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Tungstophosphoric acid as a new reagent for the spectrophotometric determination of phenothiazines
MICROCHEMICAL
JOURNAL
28, 586-594 (1983)
Tungstophosphoric Spectrophotometric P. G. RAMAPPA, Department
Acid as a New Reagent for the Determination of Phenothiazines
H. SANKE GOWDA, AND ANANT
of Post-graduate Studies and Research in Chemistry, Manasa Gangotri, Mysore-570006, India Received
November
N. NAYAK University
of Mysore,
30, 1979
INTRODUCTION Blazek and Travnickova (3) used tungstophosphoric acid as a precipitant for the gravimetric determination of phenothiazines. No attempt was made to study the color reaction of tungstophosphoric acid with triflupromazine hydrochloride (TPH), fluphenazine dihydrochloride (FPH), promethazine hydrochloride (PH), promazine hydrochloride (PMH), diethazine hydrochloride (DH), chlorpromazine hydrochloride (CPH), and prochlorperazine maleate (PCPM). The present communication reports the investigations for the use of tungstophosphoric acid as a spectrophotometric reagent for the phenothiazines listed in Table 1. The proposed method offers the advantages of simplicity, rapidity, stability, and wider range of determination without the need for heating or extraction. EXPERIMENTAL
Reagents Solutions of phenothiazines. Stock solutions of TPH, FPH, PH, PMH, DH, CPH, and PCPM were prepared by dissolving the requisite amount of the samples in doubly distilled water and standardized gravimetrically (2). The stock solutions were stored in ambercolored bottles in a refrigerator. Tungstophosphoric acid solution. A 10% (w/v) aqueous solution was prepared. Solutions of diverse ions of suitable concentrations were prepared using analytical grade reagents.
Apparatus Beckman Model DB spectrophotometer with l.OO-cm silica cells; PerkinElmer 257 spectrophotometer; Varian E-4 X-band spectrometer, and pHmeter Model Ll-10 were used. 586 0026-265X/83 $1.50 Copyright 62 1983 by Academic Press. Inc. AU rights of reproduction in any form reserved.
DETERMINATION
OF PHENOTHIAZINES
587
TABLE 1
No.
1
Derivative studied
Triflupromazine (hydrochloride)
Abbreviation
TPH
CH3 -CH2-(CH2)2-N
< 2
3
Fluphenazine (hydrochloride)
FPH
Promethazine (hydrochloride)
PH
N-(CH2)2-OH
CH3 4
Promazine (hydrochloride)
CH3
-CH2-(CH&-N
-CH2-CH-N < I
CH3 CH3
-CH2-(CH&N <
5
Diethazine (hydrochloride)
DH
Chlorpromazine (hydrochloride)
CPH
-H
CH3
C2H5 -H
-CH2-CH2-N
< 6
-CF3
-H
CH3 PMH
-CF3
Cz”5
,CH3 -CH2-(CH2)2-N\CH
-Cl 3
7
Prochlorperazine (maleate)
PCPM
-CH,-(CH&-N
-Cl
588
RAMAPPA,
GOWDA,
AND
NAYAK
Standard Procedure
An aliquot of the sample containing 75-1500 Fg of TPH, 75-1400 kg of FPH, 40-1050 Fg of PH, 38-1050 pg of PMH, 125-1250 Fg of DH, 125-1000 pg of CPH, or 40-1350 kg of PCPM was transferred to a 25-ml volumetric flask. Fifteen milliliters of 10% tungstophosphoric acid solution was added and diluted to the mark with doubly distilled water. After 15 min the absorbance was measured at 510 nm for TPH and FPH, at 525 nm for PH, PMH, and DH, and at 540 nm for CPH and PCPM against the corresponding reagent blank. The amount of phenothiazine was then deduced from the calibration curve. RESULTS AND DISCUSSION
Tungstophosphoric acid oxidizes phenothiazines to a radical cation which forms a colored compound with unreacted tungstophosphoric acid in a solution of pH range 0.9-I .75. Hence a medium of pH 1.5 obtained by mixing aqueous solutions of tungstophosphoric acid and phenothiazine derivative has been selected for further studies. Spectral Characteristics
The absorption spectra of tungstophosphoric acid and its colored compounds with phenothiazines are shown in Fig. 1. PH, DH, and PMH with hydrogen at C2 form pink compounds having absorption maximum at 525 nm, CPH, and PCPM with chlorine at CZ show a bathochromic effect shifting absorption maximum to 540 nm whereas CFs in TPH and FPH causes a hypsochromic effect shifting absorption maximum to 510 nm. The absorbance of tungstophosphoric acid and phenothiazines in the range 400-700 nm is insignificant, thus promoting excellent analytical conditions. infrared
and ESR Spectra
Infrared spectra of the colored compounds of tungstophosphoric acid with phenothiazines were measured (KBr disks) in the region 650-4000 cm-i. The ion -RsNH+ combined with halide ion, X-, in the molecule of many phenothiazine drugs gives rise to a broad band in the range 23002500 cm-’ (5). For example, in the case of CPH, a broad band between 2320 and 2600 cm-l is observed in the ir spectrum of CPH corresponding to
group combined with Cl- ion. But in the ir spectrum of tungstophosphoric acid-CPH this band has totally disappeared showing thereby nitrogen of the side chain to be the site of reaction as is the case in organic bases in
DETERMINATION
589
OF PHENOTHIAZINES
0.5 -
0.01
400
I
I
4
I
I
1
450
500
550
600
650
700
WAVELENGTH.
