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A direct titrimetric method for the microdetermination of some phenothiazine derivatives in pharmaceutical preparations
Talanto, Vol. 29, pp. 58 to 60, 1982 Printed in Great Britain
0039.9140/82/010058-03f03.0/0 Pergamon Press Ltd
A DIRECT TITRIMETRIC METHOD FOR THE MICRODETERMINATION OF SOME PHENOTHIAZINE DERIVATIVES IN PHARMACEUTICAL PREPARATIONS V. N.
PATHAK
and I. C. SHUKLA
Department of Chemistry, University of Allahabad, Allahabad, 211002, India and S. R. SHUKLA Department of Pharmacology, M.L.N. Medical College, Allahabad 211002, India (Received 22 May 1980. Revised 18 May 1981. Accepted 30 May 1981) Summary-A micro method has been developed for the determination of some phenothiazine derivatives in pure form and in pharmaceutical preparations, l-5 mg of sample being titrated directly with 0.02M N-bromosuccinimide, with Methyl Red as indicator. The error does not exceed k 1%.
Phenothiazine derivatives are used variously as antipsychotropic, anticholinergic and antihistaminic drugs, ‘J and methods for their assay are important. Kasakalian and McGlotten3 have reported determination by anodic oxidation of about 1.5 mg of chlorpromazine. Blaiek4 has used an amperometric method for the determination of 50mg of chlorpromazine. Porter’ has determined microgram quantities of chlorpromazine polarographically with OSM hydrochloric acid as supporting electrolyte. The pharmacology and assay of phenothiazine and prochlorperazine have been discussed.6-9 Some new phenothiazine derivatives such as triflupromazine and trifluperazine have been estimated by Schrine.” In this paper we describe a quick and convenient method for the microdetermination of phenothiazine derivatives with N-bromosuccinimide (NBS), a wellknown brominating and oxidizing agent.“3’2
chloric acid and 2 drops of 0.04% Methyl Red indicator solution were added. The mixture was titrated with 0.02M NBS until the indicator was decolorized. The excess of NBS was back-titrated iodometrically. The same volume of NBS was then titrated iodometrically under identical conditions. The amount of drug was calculated from the difference between volumes of NBS consumed in the blank and the determination. mg ofdrug = (B - :)MN where A = volume of NBS consumed by the blank (ml); B = volume of NBS consumed by the drug (ml); M = molecular weight of the drug; N = molar concentration of NBS; n = moles of NBS consumed per mole of the sample. RESULTS AND
DISCUSSION
The precision is shown in Table 1, and the accuracy (established by recovery tests based on determination of the drug content of spiked and unspiked samples) in Table 2. The effects of variables such as temperature, acidity, NBS concentration and amount of sample were studied. Temperatures above 26” tend to cause inaccurate results and create difficulty in detecting the end-point, because of decomposition of NBS at higher temperature. Room temperature (- 25”) is the most suitable. The reaction of phenothiazine derivatives with NBS at pH 4-5 is not quantitative and gives variable results. An approximately 0.084.15M hydrochloric acid medium gives consistent and accurate results.
EXPERIMENTAL Sample solutions
These were prepared by dissolving 25 mg of sample in distilled water and diluting to volume in a 25-ml standard flask. N-Bromosuccinimide solution, 0.02M The reagent (0.3560 g) was dissolved in the minimum of warm distilled water, made up to 100 ml with cold distilled water, and standardized iodometrically.‘3.‘4 Procedure
A portion of solution, containing l-5 mg of drug, was placed in a lOO-ml titration flask, and 6ml of 2M hydro58
59
SHORT COMMUNICATIONS
Table 1. Microdetermination of phenothiazine (l-5 mg) with NBS (10 variates)
derivatives
Coefficient of variation, y0
Sample Chlorpromazine hydrochloride Prochlorperazine di(hydrogen maleate) Promethazine hydrochloride Triflupromazine hydrochloride Trifluperazine dihydrochloride
The best recovery was obtained with 0.02M NBS, which should be prepared just before use and kept in a cool dark place. Because the Methyl Red reacts with the reagent, the amount of indicator taken should be
0.3 0.8 0.3 0.4 0.4
kept constant and only a small quantity (2 drops) should be used. Excipients do not interfere. The method is applicable to sample weights ranging from 1 to 20 mg.
