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Ravi SSJ COLLEGE OF PHARMACY e-mail: Pharmaravi.email@example.com ANALYTICAL METHODS OF ANTIPYRETIC-ANALGESICS Contents: : Introduction Analytical methods of different drugs: Paracetamol Analgin Antipyrine Aminopyrine Aspirin Conclusion Reference Contents: Antipyretic-analgesic and anti-inflammatory : NSAIDs have three major actions, all of which are due mainly to the inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis. An anti-inflammatory action: The decrease in vasodilator prostaglandins (PGE2, PGI2) means less vasodilatation and, indirectly, less oedema. The inhibition of activity of adhesion molecule. Accumulation of inflammatory cells is also reduced Antipyretic-analgesic and anti-inflammatory Slide 4: An analgesic effect: Decreased prostaglandin generation means less sensitization of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is probably due to decreased prostaglandin-mediated vasodilatation. An antipyretic effect: : This is partly due to a decrease in the mediator prostaglandin that is responsible for elevating the hypothalamic set-point for temperature control in fever. Some important examples are aspirin, ibuprofen, naproxen, indomethacin, paracetamol. The last agents has analgesic and antipyretic effects but little anti-inflammatory An antipyretic effect: CLASSIFICATION : CLASSIFICATION PARACETAMOL : METHODS OF ANALYSIS: 1. GRAVIMETRIC METHOD 2. TITRIMETRIC METHOD 3. POLAROGRAPHIC METHOD 4. U.V SPECTROPHOTO METRIC METHOD 5. ION EXCHANGE CHROMATOGRAPHIC METHOD 6. PAPER –THIN LAYER CHROMATOGRAPHIC METHOD 7. COLORIMETRIC METHOD PARACETAMOL 1. GRAVIMETRIC METHOD : Quantitative precipitation of acetaminophen with l-fluoro-2,4- dinitrobenzene in a sodium bicarbonate- di methyl formamide medium To give p-(2,4-dinitrophenoxy) acetanilide. The precipitation is carried out over a 4 hours period . Caffeine, phenazone, 4-aminophenazone, phenacetin and Codeine phosphate does not interfere. 1. GRAVIMETRIC METHOD 2. TITRIMETRIC PROCEDURE : Acetaminophen may be determined by titration with sodium nitrite after prior acid hydrolysis of the acetaminophen to p-amino phenol both visual and potentiometrically.The End-points have been used.Ce+4 quantitatively oxidises acetaminophen thus rendering it possible to titrate acetaminophen with 0.1N Ce(S04)2 in an ethanolic HC1 medium. Acetaminophen may be successfully titrated in a dimethylformamide medium with 0.1N sodium methoxide (in benzene-methanol) . The end-point may be determined visually using azo violet indicator or potentiometrically. 2. TITRIMETRIC PROCEDURE 3. POLAROGRAPHIC METHOD: : The anode polarographic behaviour of acetaminophen has been studied at the wax impregnated graphite electrode. This system employs a solution of acetaminophen in aqueous ethanol/phosphate buffer (l:l), pH 7.1 and gives a value for E1/2 vs. S.C.E. of 333mV. Brockelt describes a cathode polarographic procedure for the determination of acetaminophen after nitration with 5N HNO3. The solution containing nitrated acetaminophen is treated with potassium hydroxide and phosphoric acid to give a solution pH of 5.8 and examined polarographically 3. POLAROGRAPHIC METHOD: 4.U.V SPECTROPHOTO METRIC METHOD: : The acetaminophen tablets are extracted with an anhydrous alcoholic solvent (B.P.-Ethanol and N.F.-methanol), the extract acidified with a small amount of dilute hydrochloric acid and then further diluted with the alcohol. The acetaminophen concentration is determined by spectrophotometer measurement at 249 nm. 4.U.V SPECTROPHOTO METRIC METHOD: 5. ION EXCHANGE CHROMATOGRAPHIC METHOD: : The separated acetaminophen from phenacetin (acetophenetidine) phenobarbitone and salicylic acid by two dimensional chromatographic developments on diethyl amino ethyl cellulose ion-exchange paper (Whattman DE 20). Initial separation was by simple development in a 0.2N ammonium hydroxide solvent.This was followed by ionophoretic development at right angles in the same solvent (5mA; 250V.). 