I
nm
FIG. 1. Absorption spectra of colored products of (1) TPH; (2) FPH; (3) PH; (4) PMH;
(5) DH; (6) CPH; (7) PCPM; (8) tungstophosphoric acid. [Tungstophosphoric acid] = 1.8 x 10-ZM, [phenothiazines] = 40 ppm.
general (7). A band at 2920 cm -’ in the ir spectrum of CPH corresponds to the heterocyclic nitrogen attached with the alkyl group. This peak has totally disappeared in the ir spectrum of the CPH-tungstophosphoric acid product, showing thereby that the heterocyclic nitrogen attached with alkyl group is also the site of interaction. The ir spectra of the other phenothiazines and their colored compounds with tungstophosphoric acid show similar behavior.
590
RAMAPPA, GOWDA, AND NAYAK
The ESR signals show that free radicals are formed by the oxidizing action of tungstophosphoric acid on the phenothiazine nucleus (Fig. 2). The g values calculated from the ESR spectra are 2.0065, 2.0059, 2.0071, 2.0071, 2.0053, and 2.0068 for the products of TPH, FPH, PH, PMH, DH, CPH, and PCPM, respectively. These values are in close agreement with the g value for free electrons (2.0023). It seems probable that the colored product obtained on treatment of an aqueous solution of the phenothiazine derivative is the tungstophosphate of a cationic radical formed by oxidation. This conclusion is supported by the color obtained which corresponds to that reported in the literature for free radicals formed by oxidation (6). Reaction Rate and Effect of Time The reaction of phenothiazines with tungstophosphoric acid is instantaneous at room temperature (27°C). The color of the compound develops fully in 15 min after mixing the reactants and the maximum absorbance reading remains constant for a period of 6, 6, 12, 16, 24, 50, and 120 hr for PMH, FPH, PH, CPH, PCPM, TPH, and DH, respectively. Effect of Reagent Concentration The effect of tungstophosphoric acid concentration was examined by measuring the absorbance at 510 nm for TPH and FPH; 525 nm for PH, PMH, and DH; and 540 nm for CPH and PCPM of the solution containing
I
rh I’I1I \‘, \I :: 1I il;’ .:
’
I
; - -.-
-.-.
- .__._
_,_
_._
-._
-
’
.’ ,’ ‘I I
Ii
’
’
----I _--2 ’ ---I
I 1,: ,U
3 -.-.-.-.-.-.--------
-0
5
-3
0
---_
._._._.. - ____
+o 5
FIG. 2. ESR spectra of phenothiazine-tungstophosphate products. (I) DH; (2) FPH, and (3) TPH. Field set; 3380 G. Microwave frequency: 9.481 CHz.
