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Spectrophotometric determination of paracetamol with iodylbenzene
Tafanfa,Vol. 32, No. 3, pp. 238-240.1985 Printed in Great Britain
0039-9140/85 $3.00f0.00
Pergamon Press Ltd
SPECTROPHOTOMETRIC DETERMINATION PARACETAMOL WITH IODYLBENZENE
OF
KRISHNA K. VERMA and ARCHANA JAIN Department of Chemistry, R.D. University of Jabalpur, Jabalpur 482001, India (Received 29 May 1984. Accepted 29 September 1984)
Summary-Paracetamol (N-aeetyl-4-aminophenol) has been determined spectrophotometrically by its oxidation with iodylbenzene in acetone to produce the yellow-orange N-acetyl-1,4-benzoquinoneimine, which attains maximum colour intensity within 1 min and absorbs maximally at 430 nm. The maximum molar absorptivity is 1.58 x 10’ I .mole-’ .cm-‘. The method is simple and rapid and has been found to be unaffected by the presence of salicylamide, oxyphenbutazone, acetylsalicylic acid, dipyrone and a number of other excipients.
Paracetamol (acetaminophen, N-acetyl-4-aminophenol) is an extensively employed antipyretic analgesic drug. Dipyrone (analgin), oxyphenbutazone, acetylsalicylic acid and salicylamide are found along with it in various pharmaceutical preparations. These substances interfere severely in one or another of the currently available methods of determining paracetamol. The titrimetric methods involve the reaction of either the phenolic group with a base in dimethylformamide medium’,2 or of the aromatic amino group (formed by hydrolysis) with nitrite,3 but there is interference with the acid-base method by salicylamide, oxyphenbutazone and acetylsalicylic acid (which are also acidic), and any free 4-aminophenol present (which is a product of decomposition). In the dipyrone and Vitamin C, other method, 4-aminophenol will all consume nitrous acid. Hydrolysis of paracetamol to 4-aminophenol which is then reacted with a substituted benzaldehydeM or 4-dimethylaminocinnamaldehyde’ to form coloured Schiffs bases is naturally affected by the presence of 4-aminophenol and phenetidine (formed by hydrolysis of phenacetin). The nitrosation and chelation given by reaction’ of paracetamol is also and oxyphenbutazone.’ Indophenol salicylamide’ simple specformation’O.” constitutes a trophotometric determination, but it is based on the oxidative coupling of 4-aminophenol with alkaline phenol, so dipyrone (being a strong antioxidant) interferes and causes low results for paracetamol. Determinations based on ultraviolet absorption’2 and its change with pH13 are too sensitive to be of general use for compound drug tablets. A rapid and highly selective spectrophotometric method for the determination of paracetamol in drug formulations is now reported. Iodylbenzene (iodoxybenzene) is insoluble in common organic solvents but its suspension in acetone brings about specific oxidation of paracetamol to a yellow-orange substance that shows maximum absorption at 430
nm. The colour is stable for about an hour and obeys Beer’s law over a wide range of paracetamol concentration. EXPERIMENTAL Reagent
Iodylbenzene was synthesized by the procedure described by Fieser and Fieser,14 and by the bromate oxidation method of Banerjee et ~1.‘~modified as follows. To a mixture of 20 g of iodobenzene, 200 ml of 40% v/v sulphuric acid and 50 ml of glacial acetic acid, heated on a boiling water-bath, slowly add a solution of 15 g of potassium bromate in 150 ml of warm water during a period of 30 min with vigorous stirring (in a fume-chamber). Continue the heating for 90 min, during which all the bromine evolved is removed. Cool to room temperature, decant the supernatant liquid, wash the product (oily owing to unreacted iodobenzene) with water, macerate it with 50 ml of chloroform, filter it off and wash it with chloroform to furnish a silky white solid, m.p. 222’ (decomposition). The product obtained in this way (12 g, 50% yield) was found to be 98% pure, by iodometric analysis.16 Samples
A high-purity sample of paracetamol. found to be 98.8% pure by the mdophenol methodlo and 98.6% pure by the nitrosation method,* was used. All drug samples tested were fresh. Procedure Preparation of calibration graph. Into a 50-ml calibrated flask accurately weigh 10 mg of paracetamol, dissolve it in acetone and make up to the mark with the same solvent; mix l-5 ml portions of this solution with about 20 mg of finely powdered iodylbenzene in lo-ml beakers, dilute each to about 5 ml with acetone and stir for 1 mm. Filter the coloured solution through a small fluted Whatman No. 41 filter paper into a IO-ml standard flask, washing the residue and makmg up to the mark with acetone. Measure the absorbance at 430 nm in a l-cm cell against acetone. Drug samples. Grind a known number of tablets, accurately weighed, into a fine powder, weigh out a portion containing about 10 mg of paracetamol and stir it with 20 ml of acetone. Filter off the residue on a fluted Whatman No. 41 filter paper, wash it with three successive 5-ml portions of acetone and make up filtrate and washings to volume with acetone in a 50-ml standard flask. Treat a 2-ml
238
SHORT
239
COMMUNICATIONS
give any colour with iodylbenzene, that the colour reaction is:
portion of this solution by the procedure described for preparation of the calibration graph.
