Titrimetric micro determination of some phenothiazine neuroleptics with potassium hexacyanoferrate(III)

Talanta 47 (1998) 59 – 66

Titrimetric micro determination of some phenothiazine neuroleptics with potassium hexacyanoferrate(III) K. Basavaiah a,*, G. Krishnamurthy b a

Department of Studies in Chemistry, Uni6ersity of Mysore, Manasagangotri, Mysore-570006, India b Department of Chemistry, PES College of Science, Mandya-571401, India Received 18 August 1997; received in revised form 14 January 1998; accepted 15 January 1998

Abstract Three simple, rapid and accurate titrimetric procedures using potassium hexacyanoferrate(III) have been developed for the micro determination of five phenothiazine drugs in pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in an acid medium to colourless sulphoxides via orange or purple coloured products. In the first procedure, phenothiazines are titrated directly in H2SO4 –H3PO4 medium to a colourless end point. In the second method, a known excess of the oxidant is added and after a specified time, the residual oxidant is determined iodometrically. The third method employs electrometric end-point detection. The optimum reactions conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drugs has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Phenothiazine drugs; Titrimetry; Potentiometric end-point detection; Potassium hexacyanoferrate(III)

1. Introduction Phenothiazines represent a major class of drugs used as neuroleptics in the treatment of schizophrenia and other psychotic illnesses [1]. They are also used as antiallergics, antiemetics, analgesics and sedatives. The therapeutic interest in these compounds justifies research to establish analytical methods for the determination of these drugs in pharmaceutical preparations and biologi* Corresponding author. Tel.: + 91 821 515525; fax: + 91 821 421263.

cal samples. Several methods have been proposed for the determination of phenothiazines and their dosage forms. Titrimetry in non-aqueous media and UV-spectrometry are the recommended procedures for the pure form and formulations, respectively, in the British Pharmacopoeia [2]. Other titrimetric methods include complexometry [3], amperometry [4], thermometry [5], coulometry [6], conductometry [7], potentiometry [8], and bromimetry using a bromate–bromide mixture [9] or N,N-dibromo dimethyl hyantoin (DBH) [10]. Spectrophotometric methods including differential spectrometry [11], the Fourier function method

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K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

[12] and derivative spectrophotometry [13] have also been reported. Other methods include fluoroimmunoassay [14], HPLC [15], adsorptive voltammetry [16], spectrofluorimetry [17], GLC [18] and chemiluminescence measurement [19]. Potassium hexacyanoferrate(III) has been used extensively in the determination of a vast number of compounds, particularly, of pharmaceutical interest [20–22]. In this paper we describe three convenient methods for the determination of five phenothiazine-based drugs in the pure form and in pharmaceutical preparations using hexacyanoferrate(III) as an oxidizing agent. The methods are of general applicability and are quick and simple compared with the established procedures [2].

2.3. Standard solutions of phenothiazines Stock standard solutions containing 2000 mg ml − 1 drug were prepared by dissolving weighed amount of promethazine hydrochloride, PH (Rhone-Poulenc); triflupromazine hydrochloride TPH (Sarabhai); prochlorperazine maleate, PCPM (Rhone-Poulenc); fluphenazine hydrochloride, FPH (Sarabhai) or thioproperazine mesylate, TPPM (Rhone-Poulenc) in distilled water. For the dissolution of PCPM, a few drops of dilute HCl were used. The solutions were kept in amber coloured bottles and stored in a refrigerator. Working solutions were prepared daily by appropriate dilution of the stock solution in water.

2.4. Analytical procedures 2. Experimental

2.1. Apparatus Potentiometric titrations were performed using Equiptronics digital potentiometer model EQDGM equipped with bright platinum and calomel electrodes.

2.2. Reagents All chemicals were of analytical reagent grade. A 1 ×10 − 2 M stock solution of potassium hexacyanoferrate(III) (BDH, Glaxo, India) was prepared by dissolving the required amount of compound in water and standardized iodometrically [23]. A titrant of lower concentration was prepared by dilution and standardized in the same manner. A 1× 10 − 2 M solution of sodium thiosulphate (S.D. Fine Chemicals, India) was prepared by dissolving the requisite amount of the compound in distilled water and standardized iodometrically [24]. Potassium iodide (10%), zinc sulphate (4%), sulphuric acid (10 M), phosphoric acid (10 M) and starch indicator (0.5%) solutions were prepared by using analytical reagent grade chemicals.