Table 2. Results obtained by the standard-addition Preparation
Added, mg
Found, mg
Recovery, 7;
18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0
17.9 35.8 44.9 17.9 35.7 44.8 18.1 36.2 45.2
99.4 99.4 99.8 99.4 99.2 99.6 100.6 100.6 100.4
18.0 36.0 54.0 18.0 36.0 54.0
17.9 35.7 53.8 17.9 35.8 53.6
99.4 99.2 99.6 99.4 99.4 99.3
18.0 36.0 45.0 18.0 36.0 45.0
18.1 36.1 45.2 18.1 36.2 45.2
100.6 100.3 100.4 100.6 100.6 100.4
18.0 36.0 54.0
17.9 35.7 53.7
99.4 99.2 99.4
18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0
18.1 36.1 45.3 17.9 35.8 44.8 18.1 35.9 44.9 17.9 35.8 44.8
100.6 100.3 100.7 99.4 99.4 99.6 100.6 99.7 99.8 99.4 99.4 99.6
Chlorpromazine hydrochloride (a) Largactil tablets*
(b) Widactil tablets?
(c) Ingatron tabletsa Prochlorperazine di(hydrogen maleate) (a) Stemetil tablets*
(b) Stemetil injection*
Promerhazine hydrochloride (a) Phenergan tablets*
(b) Phenergan injection*
Trijupromazine
hydrochloride
Siquil tablets1 Trijluperazine dihydrochloride (a) Eskazine tablets /I
(b) Eskazine injection
11
(c) Fluozine tablets7 (d) Ifizine tabletst
* May & Baker. t Unique. $ Sarabhai. 5 Inga. /(Smith, Kline & French (Stelazine). 7 Medicare.
TAL. 29/l-~
method
60
SHORT
COMMUNICATIONS
The value of n in the calculation equation is 20 for all the drugs tested, except prochlorperazine di(hydrogen maleate), for which it is 28 (the maleate consumes the extra NBS15). Although its mechanism is not clear, the reaction could be useful for quality control. The method has not been tested in the presence of degradation products of the drugs, so it is not known whether it is suitable for metabolic studies. In the case of prochlorperazine di(hydrogen maleate), any maleic acid present, owing to poor preparation, will cause a positive error.
REFERENCES
1. R. Cass and T. L. B. Spring, Br. J. Pharmac. Chemother., 1961, 17, 442.
2. J. J. Lewis, An Introduction to Pharmacology, 3rd Ed., pp. 251-261. Churchill Livingstone, Edinburgh, 1965. 3. P. Kasakalian and J. McGlotten, Anal. Chem. 1959, 31, “~, 431.
J. Blaiek, Cesk. Farm., 1956, 4, 210. G. S. Porter, J. Pharm. Pharmacol., 1964, 1, 24T. B. M. Alturs, Ph.D. Thesis, New York Universitv. 1964. B. M. Alturs and B. W. Zweifach, Fed. Proc. Fed. Am. Sot., Exp. Biol., 1964. 23. 252. 8. T. J. Haiey and M. R. Andern, J. Pharmac. Exp. Ther., 1950, loo, 393. 9. H. A. Zarem, B. W. Zweifach and J. M. McGehee, Am. J. Physiol., 1967, 212, 1081. 10. I. Schrine, Lancer, 1963, 1, 174. 11. R. D. Tiwari, J. P. Sharma and I. C. Shukla, Talanta, 1967, 14, 853. 12. R. D. Tiwari and U. C. Pande, Analyst, 1969, 94, 813. 13. K. Ziegler, A. Spath, E. Schaaf, W. Schumann and E. Winkelmann, Ann., 1942, 551, 80. 14. T. Takizawa and K. Hoshiai, Mem. Inst. Sci. Ind. Research, Osaka Univ., 1950, 7, 136. 15. M. Z. Barakat, J. Pharm. Pharmacol., 1952, 4, 582. 4. 5. 6. 7.