DETERMINATION
591
OF PHENOTHIAZINES
a known concentration of the derivative and varying amount of tungstophosphoric acid. The rate of formation and color intensity of the product increased with increasing concentration of tungstophosphoric acid, but the stability of the colored product decreased. The optimum amount of tungstophosphoric acid was 12-20 ml of 10% solution. Hence 15 ml of 10% solution in a total volume of 25 ml was used in all subsequent work. Effect of Temperature The color reaction as recommended in the procedure was investigated at temperatures ranging from 5 to 90°C. The maximum absorbance readings remain constant in the temperature range 5-40°C for PH, PMH, DH, and PCPM, 5-45°C for TPH, and 5-50°C for FPH and CPH. Calibration Graph and Optimum Concentration The calibration graphs for TPH, FPH, PH, PMH, DH, CPH, and PCPM were obtained under the optimum conditions. Good linear relationships were obtained over the concentration ranges 3-60 ppm of TPH, 3-56 ppm of FPH, 1J-42 ppm of PH, 1.5-42 ppm of PMH, 5-50 ppm of DH, TABLE
2
TOLERANCEOF DWERSEIONS 1~ THE DETERMINATIONOF 24
ppm OF PHENOTHIAZINES
Tolerance limit” (ppm) Ion added Fluoride Chloride Bromide Iodide Nitrate Sulfate SulFte Carbonate Phosphate Acetate Citrate Formate Oxalate Tartrate Ascorbic acid Dextrose Sodium alginate Gum acacia Starch Barbitone
TPH
FPH
PH
PMH
DH
CPH
PCPM
80
88 1080 1080 20
40 600 600 600 400 12 200 200 40 30 30 30 30 8
80 1280 1280 20 1280 1000 14 200 300 80 60 60 60 60 12 2000 120 40 24 2000
80 1200 1200 20 1200 800 12 200 120 60 40 40 40 40 8 2000 200 80 80 2000
80 1200
960
80 1300 1400 24 1280
1000 1000 20 900 800 16 400 300 80 50 60 60 60 12 2000 60 20 64 2400
880 18 500 320 80 60 64 64 60 12 2000 20 24 64 2000
12
1800 120 24 40 2400
8 Amount causing an error of less than 2%
1000 10 200 100 70 52 48 48 48
10 2000 16 60 80 2000
1100 20 1250 850 14 400 350 60 45 40 40 45 10 2000 8 24 16 2000
592
RAMAPPA,
GOWDA,
AND
NAYAK
5-40 ppm of CPH, and 1.8-54 ppm of PCPM (the lines do not pass through the origin in DH and CPH). The optimum concentration range for effective spectrophotometric determination of TPH, FPH, PH, PMH, DH, CPH, and PCPM evaluated by Ringbom’s method (2, 8) are 7-56, 7-54, 5-40, 5-41, 7-41.5, 7-35.6, and 4-52 ppm, respectively. Sensitivity and Molar Absorptivity For log lo/l =O.OOl, the sensitivities of the reactions calculated from Beer’s law data are 186, 171, 190, 65.4, 128, 97, and 138 &cm2 and the corresponding molar absorptivities are 2.09 x 103, 2.98 x 103, 1.69 x 103,4.90 x 103, 2.63 x 103,3.66 x 103,and 4.4 x lo3 liters mol-‘cm-’ for TPH, FPH, PH, PMH, DH, CPH, and PCPM, respectively. Effect of Diverse Ions In order to assess the possible analytical applications of the proposed method, the effect of some foreign ions which often accompany pheno-
TABLE
3
DETERMINATIONOF PHENOTHIAZINEDRUGSIN PHARMACEUTICAL PRODUCTS Amount of drug (mg) Found Pharmaceutical product analyzed
Dwz content
Labeled
B.P.C. method (4)
1. Tablets Siquilb Anatensolb PhenerganC Largactil’ StemetilC
TPH FPH PH CPH PCPM
10.0 1.0 25.0 100.0 5.0
0.98 24.40 97.05 5.08
2. Solutions (injection) Siquilb PhenerganC Largactil’ Stemetil”
TPH PH CPH PCPM
25.0 25.0 12.5
10.0
-
24.82 24.92 12.50
Proposed method” 9.96 0.98 24.77 98.82 5.04 9.92 24.92 24.61 12.40
3. syrup
LargactilC 4. Elixir Phenergan’
CPH
5.0
PH
1.0
a Average of 10 determinations. b Marketed by Sarabhai Chemicals. c Marketed by May & Baker, Ltd.