2.4.1. Direct titration (A) A 5.0 ml aliquot of phenothiazine drug solution containing 1–8 mg PH, 1–7 mg TPH, 1–10 mg PCPM, FPH or TPPM was transferred to a 50 ml titration flask and 10 ml of 10 M sulphuric acid and 2 ml 10 M orthophosphoric acid were added. Potassium hexacyanoferrate(III) (1× 10 − 2 M) was added slowly from a 10 ml burette with continuous stirring by magnetic stirrer. At first, a purple or orange colour developed and the titration was continued until the colour discharged completely. From the volume of hexacyanoferrate(III) consumed, the amount of drug was calculated using the following equation: Amount of drug (mg)=

VMR n

where V is millilitres of hexacyanoferrate(III) consumed in the titration, M is the molecular weight of the drug, R is the molarity of hexacyanoferrate(III) solution, and n is the number of moles of hexacyanoferrate(III) reacting with 1 mol of the drug.

2.4.2. Back titration (B) A known volume (5 ml) of the drug solution containing 1–6 mg PH or TPH, 1–10 mg PCPM, FPH or TPPM was placed in an 100 ml Erlenmeyer flask and 5 ml 10 M sulphuric acid (7 ml in

K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

the case of FPH and TPPM) and 5 ml 1 × 10 − 2 M hexacyanoferrate(III) (accurately measured) were added. The mixture was shaken occasionally and, after a specific time (Table 1) the mixture was diluted to about 60 ml and 5 ml 4% zinc sulphate and 5 ml 10% potassium iodide solutions were added and the liberated iodine was titrated with 1× 10 − 2 M sodium thiosulphate using starch indicator. A blank was run in the same way. The amount of the drug was calculated from the equation: Amount of Drug (mg)=

(V1 −V2)MR n

where V1 is millilitres of thiosulphate solution consumed in the blank titration, V2 is millilitres of thiosulphate solution consumed in the test sample titration, M is the molecular weight of the drug, R is the molarity of hexacyanoferrate(III) solution, and n is the number of mol of hexacyanoferrate(III) reacting with 1 mol of the drug.

2.4.3. Potentiometric titration (C) In the potentiometric titration, a 5.0 ml aliquot containing 2 – 5 mg PH, or TPH 2–10 mg PCPM, FPH or TPPM was transferred to a 100 ml beaker. Sulphuric acid (10 ml 10 M) was added, the mixture was stirred magnetically and the titrant (1 ×10 − 2 or 1 × 10 − 3 M) added using a 10 ml burette. From the volume of hexacyanoferrate(III) consumed, the amount of drug was calculated from the same equation given for method A. 2.5. Procedure for pharmaceutical formulations 2.5.1. Tablets Forty tablets were weighed and pulverised (80 in the case of stemetil, emidoxyn and majeptil). An amount of the powder equivalent to about 200 mg of the pure drug was weighed. The powder was extracted with three 30 ml portions of water (a few drops of dilute HCl were used in the case of PCPM) and filtered into a 100 ml standard flask, the filter was washed and the flask made up to the mark with water. A suit-

61

able aliquot of this solution was analysed by either of the above methods.

2.5.2. Ampoules The contents of 20 ampoules were mixed. An accurately measured volume equivalent to 200 mg of the pure drug was transferred into a 100 ml calibrated flask, made up to the mark with water and an aliquot was analysed as for the tablets. In the case of anatensol and prolinate injections, the contents of the ampoules were treated with a few drops of dilute HCl and warmed before making up to the mark.

3. Results and discussion Chemical oxidation is a well known reaction that has been extensively exploited for the determination of phenothiazines [25]. The proposed methods are based on the fact that hexacyanoferrate(III) ions in an acidic medium directly oxidise phenothiazine to a purple or orange phenothiazonium radical cation and finally to the colourless sulphoxide. A proposed mechanism is presented in Fig. 1 in conformity with the 1:2 reaction ratio observed. For all the three procedures sulphuric acid was found to be the ideal reaction medium. In direct titration, the presence of phosphoric acid was found to be necessary to sharpen the colour change at the end point. For detection of the end-point in the direct titration as well as the potentiometric titration, the titration should be performed slowly around the end-point. The back titration was attempted to decrease the amount of acid used in the direct titration and the zinc salt was added to ensure quick and irreversible oxidation of iodide by hexacyanoferrate(III) [26] through the removal of ferrocyanide [27]. In all the cases, only 2 mol hexacyanoferrate(III) per mol of the drug were consumed, indicating that the oxidation of phenothiazines stopped at the sulphoxides formation and further oxidation to sulphones did not take place despite a high acid concentration, in contrast to the assumption that sulphones would be formed under high acid conditions [28].

1–8 1–7 1–10 1–10 1– 10

Range (mg)

98.63 97.78 97.69 98.26 98.84

Recovery (%)

1:2 1:2 1:2 1:2 1:2

Molar ratio

Method B

5 6 5 10 15

Reaction time (min)

1–6 1–6 1–10 1–10 1–10

Range (mg)

For titrations of 2.5×10−3 –3.4×10−3 M drug solutions vs. 1×10−2 M hexacyanoferrate(III).