0039.9140/82/010058-03f03.0/0 Pergamon Press Ltd
A DIRECT TITRIMETRIC METHOD FOR THE MICRODETERMINATION OF SOME PHENOTHIAZINE DERIVATIVES IN PHARMACEUTICAL PREPARATIONS V. N.
PATHAK
and I. C. SHUKLA
Department of Chemistry, University of Allahabad, Allahabad, 211002, India and S. R. SHUKLA Department of Pharmacology, M.L.N. Medical College, Allahabad 211002, India (Received 22 May 1980. Revised 18 May 1981. Accepted 30 May 1981) Summary-A micro method has been developed for the determination of some phenothiazine derivatives in pure form and in pharmaceutical preparations, l-5 mg of sample being titrated directly with 0.02M N-bromosuccinimide, with Methyl Red as indicator. The error does not exceed k 1%.
Phenothiazine derivatives are used variously as antipsychotropic, anticholinergic and antihistaminic drugs, ‘J and methods for their assay are important. Kasakalian and McGlotten3 have reported determination by anodic oxidation of about 1.5 mg of chlorpromazine. Blaiek4 has used an amperometric method for the determination of 50mg of chlorpromazine. Porter’ has determined microgram quantities of chlorpromazine polarographically with OSM hydrochloric acid as supporting electrolyte. The pharmacology and assay of phenothiazine and prochlorperazine have been discussed.6-9 Some new phenothiazine derivatives such as triflupromazine and trifluperazine have been estimated by Schrine.” In this paper we describe a quick and convenient method for the microdetermination of phenothiazine derivatives with N-bromosuccinimide (NBS), a wellknown brominating and oxidizing agent.“3’2
chloric acid and 2 drops of 0.04% Methyl Red indicator solution were added. The mixture was titrated with 0.02M NBS until the indicator was decolorized. The excess of NBS was back-titrated iodometrically. The same volume of NBS was then titrated iodometrically under identical conditions. The amount of drug was calculated from the difference between volumes of NBS consumed in the blank and the determination. mg ofdrug = (B - :)MN where A = volume of NBS consumed by the blank (ml); B = volume of NBS consumed by the drug (ml); M = molecular weight of the drug; N = molar concentration of NBS; n = moles of NBS consumed per mole of the sample. RESULTS AND
DISCUSSION
The precision is shown in Table 1, and the accuracy (established by recovery tests based on determination of the drug content of spiked and unspiked samples) in Table 2. The effects of variables such as temperature, acidity, NBS concentration and amount of sample were studied. Temperatures above 26” tend to cause inaccurate results and create difficulty in detecting the end-point, because of decomposition of NBS at higher temperature. Room temperature (- 25”) is the most suitable. The reaction of phenothiazine derivatives with NBS at pH 4-5 is not quantitative and gives variable results. An approximately 0.084.15M hydrochloric acid medium gives consistent and accurate results.
EXPERIMENTAL Sample solutions
These were prepared by dissolving 25 mg of sample in distilled water and diluting to volume in a 25-ml standard flask. N-Bromosuccinimide solution, 0.02M The reagent (0.3560 g) was dissolved in the minimum of warm distilled water, made up to 100 ml with cold distilled water, and standardized iodometrically.‘3.‘4 Procedure
A portion of solution, containing l-5 mg of drug, was placed in a lOO-ml titration flask, and 6ml of 2M hydro58
59
SHORT COMMUNICATIONS
Table 1. Microdetermination of phenothiazine (l-5 mg) with NBS (10 variates)
derivatives
Coefficient of variation, y0
Sample Chlorpromazine hydrochloride Prochlorperazine di(hydrogen maleate) Promethazine hydrochloride Triflupromazine hydrochloride Trifluperazine dihydrochloride
The best recovery was obtained with 0.02M NBS, which should be prepared just before use and kept in a cool dark place. Because the Methyl Red reacts with the reagent, the amount of indicator taken should be
0.3 0.8 0.3 0.4 0.4
kept constant and only a small quantity (2 drops) should be used. Excipients do not interfere. The method is applicable to sample weights ranging from 1 to 20 mg.