4.90
-
0.99
DETERMINATION
593
OF PHENOTHIAZINES
thiazines in pharmaceutical products were studied by adding different amounts of foreign ions to fixed amount of phenothiazines. The color was developed and the absorbance measured following the procedure described earlier. The results are summarized in Table 2. Many associated materials like reserpin, talc, magnesium stearate, and dextrose in phenothiazine drugs do not interfere. Determination of Phenothiuzine Dwgs in Pharmaceutical Products A known amount of the pharmaceutical product (tablet, solution, and syrup) containing phenothiazine drug was dissolved in doubly distilled water and filtered. The filtrate was then diluted with doubly distilled water to an appropriate volume. Phenothiazine drug content was then determined from this solution using the recommended procedure. However, in some cases, where there was large amount of interfering ions preliminary extraction with ether in presence of 5% sodium hydroxide was necessary. The organic phase was then back extracted with 0.5 M hydrochloric acid. This acid extract was then warmed to remove any ether present in it, cooled, and diluted to 100 ml with doubly distilled water. An aliquot (3-7 ml) of the diluted solution was used for the determination of the phenothiazine content following the recommended procedure. Table 3 gives typical results for pharmaceutical products. Results are in good agreement with those obtained by the official British Pharmacopoeia method (4). SUMMARY A simple and rapid spectrophotometric method for the determination of phenothiazines based on the formation of a colored compound between tungstophosphoric acid and phenothiazines is described. The proposed method is successfully employed for the determination of phenothiazine drugs in various pharmaceutical products.
ACKNOWLEDGMENTS Messrs. Bayer A.G., Germany; Messrs. Schering Corporation, U.S.A.; Messrs. British Pharmaceutical Laboratories, India; Messrs. Sarabhai Chemicals, India and Messrs. May & Baker, Ltd., India, are thanked for supply of pure phenothiazines. One of the authors (A.N.N) is grateful to U.G.C.,New Delhi, University of Mysore and Government of Karnataka, for the award of a Teacher Fellowship under the U.G.C. Scheme of Faculty Improvement Programme.
REFERENCES 1. Ayres, G. H., Evaluation of accuracy in photometric analysis. And.
Chem. 21, 652-
657 (1949). 2. Blazek, J., and Mares, V., Analysis of drugs of the phenothiazine group III. Cesk. Farm. 15, 349-355 (1966). 3. Blazek, J., and Travnickova, M., Analytical studies of phenothiazine drugs IX. Cesk. Farm. 21, 436-441 (1972).
594
RAMAPPA, GOWDA, AND NAYAK
4. “British Pharmacopoeia,” pp. 107, 210, 388, and 393. H. M. Stationary Offtce, London, 1973. 5. Recent advances in the chemistry of phenothiazines, In “Advances in Heterocyclic Chemistry” (A. R. Katritzky and A. J. Boulton, eds.), Vol. 9, p. 338. Academic Press, New York, 1968. 6. Meunier, J., Viossat, B., Leterrier, F., and Douzou, P., Reaction of SbCls with phenothiazine and some of its derivatives. Ann. Pharm. Fr. 25, 683-696 (1967). 7. Pascal, I?, “Nouveau traite de chimie minerale,” Vol. XIV, p. 914, Masson, Paris, 1959. 8. Ringbom, A., Accuracy of calorimetric determinations, I. Z. Anal. Chem. 115, 332343 (1939).
JOURNAL
28, 586-594 (1983)
Tungstophosphoric Spectrophotometric P. G. RAMAPPA, Department
Acid as a New Reagent for the Determination of Phenothiazines
H. SANKE GOWDA, AND ANANT
of Post-graduate Studies and Research in Chemistry, Manasa Gangotri, Mysore-570006, India Received
November
N. NAYAK University
of Mysore,
30, 1979
INTRODUCTION Blazek and Travnickova (3) used tungstophosphoric acid as a precipitant for the gravimetric determination of phenothiazines. No attempt was made to study the color reaction of tungstophosphoric acid with triflupromazine hydrochloride (TPH), fluphenazine dihydrochloride (FPH), promethazine hydrochloride (PH), promazine hydrochloride (PMH), diethazine hydrochloride (DH), chlorpromazine hydrochloride (CPH), and prochlorperazine maleate (PCPM). The present communication reports the investigations for the use of tungstophosphoric acid as a spectrophotometric reagent for the phenothiazines listed in Table 1. The proposed method offers the advantages of simplicity, rapidity, stability, and wider range of determination without the need for heating or extraction. EXPERIMENTAL
Reagents Solutions of phenothiazines. Stock solutions of TPH, FPH, PH, PMH, DH, CPH, and PCPM were prepared by dissolving the requisite amount of the samples in doubly distilled water and standardized gravimetrically (2). The stock solutions were stored in ambercolored bottles in a refrigerator. Tungstophosphoric acid solution. A 10% (w/v) aqueous solution was prepared. Solutions of diverse ions of suitable concentrations were prepared using analytical grade reagents.
