) Preparation : It is prepared from soda ash (sodium carbonate), sulphur dioxide and sulphur. Soda ash is first dissolved in water and SO2 gas is made to pass through it. The resultant bisulphite solution is treated with a further qty. of soda ash and then sulphur is added to it and heated. The final solution is concentrated to crystallize out sodium thiosulphate crystals. Na2CO3 + H2O + 2SO2
2NaHSO3 + CO2
2NaHSO3 + Na2CO3 Na2SO3 + S
2Na2SO3 + H2O + CO2 Na2S2O3
Properties : Found in the form of large colourless crystals or a coarse crystalline powder. Odourless and having alkaline taste. Soluble in water but insoluble in alcohol. Its alkaline solution is more stable. Tests for purity : To be tested for presence of arsenic, calcium and heavy metals. Assay : 1gm of sample is dissolved in 20ml of water and titrated with 0.1N Iodine solution using starch solution as indicator. 2Na2S2O3 + I2
Na2S4O6 + 2NaI
Each ml of 0.1N Iodine solution is equivalent to 0.02482 gm of Na2S2O3 . 5H2O Uses : It is an important antidote for cyanide poisoning
Filter-Aids Filtration is the separation of solids from liquids by forcing the liquid to flow through a porous medium and depositing the solids on the medium. Filter-aids are inorganic compounds/substances used in fine filtration processes. The fine particles which usually pass through the filter medium ( filter cloth / filter paper ) can be easily retained by the filter-aids which are made as a layer or bed on the filter media. The various filter aids used for clarification processes are Kieselguhr/diatomaceous earth/siliceous earth (pure silicon dioxide), Fuller’s earth (hydrated aluminium silicate, sometimes associated calcium carbonate), Light Kaolin, Precipitated Chalk, Talc, etc.
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Dr.D.Panda – Pharmaceutical Aids
Adsorbents Adsorption is the adhesion of atoms, ions, or molecules from a gas, liquid, or dissolved solid to a surface. This process creates a film of the adsorbate on the surface of the adsorbent. This process differs from absorption, in which a fluid (the absorbate) permeates or is dissolved by a liquid or solid (the absorbent). Note that adsorption is a surface-based process while absorption involves the whole volume of the material. Adsorbent is a porous substance that has a high surface area and has the ability to absorb or adsorb other substances using intermolecular forces onto its surface. A good example of an adsorbent material is activated charcoal. Other adsorbents are Soda lime/Sodium hydroxide (used as adsorbent of CO2 during surgical operations), Aluminium sulphate{Al2(SO4)3}(used as pharmaceutical aid in adsorbed bacterial toxoids – vaccines), Aluminium phosphate (AlPO4 – used as pharmaceutical aid for adsorbing bacterial toxoids in the preparation of vaccines).
Diluents (Fillers) The diluents or diluting agents are used in pharmaceutical dosage forms to increase the bulk of the product to make it easy to have single dosage forms that can be confortably taken by the patients as the quantity of actual medicinal ingredients are very low. These agents are physiologically inert. Some of the diluents are Lactose (C12H22O11), Calcium sulphate (CaSO4), Colloidal silicon dioxide (SiO2 - submicroscopic fused silica), Starch, Powdered cellulose, Sucrose, Manitol, Sorbitol, etc. Lactose : It is a most commonly used diluent in tablet and capsule formulations. Calcium sulphate : It is specially used as a diluent in tablet preparations and its hydrated form as plaster of paris. Colloidal Silicon dioxide : It is a submicroscopic fumed silica prepared by the vapor-phase hydrolysis of a silicon compound; used as a tablet diluent and as a suspending and thickening agent.
Suspending Agents These are otherwise known as thickening agents or stabilising agents which are used in the preparation of suspensions. Suspensions are dispersions of finely divided insoluble ingredients in liquid media. To avoid agglomeration of dispersed particles, suspending agents or thickening agents are added to the suspensions so that the dispersed particles settle down slowly due to increase in viscosity of the medium.
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Dr.D.Panda – Pharmaceutical Aids
Some of the suspending agents used in pharmaceutical preparations are Bentonite (Al2O3.4SiO2.H2O – colloidal hydrated aluminium silicate), Colloidal Silicon dioxide, Aluminium stearate (Al(OH)2C18H35O2 – a salt of stearic acid and aluminium – an organic compound), etc.
Colorants or Colouring Agents Colorants are mainly used to impart a distinctive appearance to the pharmaceutical dosage forms. There are many types of pharmaceutical formulations which need to be coloured such as tablets, tablets coatings, capsules (hard gelatin, soft gelatin), liquid orals, tooth pastes, ointments etc. The purpose of colouring varies with different formulations. Colouring may be required to increase the aesthetic appearance or to prolong the stability or to produce standard preparations or for identification of a particular formulation. The various colouring agents used in pharmaceutical preparations are β–carotene (red crystals), Indigo carmine (dark blue powder), Sunset yellow (reddish yellow powder), Tartrazine (yellow or orange yellow powder), Quinoline yellow (bright yellow dye), Quinizarine Green (green dye), Ferric oxides (red and yellow oxides), etc.
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