RESULTS AND DISCUSSION
-
HO+NHCOCH,
Iodylbenzene is insoluble in the commonly used organic solvents, but a suspension of it in acetone oxidizes paracetamol to a yellow-orange product that has maximum absorption at 430 nm. The reaction is
00
+
NCOCH,
+
@)-IO,
@IO
-
+ H,O
The colour develops almost instantaneously and remains stable for about 1 hr. There is a 10% decrease in colour intensity after 2 hr. Other common oxidizing agents, e.g., iodosobenzene diacetate or dichloride, chloramine-T and N-bromosuccinimide, do not produce a colour, perhaps because the
reversible, the product being decolorized on addition of ascorbic acid and reoxidized to the coloured product by iodylbenzene. The observation that iodosobenzene does not yield a colour reaction and that paracetamol acetylated at the phenolic group fails to Table 1. Determination
led us to believe
of paracetamol in drugs Paracetamol, mg/rablelt
Drug*
Maker’s specification
Present method
CV, %
Laboratory-made tablet No. 1’ No. 2” No. 3”’ Crocin Metacin Panjon” Arumin’ Malidens” Arthopa? Actimol”“’ Canapar* Neogene” Flamar-P” Parazolandin”“’ Panbin”’ Reducin A”’ Paramide”” Vikoryl”“’ Ultragin” Corbutyl”” Contac-CC” Prydonnal”” Spasmindon”‘”
258 504 246 500 500 150 200 250 500 500 250 250 250 500 150 650 250 120 250 650 450 400 250
263 502 244 538 497 142 181 267 512 475 225 236 210 506 138 596 284 140 228 600 409 415 246
0.4 0.2 0.3 0.2 0.2 0.3 0.4 0.4 0.5 0.3 0.5 0.5 0.3 0.4 0.3 0.4 0.3 0.2 0.2 0.4 0.4 0.5 0.2
Comparison method
:0y 139§ 2718 4803 243 + 5103 1355 2785 139§ 2328 612$ 4161 4055 2485
Other substances present include the following: (i) Caminophenol(50 mg); (ii) dipyrone (250 mg) and salicylamide (100 mg); (iii) oxyphenbutazone (100 mg) and acetylsalicylic acid (150 mg); (it)) acetylsalicylic acid (300 mg) and caffeme (30 mg); (L’) oxyphenbutazone (500 mg). dried aluminmm hydroxide gel (750 mg) and magnesium trisilicate (500 mg); (vi) salicylamtde (250 mg) and caffeine (25 mg); (vii) oxyphenbutazone (100 mg) and diazepam (2.5 mg); (viii) phenylbutazone (500 mg); (ix) dipyrone (250 mg) and cafferne (25 mg); (x) dipyrone (250 mg). caffeine (30 mg), codeine phosphate (7.5 mg) and chlorpromazine hydrate (7.5 mg); (.yi) oxyphenbutazone (100 mg); (xii) salicylamide (200 mg). methaqualone hydrochloride (20mg), caffeine (20 mg) and chlorpheniramine (2 mg); (xiii) phenylephrine hydrochloride (5 mg), salicylamide (200 mg) and chlorpheniramine maleate (2 mg); (xic) dextropropoxyphene hydrochloride (65 mg); (xc) noscapine (15 mg) and phenylpropanolamme hydrochloride (25 mg); (xvi) hyoscyamine sulphate (0.22 mg), scopolamine hydrobromide (0.02 mg), atropine sulphate (0.02 mg) and phenobarbitone (30 mg); and (xvii) phenylisopropyl pyrazolone (150 mg), dicyclomine hydrochloride (10 mg) and ethylmorphine hydrochloride (11 mg). tMean of 6 replicates; CV = coefficient of variation. §Method in reference 10. IMethod in reference 8. *Method in reference 1.