Apparatus Beckman Model DB spectrophotometer with l.OO-cm silica cells; PerkinElmer 257 spectrophotometer; Varian E-4 X-band spectrometer, and pHmeter Model Ll-10 were used. 586 0026-265X/83 $1.50 Copyright 62 1983 by Academic Press. Inc. AU rights of reproduction in any form reserved.
DETERMINATION
OF PHENOTHIAZINES
587
TABLE 1
No.
1
Derivative studied
Triflupromazine (hydrochloride)
Abbreviation
TPH
CH3 -CH2-(CH2)2-N
< 2
3
Fluphenazine (hydrochloride)
FPH
Promethazine (hydrochloride)
PH
N-(CH2)2-OH
CH3 4
Promazine (hydrochloride)
CH3
-CH2-(CH&-N
-CH2-CH-N < I
CH3 CH3
-CH2-(CH&N <
5
Diethazine (hydrochloride)
DH
Chlorpromazine (hydrochloride)
CPH
-H
CH3
C2H5 -H
-CH2-CH2-N
< 6
-CF3
-H
CH3 PMH
-CF3
Cz”5
,CH3 -CH2-(CH2)2-N\CH
-Cl 3
7
Prochlorperazine (maleate)
PCPM
-CH,-(CH&-N
-Cl
588
RAMAPPA,
GOWDA,
AND
NAYAK
Standard Procedure
An aliquot of the sample containing 75-1500 Fg of TPH, 75-1400 kg of FPH, 40-1050 Fg of PH, 38-1050 pg of PMH, 125-1250 Fg of DH, 125-1000 pg of CPH, or 40-1350 kg of PCPM was transferred to a 25-ml volumetric flask. Fifteen milliliters of 10% tungstophosphoric acid solution was added and diluted to the mark with doubly distilled water. After 15 min the absorbance was measured at 510 nm for TPH and FPH, at 525 nm for PH, PMH, and DH, and at 540 nm for CPH and PCPM against the corresponding reagent blank. The amount of phenothiazine was then deduced from the calibration curve. RESULTS AND DISCUSSION
Tungstophosphoric acid oxidizes phenothiazines to a radical cation which forms a colored compound with unreacted tungstophosphoric acid in a solution of pH range 0.9-I .75. Hence a medium of pH 1.5 obtained by mixing aqueous solutions of tungstophosphoric acid and phenothiazine derivative has been selected for further studies. Spectral Characteristics
The absorption spectra of tungstophosphoric acid and its colored compounds with phenothiazines are shown in Fig. 1. PH, DH, and PMH with hydrogen at C2 form pink compounds having absorption maximum at 525 nm, CPH, and PCPM with chlorine at CZ show a bathochromic effect shifting absorption maximum to 540 nm whereas CFs in TPH and FPH causes a hypsochromic effect shifting absorption maximum to 510 nm. The absorbance of tungstophosphoric acid and phenothiazines in the range 400-700 nm is insignificant, thus promoting excellent analytical conditions. infrared
and ESR Spectra
Infrared spectra of the colored compounds of tungstophosphoric acid with phenothiazines were measured (KBr disks) in the region 650-4000 cm-i. The ion -RsNH+ combined with halide ion, X-, in the molecule of many phenothiazine drugs gives rise to a broad band in the range 23002500 cm-’ (5). For example, in the case of CPH, a broad band between 2320 and 2600 cm-l is observed in the ir spectrum of CPH corresponding to
group combined with Cl- ion. But in the ir spectrum of tungstophosphoric acid-CPH this band has totally disappeared showing thereby nitrogen of the side chain to be the site of reaction as is the case in organic bases in
DETERMINATION
589
OF PHENOTHIAZINES
0.5 -
0.01
400
I
I
4
I
I
1
450
500
550
600
650
700
WAVELENGTH.
I
nm
FIG. 1. Absorption spectra of colored products of (1) TPH; (2) FPH; (3) PH; (4) PMH;
(5) DH; (6) CPH; (7) PCPM; (8) tungstophosphoric acid. [Tungstophosphoric acid] = 1.8 x 10-ZM, [phenothiazines] = 40 ppm.
general (7). A band at 2920 cm -’ in the ir spectrum of CPH corresponds to the heterocyclic nitrogen attached with the alkyl group. This peak has totally disappeared in the ir spectrum of the CPH-tungstophosphoric acid product, showing thereby that the heterocyclic nitrogen attached with alkyl group is also the site of interaction. The ir spectra of the other phenothiazines and their colored compounds with tungstophosphoric acid show similar behavior.