Table 2. Results obtained by the standard-addition Preparation
Added, mg
Found, mg
Recovery, 7;
18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0
17.9 35.8 44.9 17.9 35.7 44.8 18.1 36.2 45.2
99.4 99.4 99.8 99.4 99.2 99.6 100.6 100.6 100.4
18.0 36.0 54.0 18.0 36.0 54.0
17.9 35.7 53.8 17.9 35.8 53.6
99.4 99.2 99.6 99.4 99.4 99.3
18.0 36.0 45.0 18.0 36.0 45.0
18.1 36.1 45.2 18.1 36.2 45.2
100.6 100.3 100.4 100.6 100.6 100.4
18.0 36.0 54.0
17.9 35.7 53.7
99.4 99.2 99.4
18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0 18.0 36.0 45.0
18.1 36.1 45.3 17.9 35.8 44.8 18.1 35.9 44.9 17.9 35.8 44.8
100.6 100.3 100.7 99.4 99.4 99.6 100.6 99.7 99.8 99.4 99.4 99.6
Chlorpromazine hydrochloride (a) Largactil tablets*
(b) Widactil tablets?
(c) Ingatron tabletsa Prochlorperazine di(hydrogen maleate) (a) Stemetil tablets*
(b) Stemetil injection*
Promerhazine hydrochloride (a) Phenergan tablets*
(b) Phenergan injection*
Trijupromazine
hydrochloride
Siquil tablets1 Trijluperazine dihydrochloride (a) Eskazine tablets /I
(b) Eskazine injection
11
(c) Fluozine tablets7 (d) Ifizine tabletst
* May & Baker. t Unique. $ Sarabhai. 5 Inga. /(Smith, Kline & French (Stelazine). 7 Medicare.
TAL. 29/l-~
method
60
SHORT
COMMUNICATIONS
The value of n in the calculation equation is 20 for all the drugs tested, except prochlorperazine di(hydrogen maleate), for which it is 28 (the maleate consumes the extra NBS15). Although its mechanism is not clear, the reaction could be useful for quality control. The method has not been tested in the presence of degradation products of the drugs, so it is not known whether it is suitable for metabolic studies. In the case of prochlorperazine di(hydrogen maleate), any maleic acid present, owing to poor preparation, will cause a positive error.
REFERENCES
1. R. Cass and T. L. B. Spring, Br. J. Pharmac. Chemother., 1961, 17, 442.
2. J. J. Lewis, An Introduction to Pharmacology, 3rd Ed., pp. 251-261. Churchill Livingstone, Edinburgh, 1965. 3. P. Kasakalian and J. McGlotten, Anal. Chem. 1959, 31, “~, 431.
J. Blaiek, Cesk. Farm., 1956, 4, 210. G. S. Porter, J. Pharm. Pharmacol., 1964, 1, 24T. B. M. Alturs, Ph.D. Thesis, New York Universitv. 1964. B. M. Alturs and B. W. Zweifach, Fed. Proc. Fed. Am. Sot., Exp. Biol., 1964. 23. 252. 8. T. J. Haiey and M. R. Andern, J. Pharmac. Exp. Ther., 1950, loo, 393. 9. H. A. Zarem, B. W. Zweifach and J. M. McGehee, Am. J. Physiol., 1967, 212, 1081. 10. I. Schrine, Lancer, 1963, 1, 174. 11. R. D. Tiwari, J. P. Sharma and I. C. Shukla, Talanta, 1967, 14, 853. 12. R. D. Tiwari and U. C. Pande, Analyst, 1969, 94, 813. 13. K. Ziegler, A. Spath, E. Schaaf, W. Schumann and E. Winkelmann, Ann., 1942, 551, 80. 14. T. Takizawa and K. Hoshiai, Mem. Inst. Sci. Ind. Research, Osaka Univ., 1950, 7, 136. 15. M. Z. Barakat, J. Pharm. Pharmacol., 1952, 4, 582. 4. 5. 6. 7.