5. ION EXCHANGE CHROMATOGRAPHIC METHOD: 6. PAPER –THIN LAYER CHROMATOGRAPHIC METHOD : Number of thin layer and paper chromatographic methods has been found suitable for the isolation and identification of acetaminophen. Stationary Phase: l- Octanol, liquid paraffin Mobile phase: Acetone/water (1:9) Acetone/water (2:8) 6. PAPER –THIN LAYER CHROMATOGRAPHIC METHOD Procedure: : Semi-quantitative procedures relying on the visual comparison of sample spot size and Intensity with standards has been described by Klutch and Bordunl and by Shand. Bekh ET a1..described a quantitative procedure in which the acetaminophen is acid to p-aminophenol which is then separated (lO-lOOµg. /spot) by thin layer chromatography on a Silica Gel G layer. The p-aminophenol is eluted with 0.5N sodium hydroxide solution and determined spectrophotometrically at240 mµ. A further paper by the same authors employs chromatographic separation of the acetaminophen (without prior hydrolysis) on a layer of Silica Gel GF followed by elution with methanol and spectrophotometric determination at 245 mµ. Procedure: 7. COLORIMETRY : PRINCIPLE Paracetamol with 1-napthol or resorcinol gave azodye and the concentration of Paracetamol was investigated spectrophotometrically. The azodyes formed with both 1-Naphthol and Resorcinol as coupling agents follow Lambert Beer’s law in the range of 0 to 10μgmL-1 of paracetamol.. 7. COLORIMETRY PROCEDURE: : Paracetamol tablets (500 mg) taken as standard. Accurately 250 mg of pure authentic sample of paracetamol was weighed. And refluxed with 20 ml of 4 M HCL with 30 ml of distilled water for about 30 minutes to prepare a standard solution. The content was appropriately diluted and required aliquots were taken for preparation of calibration curve. Solution containing 2-10 μgmL-1 of paracetamol equivalent was taken in 25 ml volumetric flask. To this aliquot 0.6 ml of 4M HCL and 1 ml of 0.1% w/v solution of sodium nitrite were added for diazotization. One ml of 0.5% w/v solution of ammonium sulfamate was added after 3 minutes to destroy excess nitrous acid and left for 2 minutes. PROCEDURE: Slide 18: Then, 1.5 ml of 0.5% w/v solution of 1-Napthol in 4 M NaOH was added as coupling agent. The absorbance of this azodye was measured at 505 nm. Tablet of paracetamol was weighed out and powdered. The powdered sample equivalent to 250 mg of paracetamol was accurately weighed out and exactly same process for hydrolysis and colour development was carried out for paracetamol Absorbance was measured at appropriate wavelengths using Perkin Elmer Lambda 40 UV/VIS spectrophotometer and paracetamol was estimated from calibration curve. Such azodye is found to be stable for at least 45 minutes. : : : PARACETAMOL WITH 1-NAPHTHOL AND RESORCINOL GIVE AZODYES: PARACETAMOL : METHOD 1: REAGENTS 1%w/v of solution 2,4dinitrobenzaldihyde (DNB) in 5% H2SO4 v/v. 0.1N, 1N HCL 100mg of equivalent tablet powder/100ml of 1NHCL =1mg/ml PROCEDURE: Take 2ml of sample and add 5ml of 1N HCL is heated 80c then add 5ml of DNB kept a side for 10-15min. Measured the yellow colour absorbance at 435nm,the yellow colour due to conformation of schiff’s base. PARACETAMOL REACTION: : REACTION: METHOD 2: : REAGENTS: 1N HCL 5% w/v solution of vanillin in isopropyl alcohol Stock solution: 1000mg/ml (1mg/ml) PROCEDURE: Take 2ml of sample and add 5ml of 1N HCL is heated in water bath in 30min at (80°c,then add 5ml of vanillin and kept a side for 10min measure the decreased lambda max absorbance is violet colour at 399nm. METHOD 2: REACTION: : REACTION: PARACETAMOL BY DIAZOTIZATION WITH NED: : 0.1%w/v solution of sodium nitrite in water. 0.5%w/v solution of ammonium sulpha mate in water 0.1%w/v solution of N-1-napththyl ethylene di amine di hydrochloride (NED) in water. 