590
RAMAPPA, GOWDA, AND NAYAK
The ESR signals show that free radicals are formed by the oxidizing action of tungstophosphoric acid on the phenothiazine nucleus (Fig. 2). The g values calculated from the ESR spectra are 2.0065, 2.0059, 2.0071, 2.0071, 2.0053, and 2.0068 for the products of TPH, FPH, PH, PMH, DH, CPH, and PCPM, respectively. These values are in close agreement with the g value for free electrons (2.0023). It seems probable that the colored product obtained on treatment of an aqueous solution of the phenothiazine derivative is the tungstophosphate of a cationic radical formed by oxidation. This conclusion is supported by the color obtained which corresponds to that reported in the literature for free radicals formed by oxidation (6). Reaction Rate and Effect of Time The reaction of phenothiazines with tungstophosphoric acid is instantaneous at room temperature (27°C). The color of the compound develops fully in 15 min after mixing the reactants and the maximum absorbance reading remains constant for a period of 6, 6, 12, 16, 24, 50, and 120 hr for PMH, FPH, PH, CPH, PCPM, TPH, and DH, respectively. Effect of Reagent Concentration The effect of tungstophosphoric acid concentration was examined by measuring the absorbance at 510 nm for TPH and FPH; 525 nm for PH, PMH, and DH; and 540 nm for CPH and PCPM of the solution containing
I
rh I’I1I \‘, \I :: 1I il;’ .:
’
I
; - -.-
-.-.
- .__._
_,_
_._
-._
-
’
.’ ,’ ‘I I
Ii
’
’
----I _--2 ’ ---I
I 1,: ,U
3 -.-.-.-.-.-.--------
-0
5
-3
0
---_
._._._.. - ____
+o 5
FIG. 2. ESR spectra of phenothiazine-tungstophosphate products. (I) DH; (2) FPH, and (3) TPH. Field set; 3380 G. Microwave frequency: 9.481 CHz.
DETERMINATION
591
OF PHENOTHIAZINES
a known concentration of the derivative and varying amount of tungstophosphoric acid. The rate of formation and color intensity of the product increased with increasing concentration of tungstophosphoric acid, but the stability of the colored product decreased. The optimum amount of tungstophosphoric acid was 12-20 ml of 10% solution. Hence 15 ml of 10% solution in a total volume of 25 ml was used in all subsequent work. Effect of Temperature The color reaction as recommended in the procedure was investigated at temperatures ranging from 5 to 90°C. The maximum absorbance readings remain constant in the temperature range 5-40°C for PH, PMH, DH, and PCPM, 5-45°C for TPH, and 5-50°C for FPH and CPH. Calibration Graph and Optimum Concentration The calibration graphs for TPH, FPH, PH, PMH, DH, CPH, and PCPM were obtained under the optimum conditions. Good linear relationships were obtained over the concentration ranges 3-60 ppm of TPH, 3-56 ppm of FPH, 1J-42 ppm of PH, 1.5-42 ppm of PMH, 5-50 ppm of DH, TABLE
2
TOLERANCEOF DWERSEIONS 1~ THE DETERMINATIONOF 24
ppm OF PHENOTHIAZINES
Tolerance limit” (ppm) Ion added Fluoride Chloride Bromide Iodide Nitrate Sulfate SulFte Carbonate Phosphate Acetate Citrate Formate Oxalate Tartrate Ascorbic acid Dextrose Sodium alginate Gum acacia Starch Barbitone
TPH
FPH
PH
PMH
DH
CPH
PCPM
80
88 1080 1080 20
40 600 600 600 400 12 200 200 40 30 30 30 30 8
80 1280 1280 20 1280 1000 14 200 300 80 60 60 60 60 12 2000 120 40 24 2000
80 1200 1200 20 1200 800 12 200 120 60 40 40 40 40 8 2000 200 80 80 2000
80 1200
960
80 1300 1400 24 1280
1000 1000 20 900 800 16 400 300 80 50 60 60 60 12 2000 60 20 64 2400
880 18 500 320 80 60 64 64 60 12 2000 20 24 64 2000
12
1800 120 24 40 2400
8 Amount causing an error of less than 2%
1000 10 200 100 70 52 48 48 48
10 2000 16 60 80 2000
1100 20 1250 850 14 400 350 60 45 40 40 45 10 2000 8 24 16 2000
592
RAMAPPA,
GOWDA,
AND
NAYAK
