NAT POWERPOINT

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NON-AQUEOUS TITRATION Presented by A.RABEYA, M.pharmacy., Department of pharmaceutical analysis Swamy vivekanandha college of pharmacy

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CONTENTS NON-AQEOUS TITRATION INTRODUCTION THEORY SOLVENTS CRITERIA FOR SELECTION OF SOLVENTS TYPES OF SOLVENTS COMMONLY USED SOLVENTS METHOD OF DETERMINATION OF END POINT IN NAT. INDICATORS POTENTIOMETRIC TITRATION BASIC METHODOLOGY ASSAY BY NAT NAT BY WEAKLY BASIC SUBSTANCE NAT BY WEAKLY ACIDIC SUBSTANCE ASSAY OF INDIVIDUAL DRUGS CONCLUSION. REFERENCES

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INTRODUTION: NON-AQEOUS TITRATION It is a volumetric or titrimetric analysis in which the titration of weakly acidic or basic substance are carried out using nonaquoeus solvents so as to get sharp end point. This type of titration is used to overcome the problem of Poor solubility. It might be weakly reactive in aqueousmedium

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THEORY: In this type of titration solvents plays amajor role LOWRY-BROWNSTED THEORY: Acid is a proton donor and base is a proton acceptor.So when an acid HA undergoes a dissociation it gives rise to a proton and the conjugated base A of acid. HA H + + A- Acid proton Base

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SOLVENTS: CRITERIA FOR SELECTION OF SOLVENT Solubility and nature of the sample. No reaction between sample and the titrant. Solvent should not affect the end point. Titrant and the solute should be readly miscible with solvent. Solvent should have a reasonably high dielectric constant. Solvent should be readly available of low cost,low toxic,easily purified.

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TYPES OF SOLVENT : APROTIC SOLVENT. PROTOGENIC SOLVENTS. PROTOPHILIC SOLVENTS. AMPHIPROTIC SOLVENTS.

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INERT OR APROTIC SOLVENTS: These are chemically inert with low dielectric constant and donot favour ionization. Eg:chloroform,carbontetrachloride,benzene. PROTOGENIC SOLVENTS: Genic-producing. These are the acdic substance and yield proton. Eg:sulphuric acid,hydrochloric acid,nitric acid. PROTOPHILIC SOLVENTS: Philic-loving. These are basic in nature and can abstract proton from acid to give solvated protons. HB + SOL SOLH+ + B- TYPES: Leveling solvents. Differentiating solvents.

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AMPHIPROTIC SOLVENTS: These have both protogenic and protophilic properties. Eg:water,aceticacid,alcohols. AUTOPROTOLYSIS it means that no other substance is neededin the proton transfer process. COMMONLY USED SOLVENTS: Eg:glacial acetic acid,acetonitrile,alcohols,dioxane,dimethylformaide. BASIC METHODOLOGY USED IN NAT: PREPARATION OF TITRANT STANDARDISATION OF TITRANT. CHOICE OF INDICATOR. EFFECT OF TEMPERATURE ON ASSAY.

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INDICATOR In NAT the end point is detected: by colour change of indicator. potentiometric method.

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POTENTIOMETRIC TITRATION: INDICATOR ELECTRODE: Glass electrode. REFERENCE ELECTRODE: Saturated calomel electrode. SALT BRIDGE: A Saturated solution of potassiumchloride. In potentiometric titration the rate of change of potential is maximum at the end point.

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End Mid point of slope Or pH End point ∆ emf/∆v Or ∆pH/∆v End point Vol .of titrant

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ASSAY BY NON-AQEOUS TITRATION. Assay of various pharmaceuticals substances either in pure form or in dosage form may be assayed successfully by NAT. NAT categorised into two groups. ACIDIMETRY IN NAT OR NAT OF WEAKLY BASIC SUBSTANCE. TITRATION OF PRIMARY,SECONDARY,TERTIARY AMINE. TITRATION OF HALOGEN SALTS OF BASES. ALKALIMETRY IN NAT OR WEAKLY ACIDIC SUBSTANCE. NAT OF WEAK BASE WITH PERCHLORIC ACID MATERIALS REQUIERD: 8.5ml perchloric acid (70-72%),1L Glacial acetic acid,30ml of acetic anhydride. PREPARATION OF 0.1N PERCHORIC ACID: 8.5ml perchloric cid +900ml glacial acetic acid mix vigorously and continuously stirre it Then add 30ml acetic anhydride and make upto 1000ml with glacial acetic acid.