5N.HCL PROCEDURE sample and added 1ml of 5N HCL and add 1ml of NaNO2 solution mix well, kept a side for 10min,then add 1ml of ammonium sulpha mate then add 1ml of NED reagent measure the absorbance at ᵡ max 555nm. PARACETAMOL BY DIAZOTIZATION WITH NED: REACTION: : REACTION: ANALGIN: : METHODS OF ANALYSIS 1. IODIMETRY METHOD 2. COLORIMETRY METHOD 1. IODIMETRY METHOD: Weigh accurately about 0.4 g, dissolve in a mixture of 40 ml of ethanol (95%) and 10 ml of 0.01 hydrochloric acid and titrate with 0.05 M iodine until a yellow colour stable for 30 seconds is produced. 1ml of 0.05 M iodine is equivalent to 0.01667 g of Analgin ANALGIN: 2. COLORIMETRY METHOD: : 0.5M Phthalate Buffer: pH:4.0 0.5%w/v 1,2-napthaquinone-4-sulfanic acid (NQS) (Na salt/water) Procedure: 2ml of sample add 5ml of buffer add 1ml of NQS-sodium heat it on water bath for 60°c for 40min then extract with chloroform, orange colour will appear and measure the absorbance at 475nm. 2. COLORIMETRY METHOD: DERIVATIVES OF PYRAZOLINE : Antipyrine (phenazone) and aminopyrine (amidopyrine, pyramidon) are the pyrazolone is common use. The analytical methods for these compounds were reviewed by borloz in 1927 but some interesting new techniques are now available. A.ANTIPYRINE METHODS OF ANALYSIS: 1. GRAVIMETRIC METHOD 2. TITRIMETRIC METHODS 3. COLORIMETRIC METHODS 4. POLAROGRAPHIC METHOD DERIVATIVES OF PYRAZOLINE 1. GRAVIMETRIC METHOD : In a sodium bicarbonate solution antipyrine reacts with iodine to form a mono iodo addition compound. This mono iodo antipyrine can be extracted into chloroform. If caffeine is present it too will go in to the organic solvent. The iodine is released from combination by the reaction of sulphur dioxide, and silver nitrate is employed to pick it up as the silver iodide. The precipitate is weighed to determine the weight of antipyrine present. 1. GRAVIMETRIC METHOD 2. TITRIMETRICMETHODS: : An assay which is variation of the iodimetric-gravimetric method may be used. After precipitation of the mono iodo antipyrine is complete the excess iodine is black titrated with standard thio sulphate. The method is successful in the presence of acetanilide, acetophentidine, and aspirin. An early method employs back titration of excess picric acid after precipitation of antipyrine picrate.The excess acid can also be measured colorimetric ally. 2. TITRIMETRICMETHODS: 3.COLORIMETRIC METHOD : When antipyrine is treated with nitrite in acid solution, a colour is produced which can be measured. The absorbance maximum is at 513nm. A sensitive method is based upon reaction with p-di methyl amino benzaldehyde. REAGENT SOLUTION: P-di methyl amino benzaldehyde (0.5g) is dissolved in a mixture of 4.5ml of concentrated sulphuric acid and 8.5ml of water. 3.COLORIMETRIC METHOD PROCEDURE : A 5ml aliquot of an aqueous antipyrine solution, containing about 1.5 mg per millilitre is mixed with an equal volume of reagent solution, and after 1hour the absorbance is measured at 513nm.The colour produced is rose-red to salmon-pink. Although 4 to 5 hours is required for development of the maximum intensity, the measurements can be made earlier since the rate of absorbance is very small after the lapse of 1hour. Aminopyrine and aspirin do not interfere PROCEDURE 4. POLAROGRAPHIC METHOD : Antipyrine is nitrosated to give a compound which is reducible at the dropping mercury electrode. PROCEDURE: One ml of 0.1N sulphuric acid and 1ml of 0.1N sodium nitrite are added to 1ml of approximately 10-2 M antipyrine. The mixture is allowed to stand for 12min at 23°C to 28°C, to ensure complete reaction. Excess nitrous acid is neutralized with 1ml of 0.1N sodium hydroxide, 0.5ml of 1%gelatin solution is added, and the solution is polarographed. Concentration is reported to be proportional to the diffusion current. 