5-40 ppm of CPH, and 1.8-54 ppm of PCPM (the lines do not pass through the origin in DH and CPH). The optimum concentration range for effective spectrophotometric determination of TPH, FPH, PH, PMH, DH, CPH, and PCPM evaluated by Ringbom’s method (2, 8) are 7-56, 7-54, 5-40, 5-41, 7-41.5, 7-35.6, and 4-52 ppm, respectively. Sensitivity and Molar Absorptivity For log lo/l =O.OOl, the sensitivities of the reactions calculated from Beer’s law data are 186, 171, 190, 65.4, 128, 97, and 138 &cm2 and the corresponding molar absorptivities are 2.09 x 103, 2.98 x 103, 1.69 x 103,4.90 x 103, 2.63 x 103,3.66 x 103,and 4.4 x lo3 liters mol-‘cm-’ for TPH, FPH, PH, PMH, DH, CPH, and PCPM, respectively. Effect of Diverse Ions In order to assess the possible analytical applications of the proposed method, the effect of some foreign ions which often accompany pheno-
TABLE
3
DETERMINATIONOF PHENOTHIAZINEDRUGSIN PHARMACEUTICAL PRODUCTS Amount of drug (mg) Found Pharmaceutical product analyzed
Dwz content
Labeled
B.P.C. method (4)
1. Tablets Siquilb Anatensolb PhenerganC Largactil’ StemetilC
TPH FPH PH CPH PCPM
10.0 1.0 25.0 100.0 5.0
0.98 24.40 97.05 5.08
2. Solutions (injection) Siquilb PhenerganC Largactil’ Stemetil”
TPH PH CPH PCPM
25.0 25.0 12.5
10.0
-
24.82 24.92 12.50
Proposed method” 9.96 0.98 24.77 98.82 5.04 9.92 24.92 24.61 12.40
3. syrup
LargactilC 4. Elixir Phenergan’
CPH
5.0
PH
1.0
a Average of 10 determinations. b Marketed by Sarabhai Chemicals. c Marketed by May & Baker, Ltd.
4.90
-
0.99
DETERMINATION
593
OF PHENOTHIAZINES
thiazines in pharmaceutical products were studied by adding different amounts of foreign ions to fixed amount of phenothiazines. The color was developed and the absorbance measured following the procedure described earlier. The results are summarized in Table 2. Many associated materials like reserpin, talc, magnesium stearate, and dextrose in phenothiazine drugs do not interfere. Determination of Phenothiuzine Dwgs in Pharmaceutical Products A known amount of the pharmaceutical product (tablet, solution, and syrup) containing phenothiazine drug was dissolved in doubly distilled water and filtered. The filtrate was then diluted with doubly distilled water to an appropriate volume. Phenothiazine drug content was then determined from this solution using the recommended procedure. However, in some cases, where there was large amount of interfering ions preliminary extraction with ether in presence of 5% sodium hydroxide was necessary. The organic phase was then back extracted with 0.5 M hydrochloric acid. This acid extract was then warmed to remove any ether present in it, cooled, and diluted to 100 ml with doubly distilled water. An aliquot (3-7 ml) of the diluted solution was used for the determination of the phenothiazine content following the recommended procedure. Table 3 gives typical results for pharmaceutical products. Results are in good agreement with those obtained by the official British Pharmacopoeia method (4). SUMMARY A simple and rapid spectrophotometric method for the determination of phenothiazines based on the formation of a colored compound between tungstophosphoric acid and phenothiazines is described. The proposed method is successfully employed for the determination of phenothiazine drugs in various pharmaceutical products.
ACKNOWLEDGMENTS Messrs. Bayer A.G., Germany; Messrs. Schering Corporation, U.S.A.; Messrs. British Pharmaceutical Laboratories, India; Messrs. Sarabhai Chemicals, India and Messrs. May & Baker, Ltd., India, are thanked for supply of pure phenothiazines. One of the authors (A.N.N) is grateful to U.G.C.,New Delhi, University of Mysore and Government of Karnataka, for the award of a Teacher Fellowship under the U.G.C. Scheme of Faculty Improvement Programme.
REFERENCES 1. Ayres, G. H., Evaluation of accuracy in photometric analysis. And.
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