240
SHORT
COMMUNICATIONS
to Table 1. 4-Aminophenol is a product of decomposition of paracetamol and interferes in almost all available methods for determining paracetamol, but the present method is free from this interference. Acknowledgement-Thanks are due to the University Grants Commission (New Delhi) for the award of a Junior Research Fellowship to A.J. REFERENCES
400
320
Wavelength
520
(nm)
Fig. 1. Absorption spectrum of paracetamol-iodylbenzene reaction product (paracetamol 40 pg/ml). oxidation continues beyond the N-acetyl-1,4benzoquinoneimine. The visible spectrum of the
chromogen is shown in Fig. 1. The molar absorptivity is 1.58 x lo3 l.mole-‘.cm-’ at 430 nm. The method is more rapid and simple than the existing procedures, and Beer’s law is obeyed over a wide range of paracetamol concentration, O-100 pg/ml in the final solution. The absorption spectrum is unaffected by the use of as high as lOO-fold molar excess of iodylbenzene. A large number of pharmaceutical preparations containing paracetamol have been analysed by the method and the results are given in Table 1 together with comparative values obtained by using established methods. Dipyrone, oxyphenbutazone, acetylsalicylic acid, salicylamide, vitamin C, phenacetin and caffeine do not affect the results. Other substances which can be tolerated are listed in a footnote
1. M. I. Walash, S. P. Agarwal and M. I. Martin, Can. J. Pharm. Sci., 1972, I, 123. 2. S. P. Agarwal and M. I. Walash, Indian J. Pharm., 1974. 36, 47. 3. M. C. Inamdar, M. A. Gore and R. V. Bhide. ibid., 1974, 36, 7. 4. N. M. Sanghavi and D. R. Vishwasrao. ibid., 1973, 35,
172. 5. F. M. Plakoviannis and A. M. Saad, J. Pharm. Set., 1975, 64, 1547.
6. E. Kalatzis and I. Zarbt, ibid., 1976, 65, 71. 7. T. Inoue, M. Tatsuzawa. S. Lee and T. Ishii. Eisei Kagaku, 1975, 21, 313.
8. S. F. Belal, M. A. H. Elsayed, A. Elwahly and H. Abdine, Analyst, 1979, 104, 919. 9. A. A. Ouf, M. I. Walash, S. M. Hassan and S. M. Elsayed, ibid., 1980, 105, 169. 10. C. T. H. Ellcock and A. G. Fogg, ibid., 1975, 100, 16. 11. D. R. Davis, A. G. Fogg, D. T. Burns and J. S. Wragg, ibid., 1974, 99, 12.
12. British Pharmacopoeia 1973, p. 340. HMSO. London, 1973. 13. M. A. H. Elsayed, S. F. Belal, A. F. M. Elwalily and H. Abdine, Analyst, 1979, 104, 620. 14. L. F. Fieser and M. Fieser, Reagents for Organtc Synthesis, Vol. 1,p. 511. Wiley-Interscience, New York, 1967. 15. A. Banerjee, G. C. Banerjee, S. Bhattacharya. S. Banerjee and H. Samaddar, J. Indian Chem. Sot.,1981.58, 605.