4. POLAROGRAPHIC METHOD B.Aminopyrine: : METHODS OF ANALYSIS 1. GRAVIMETRIC METHOD 2. TITRIMETRIC METHOD 3. COLORIMETRIC METHOD 4. SPECTROPHOTOMETRIC METHOD B.Aminopyrine: Extraction : The sample is dissolved in alkali solution, and the aminopyrine is extracted with successive portions of chloroform. The aminopyrine is extracted with successive portions of chloroform. The aminopyrine is recovered by evaporation, dried at 80c for 2 hours and weighed. Hydrochloride Method: An aminopyrine forms salt with acids. The Hydrochloride has been used as a convenient form in which to weight the compound. Excess hydrochloric cid is added to the sample solution, which is then evaporated to dryness to drive off the excess HCL.The aminopyrine is dried and weighed.If preferred, the salts can be reacted with silver nitrate and the precipitate weighed as silver chloride to find the amount of chloride bound by the aminopyrine. Extraction 2. TITRIMETRIC METHOD : ACIDIMETRY: Aminopyrine is a strong base to be titratable in water with mineral acids .Methyl orange is a suitable indicator. In glacial acetic acid aminopyrine can easily be titrated with 0.1N perchloric acid. Most other tablet ingredients will not interfere, though magnesium stearate will consume some acid.Quinaldine red and p-naphtholbenzein is good indicator for this titration BROMIMETRIC METHOD: To 4to 6ml approximately 0.01M aminopyrine is added double volume of 6N HCl.The solution is heated to less than 60°C, and is titrated with 0.05N Potassium bromate.Methyl red is the indicator.. 2. TITRIMETRIC METHOD 3. COLORIMETRIC METHOD : A procedure which has been used analysed for aminopyrine in body fluids is based upon its reaction with diazotized p-nitroaniline.A yellow colour is obtained. In acid or neutral solutions a violet colour results from reaction with ferric chloride. The absorption maximum is at 570mµ. 4. SPECTROPHOTOMETRICMETHOD: Aminopyrine has been analysed spectrophotometriclly in mixture with quinine .In ethanol solution it has an absorption maximum at 270mµ. 3. COLORIMETRIC METHOD ASPIRIN : BROMIMETRY Mix 5.0 g with 3 g of anhydrous sodium carbonate, add 10 ml of bromine solution and mix thoroughly. Evaporate to dryness on a water-bath, gently ignite, and dissolve the cooled residue in 16 ml of brominated hydrochloric acid and 45 ml of water. Remove the excess of bromine with 2 ml of stannous chloride AsT. The resulting solution complies with the limit test for arsenic (2 ppm). ASPIRIN ASPIRIN TABLET : Weigh and powder 20 tablets. Weigh accurately a quantity of the powder containing about 0.5 g of Aspirin, add 30.0 ml of 0.5 M sodium hydroxide, boil gently for 10 minutes, cool and titrate the excess of alkali with 0.5 M hydrochloric acid using phenol red solution as indicator. Repeat the operation without the substance under examination. The difference between the titrations represents the amount of sodium hydroxide required. 1 ml of 0.5 M sodium hydroxide is equivalent to 0.04504 g aspirin tablets ASPIRIN TABLET CONCLUSION: : I here by conclude that there is a much necessity for the study of analytical methods of Antipyretics as they are widely used class of drugs. CONCLUSION: REFERENCES : The Indian Pharmacopeia volume( ii) 2007 Analgin page numbers : 117-118 Aspirin page numbers: 127-128 Pharmaceutical Analysis Book: Takeru Higuchi. A.S.Doniger Kenneth A. Connors Antipyrine : (557-559), Amino pyrine: (559-561) P. D. Sethi, “Quantitative Analysis of Drugs in Pharmaceutical Formulations”,. B. Morelli, J. Pharm. Biomed. Anal.,1989, 7, 577. P. B. Issopoulos, Acta. Pharm. Hung.,1992, 6, 3138. M. Knochen, J. Giglio and B.F. Reis, J. Pharm. Biomed. Anal., 2003, 33, 191. Hawrylyshyn, M., Hoffmann-La Roche Inc., Personal Communication. Johnson, J. H., Hoffmann-La Roche Inc., Personal Communication. Rubia, L. B., Hoffmann-La Roche Inc., Personal Communication. Boatman, J., Hoffmann-La Roche Inc. , Personal Communication REFERENCES Slide 42: THANKYOU You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.