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STANDARDISATION OF 0.1N PERCHLORIC ACID. PROCEDURE: 0.5g of PHP +25ml glacialacetic acid in 100ml conical flask . Attach a reflux condenser with a silica gel drying tube. Warm until the salt get dissolved completely. Cool and titrate with 0.1N perchloric acid. End point is detected by use of either the following indicator Acetous crystals violet(0.5%W/V) =========== Blue to blue green. Acetous oracetblueB ======================Blue to pink. Each ml of 0.1N perchloric acid is equvivalent to0.02041g of PHP. OFFICIAL TITRANT: 0.1N SOLUTION OF PERCHLORIC ACID IN DIOXANE. 1.DIRECT TITRATION OF PRIMARY,SECONDARY,TERTIARY AMINE: FOR RAW MATERIALS: Weigh and powder the raw material, dissolved it in glacial acetic acid and acetic anhydride. Few drops of indicator is added such as crystalviolet, napthobenzein etc The content of flask is titrated with 0.1N perchloric acid with sutiable indicator.

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SUBSTANCE TITRATED BY THIS METHOD

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2.TITRATION OF HALOGENACID SALT OF WEAK BASE: PRINCIPLE: Halides salts like chloride bromide or iodide are too weakly basic to be determined by direct titration . So mercuric acid is added which liberates equivalent quantity of acetate ions. PROCEDURE: Weighhed amount of sample is dissolved in warm glacial acetic acid. 15ml of 5%W/V mercuric acetate in glacialacetic acid is added with indicator. Then it is titrated with 0.1N perchloric acid. SUBSTANCE TITRATED BY THIS METHOD:

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NAT OF WEAKLY ACIDIC SUBSTANCE There are several drugs which are weakly acidic .the substance are titrated against Strong bases like , Potassium methoxide Sodium methoxide Lithium methoxide Tetrabutyl ammonium hydroxide in solvents like toluene-methanol.

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Preparation of 0.1N sodium methoxide 2.5g of freshly cut sodium into 150ml of methyl alcohol previously cooled in ice water .when sodium is completely dis solved add sufficient toluene dried previousely over sodium wire make up to 1000ml. protect the container from moistrure and carbondioxide Standardization of 0.1N sodium methoxide o.4g of benzoic acid is dis solved 80ml of DMF .Add 3 drops of thymolpthalein and titrate with of sodium methoxide solution to a blue endpoint. Perform a blank titration without benzoic acid and substract with volume of sodium methoxide consumed by 80 ml of DMF.each ml of 0.01221g of benzoic acid is equal to 0.1N sodium methoxide .

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Preparation of 0.1N tetrabutyl ammonium hydroxide 40g of tetrabutyi ammonium iodide is dissolved in 90ml of absolute methanol.add 20g of silver oxide shake vigorously for an hour.supernatant liquid of iodide was tested by centrifugation.if iodide is present add more silver oxide to get negative reaction. filter it. Rinse the vessel with dry toluene.combine the filter it and washing and make to 100ml with dry toluene Standardization of 0.1N tetrabutyl ammonium hydroxide. 10 ml of DMF is neutralized to the full blue colour of thymol blue by titration with 0.1N tetrabutyl ammonium hydroxide .add 60mg of benzoic acid and continue the titration with 0.1N tetrabutyl ammonium hydroxide.Each ml of 0.1N tetrabutyl ammonium hydroxide equivalent 0.01221g of benzoic acid

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Prepation of 0.1N LITHIUM METHOXIDE. Add 0.7g freshly cut lithium to a mixer of 40ml methanol and 50ml of dry toluene.when lithium has been dis so;lved add sufficient methanol to produce a clear solution.add toluene with constant stirring.repeat alternate addition of methanol and toluene until 1l of solution is obtained. Standardization of 0.1N LITHIUM METHOXIDE Pipette out of 10ml DMF and 3 drops of thymol blue and titrate with 0.1N lithium methoxide until acidic impurities neutralized .Add at once 0.06g benzoic acid and titrated with lithium methoxide