16. L. F. Fieser and M. Fieser, op. ctt., p. 507.
0039-9140/85 $3.00f0.00
Pergamon Press Ltd
SPECTROPHOTOMETRIC DETERMINATION PARACETAMOL WITH IODYLBENZENE
OF
KRISHNA K. VERMA and ARCHANA JAIN Department of Chemistry, R.D. University of Jabalpur, Jabalpur 482001, India (Received 29 May 1984. Accepted 29 September 1984)
Summary-Paracetamol (N-aeetyl-4-aminophenol) has been determined spectrophotometrically by its oxidation with iodylbenzene in acetone to produce the yellow-orange N-acetyl-1,4-benzoquinoneimine, which attains maximum colour intensity within 1 min and absorbs maximally at 430 nm. The maximum molar absorptivity is 1.58 x 10’ I .mole-’ .cm-‘. The method is simple and rapid and has been found to be unaffected by the presence of salicylamide, oxyphenbutazone, acetylsalicylic acid, dipyrone and a number of other excipients.
Paracetamol (acetaminophen, N-acetyl-4-aminophenol) is an extensively employed antipyretic analgesic drug. Dipyrone (analgin), oxyphenbutazone, acetylsalicylic acid and salicylamide are found along with it in various pharmaceutical preparations. These substances interfere severely in one or another of the currently available methods of determining paracetamol. The titrimetric methods involve the reaction of either the phenolic group with a base in dimethylformamide medium’,2 or of the aromatic amino group (formed by hydrolysis) with nitrite,3 but there is interference with the acid-base method by salicylamide, oxyphenbutazone and acetylsalicylic acid (which are also acidic), and any free 4-aminophenol present (which is a product of decomposition). In the dipyrone and Vitamin C, other method, 4-aminophenol will all consume nitrous acid. Hydrolysis of paracetamol to 4-aminophenol which is then reacted with a substituted benzaldehydeM or 4-dimethylaminocinnamaldehyde’ to form coloured Schiffs bases is naturally affected by the presence of 4-aminophenol and phenetidine (formed by hydrolysis of phenacetin). The nitrosation and chelation given by reaction’ of paracetamol is also and oxyphenbutazone.’ Indophenol salicylamide’ simple specformation’O.” constitutes a trophotometric determination, but it is based on the oxidative coupling of 4-aminophenol with alkaline phenol, so dipyrone (being a strong antioxidant) interferes and causes low results for paracetamol. Determinations based on ultraviolet absorption’2 and its change with pH13 are too sensitive to be of general use for compound drug tablets. A rapid and highly selective spectrophotometric method for the determination of paracetamol in drug formulations is now reported. Iodylbenzene (iodoxybenzene) is insoluble in common organic solvents but its suspension in acetone brings about specific oxidation of paracetamol to a yellow-orange substance that shows maximum absorption at 430
nm. The colour is stable for about an hour and obeys Beer’s law over a wide range of paracetamol concentration. EXPERIMENTAL Reagent
Iodylbenzene was synthesized by the procedure described by Fieser and Fieser,14 and by the bromate oxidation method of Banerjee et ~1.‘~modified as follows. To a mixture of 20 g of iodobenzene, 200 ml of 40% v/v sulphuric acid and 50 ml of glacial acetic acid, heated on a boiling water-bath, slowly add a solution of 15 g of potassium bromate in 150 ml of warm water during a period of 30 min with vigorous stirring (in a fume-chamber). Continue the heating for 90 min, during which all the bromine evolved is removed. Cool to room temperature, decant the supernatant liquid, wash the product (oily owing to unreacted iodobenzene) with water, macerate it with 50 ml of chloroform, filter it off and wash it with chloroform to furnish a silky white solid, m.p. 222’ (decomposition). The product obtained in this way (12 g, 50% yield) was found to be 98% pure, by iodometric analysis.16 Samples
A high-purity sample of paracetamol. found to be 98.8% pure by the mdophenol methodlo and 98.6% pure by the nitrosation method,* was used. All drug samples tested were fresh. Procedure Preparation of calibration graph. Into a 50-ml calibrated flask accurately weigh 10 mg of paracetamol, dissolve it in acetone and make up to the mark with the same solvent; mix l-5 ml portions of this solution with about 20 mg of finely powdered iodylbenzene in lo-ml beakers, dilute each to about 5 ml with acetone and stir for 1 mm. Filter the coloured solution through a small fluted Whatman No. 41 filter paper into a IO-ml standard flask, washing the residue and makmg up to the mark with acetone. Measure the absorbance at 430 nm in a l-cm cell against acetone. Drug samples. Grind a known number of tablets, accurately weighed, into a fine powder, weigh out a portion containing about 10 mg of paracetamol and stir it with 20 ml of acetone. Filter off the residue on a fluted Whatman No. 41 filter paper, wash it with three successive 5-ml portions of acetone and make up filtrate and washings to volume with acetone in a 50-ml standard flask. Treat a 2-ml
238
SHORT
239
COMMUNICATIONS
give any colour with iodylbenzene, that the colour reaction is:
portion of this solution by the procedure described for preparation of the calibration graph.
RESULTS AND DISCUSSION
-
HO+NHCOCH,
Iodylbenzene is insoluble in the commonly used organic solvents, but a suspension of it in acetone oxidizes paracetamol to a yellow-orange product that has maximum absorption at 430 nm. The reaction is
00
+
NCOCH,
+
@)-IO,
@IO
-
+ H,O
The colour develops almost instantaneously and remains stable for about 1 hr. There is a 10% decrease in colour intensity after 2 hr. Other common oxidizing agents, e.g., iodosobenzene diacetate or dichloride, chloramine-T and N-bromosuccinimide, do not produce a colour, perhaps because the
reversible, the product being decolorized on addition of ascorbic acid and reoxidized to the coloured product by iodylbenzene. The observation that iodosobenzene does not yield a colour reaction and that paracetamol acetylated at the phenolic group fails to Table 1. Determination
led us to believe
of paracetamol in drugs Paracetamol, mg/rablelt
Drug*
Maker’s specification
Present method
CV, %
Laboratory-made tablet No. 1’ No. 2” No. 3”’ Crocin Metacin Panjon” Arumin’ Malidens” Arthopa? Actimol”“’ Canapar* Neogene” Flamar-P” Parazolandin”“’ Panbin”’ Reducin A”’ Paramide”” Vikoryl”“’ Ultragin” Corbutyl”” Contac-CC” Prydonnal”” Spasmindon”‘”
258 504 246 500 500 150 200 250 500 500 250 250 250 500 150 650 250 120 250 650 450 400 250
263 502 244 538 497 142 181 267 512 475 225 236 210 506 138 596 284 140 228 600 409 415 246
0.4 0.2 0.3 0.2 0.2 0.3 0.4 0.4 0.5 0.3 0.5 0.5 0.3 0.4 0.3 0.4 0.3 0.2 0.2 0.4 0.4 0.5 0.2
Comparison method
:0y 139§ 2718 4803 243 + 5103 1355 2785 139§ 2328 612$ 4161 4055 2485
Other substances present include the following: (i) Caminophenol(50 mg); (ii) dipyrone (250 mg) and salicylamide (100 mg); (iii) oxyphenbutazone (100 mg) and acetylsalicylic acid (150 mg); (it)) acetylsalicylic acid (300 mg) and caffeme (30 mg); (L’) oxyphenbutazone (500 mg). dried aluminmm hydroxide gel (750 mg) and magnesium trisilicate (500 mg); (vi) salicylamtde (250 mg) and caffeine (25 mg); (vii) oxyphenbutazone (100 mg) and diazepam (2.5 mg); (viii) phenylbutazone (500 mg); (ix) dipyrone (250 mg) and cafferne (25 mg); (x) dipyrone (250 mg). caffeine (30 mg), codeine phosphate (7.5 mg) and chlorpromazine hydrate (7.5 mg); (.yi) oxyphenbutazone (100 mg); (xii) salicylamide (200 mg). methaqualone hydrochloride (20mg), caffeine (20 mg) and chlorpheniramine (2 mg); (xiii) phenylephrine hydrochloride (5 mg), salicylamide (200 mg) and chlorpheniramine maleate (2 mg); (xic) dextropropoxyphene hydrochloride (65 mg); (xc) noscapine (15 mg) and phenylpropanolamme hydrochloride (25 mg); (xvi) hyoscyamine sulphate (0.22 mg), scopolamine hydrobromide (0.02 mg), atropine sulphate (0.02 mg) and phenobarbitone (30 mg); and (xvii) phenylisopropyl pyrazolone (150 mg), dicyclomine hydrochloride (10 mg) and ethylmorphine hydrochloride (11 mg). tMean of 6 replicates; CV = coefficient of variation. §Method in reference 10. IMethod in reference 8. *Method in reference 1.