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ASSAY OF INDIVIDUAL DRUGS Methyldopa Material required methyldopa 0.2g ,anhydrous formic acid 15ml,glacial acetic acid 30ml, dioxane 30ml, 0.1 N perchloricacid and crystal violet sol. Procedure : 0.2g and dissolved 15 ml of anhydrous formic acid and 30ml dioxane.add0.1ml of crystal violet sol. and titrate with 0.1Nperchloric acid. Perform a blank titration and make correction.each ml of 0.1N perchloricacid is equivalent to o.02112g of c10H13NO4. CALCULATIONS :The percentage of methyldopa present in the sample is given by : % methyldopa = ml x 0.1x 0.02112x100 Wt.of sample

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Methacholine clloride Material required : methacholine chloride : 0.4 g .glacial acetic acid,50ml ,mercuric acetate . Solution : 10 ml ,0.1 N perchloric acid and crystal violet solution. Procedure : weigh accurately about 0.4 g, previously dried and stored in a vacuum desiccators ,and dis solve in 50 ml of glacial acetic acid, add 10 ml of mercuric acetate solution,one drop of violet solution and totrate with 0.1N perchloric acid to a blue-green end point. Perform a blank determination and make any necessary correction.each ml of 0.1 N Perchlortc acid is equivalent to 0.01957 g of c8h18CINO 2 mercuric accetate : IT IS essentially added to prevent the interference of the hydrochloric acid dis placed hrough the information of the relatively un-ionized hgcl2. Blank titration : it is usually carried out to account for the possible reaction of atmospheric moisture with the titrant percholoric acid being employed to bring about the blue –green end –point. Calculations : the % of methocholine choride in the sample may be calculated by the following expression : % methacholine choride = mlx0.1x0.01957x100 Wt.of sample

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CHLORTHALIDONE: MATERIAL REQURIED: Chlorthalidone 0.3g, pyridine50ml, 0.1Ntetrabutylammoniumhydroxide. PROCEDURE: Weigh accurately about 0.3g and dissolve in 50ml of dehydrated pyridine. Titrate with 0.1N tetrabutylammoniumhydroxide. End point detected by potentiometry. Perform blank titration. Each ml of 0.1N tetrabutylammoniumhydroxide equivalent to 0.03388 of C14H11CLN2O4S. ETHOUSUXIMIDE: PROCEDURE: Weigh about 0.2g dissolved in 50ml of DMF. Add 2 drops of azoviolet. Titrate with 0.1N sodiummeth oxide to a deep blue end point. Perform blank titration. Each ml of 0.1N Sodium methodizes equivalent to0.01412g of C7H11N02.

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CONCLUSION: NAT is more beneficial due to following advantages: Elimination of poor solubility of substances, Elimination of weak reactivity of substances, Selective titration by using suitable solvent and titrant of acidic/basic components of physiologically active moiety of a salt, Maintenance of speed, precision, accuracy and simplicity.

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REFERENCE DG GARRATT., “THE QUALITATIVE ANALYSIS OF DRUG”, 3rd EDITION . J.MENDHAM, R.C. DENNY, JD BARNES, MJK THOMAS., “VOLGEL’S TEXT BOOK OF QUANTITATIVE CHEMICAL ANALYSIS”, 6th EDITION. G.DEVALA RAO., “A TEXT BOOK OF PHARMACEUTICAL ANALYSIS VOL-I”. A.A.NAPOLEON., “A TEXT BOOK OF PHYSICAL CHEMISTRY AND PHARMACEUTICAL ANALYSIS”. DR.S.RAVI SANKAR., “A TEXT BOOK OF PHARMACEUTICAL ANALYSIS”. DAVID G. WATSON., “A TEXT BOOK FOR PHARMACY STUDENTS AND PHARMACEUTICAL CHEMISTRY”, 2nd EDITION. ASHUTOSH KAR., “PHARMACEUTICAL DRUG ANALYSIS”, REVISED SECOND EDITION. INDIAN PHARMACOPIEA - 1996

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THANK YOU