240
SHORT
COMMUNICATIONS
to Table 1. 4-Aminophenol is a product of decomposition of paracetamol and interferes in almost all available methods for determining paracetamol, but the present method is free from this interference. Acknowledgement-Thanks are due to the University Grants Commission (New Delhi) for the award of a Junior Research Fellowship to A.J. REFERENCES
400
320
Wavelength
520
(nm)
Fig. 1. Absorption spectrum of paracetamol-iodylbenzene reaction product (paracetamol 40 pg/ml). oxidation continues beyond the N-acetyl-1,4benzoquinoneimine. The visible spectrum of the
chromogen is shown in Fig. 1. The molar absorptivity is 1.58 x lo3 l.mole-‘.cm-’ at 430 nm. The method is more rapid and simple than the existing procedures, and Beer’s law is obeyed over a wide range of paracetamol concentration, O-100 pg/ml in the final solution. The absorption spectrum is unaffected by the use of as high as lOO-fold molar excess of iodylbenzene. A large number of pharmaceutical preparations containing paracetamol have been analysed by the method and the results are given in Table 1 together with comparative values obtained by using established methods. Dipyrone, oxyphenbutazone, acetylsalicylic acid, salicylamide, vitamin C, phenacetin and caffeine do not affect the results. Other substances which can be tolerated are listed in a footnote
1. M. I. Walash, S. P. Agarwal and M. I. Martin, Can. J. Pharm. Sci., 1972, I, 123. 2. S. P. Agarwal and M. I. Walash, Indian J. Pharm., 1974. 36, 47. 3. M. C. Inamdar, M. A. Gore and R. V. Bhide. ibid., 1974, 36, 7. 4. N. M. Sanghavi and D. R. Vishwasrao. ibid., 1973, 35,
172. 5. F. M. Plakoviannis and A. M. Saad, J. Pharm. Set., 1975, 64, 1547.
6. E. Kalatzis and I. Zarbt, ibid., 1976, 65, 71. 7. T. Inoue, M. Tatsuzawa. S. Lee and T. Ishii. Eisei Kagaku, 1975, 21, 313.
8. S. F. Belal, M. A. H. Elsayed, A. Elwahly and H. Abdine, Analyst, 1979, 104, 919. 9. A. A. Ouf, M. I. Walash, S. M. Hassan and S. M. Elsayed, ibid., 1980, 105, 169. 10. C. T. H. Ellcock and A. G. Fogg, ibid., 1975, 100, 16. 11. D. R. Davis, A. G. Fogg, D. T. Burns and J. S. Wragg, ibid., 1974, 99, 12.
12. British Pharmacopoeia 1973, p. 340. HMSO. London, 1973. 13. M. A. H. Elsayed, S. F. Belal, A. F. M. Elwalily and H. Abdine, Analyst, 1979, 104, 620. 14. L. F. Fieser and M. Fieser, Reagents for Organtc Synthesis, Vol. 1,p. 511. Wiley-Interscience, New York, 1967. 15. A. Banerjee, G. C. Banerjee, S. Bhattacharya. S. Banerjee and H. Samaddar, J. Indian Chem. Sot.,1981.58, 605.
16. L. F. Fieser and M. Fieser, op. ctt., p. 507.