1:2 1:2 1:2 1:2 1:2

PH TPH PCPM FPH TPPM

a

Molar ratio

Drug

Method A

Table 1 Analytical data for the tritration of phenothiazines

100.79 99.84 99.52 99.04 98.65

Recovery (%)

1:2 1:2 1:2 1:2 1:2

Molar ratio

Method C

235 255 215 235 210

Overall potential break (mV)a

225 205 145 165 145

Steepness near the equivaence point (mV 0.1 ml−1)a

2–5 2–5 2 – 10 2 – 10 2 – 10

Range (mg)

100.34 100.46 99.93 99.63 100.66

Recovery (%)

100.34 99.41 100.71 99.63 —

Recovery (%)

BP method

62 K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

63

Fig. 1. mechanism of reaction between phenothiazines and hexacyanoferrate(III).

3.1. Interference studies

3.2. Application of the procedures

Interference from the common excipients and additives likely to be present together with the phenothiazines in commercial formulations was studied. Starch, talc, dextrose, magnesium stearate, sodium alginate, gelatin, and sodium sulphite in levels found in formulations did not interfere under experimental conditions.

The proposed methods were applied to the determination of the drugs studied in dosage forms. The results in Table 2 indicate that the methods give good accuracy and precision, with satisfactory agreement with the results obtained by the methods in the British Pharmacopoeia (BP) [2]. The calculated F- and t-values given in Table 3 do not exceed the tabulated values except in

b

a

4.89

24.66

25

5

24.72

12.36

12.5

25

4.92

9.78

10

5

9.82

9.86 24.60 9.70 24.80 24.20

10

10 25 10 25 25

97.8

98.6

98.8

98.8

98.4

97.8

98.2

98.6 98.4 97.0 99.2 96.8

Recoverya (%)

Method A

or mg ml−1 Found (mg)

Proposed methods

mg/tablet

Average of five detreminations. Average of three determinations.

TPPM Majeptil tablets

FPH Anatensol injection (as deconate) Prolinate injection (as deconoate)

PCPM Stemetil tablets Stemetil injection (as mesylate)

TPH Siquil tablets Siquil injection

PH Phenergan tablets Phena tablets Phenergan injection

Formulation

Table 2 Analysis of phenothiazines in various formulations

0.76

1.38

1.56

0.49

0.55

0.60

0.39

0.52 0.71 1.14 0.97 0.62

R.S.D. (%)

4.93

24.62

24.84

12.58

4.96

9.86

10.20

10.09 24.78 10.14 25.01 25.34

Found (mg)

Method B

98.6

98.5

99.3

100.6

99.2

98.6

102.0

100.9 99.12 101.4 100.0 101.3

Recoverya (%)

1.50

0.63

0.84

0.85

0.64

0.85

1.04

1.65 1.32 0.96 0.73 1.14

R.S.D. (%)

4.96

25.12

25.34

12.42

5.02

9.94

9.85

10.15 24.90 9.87 24.78 24.60

Found (mg)

Method C

99.2

100.4

101.3

99.3

100.4

99.4

98.5

101.5 99.6 98.7 99.1 98.4

Recoveryb (%)

0.38

0.40

0.22

0.48

0.66

1.14

0.72

0.38 0.71 0.53 0.22 0.84

R.S.D. (%)

—

25.13

25.24

12.62

5.02

9.85

9.92

9.98 24.90 10.01 25.20 24.85

Found (mg)

BP method

—

100.5

101.0

100.9

100.40

98.5

99.2

99.8 99.6 100.1 100.8 99.0

Recoverya (%)

—

0.62

0.53

0.49

0.48

0.52

0.35

0.55 0.48 0.36 0.28 0.71

R.S.D. (%)

64 K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

5 100.34 0.90 0.81 — — — —

6 97.78 1.07 1.14 3.63 (2.26) 5.45 (6.26)

6 100.79 1.21 1.46 0.70 (2.26) 1.80 (6.26)

6 98.63 0.95 0.90 3.05 (2.26) 1.11 (6.26)

4 100.31 0.52 0.27 0.06 (2.36) 0.33 (9.12)

TPH A

Official

A

C

B

PH

Figures in parentheses are the tabulated values at 95% probability level.

Variance ratio (F-test)

n Mean S.D. (S) Variance (S 2) Student’s t-test

Value

Table 3 Statistical analysis between the proposed and BP methods

6 99.84 0.66 0.44 1.26 (2.26) 2.1 (6.26)

B 4 100.46 0.74 0.55 2.60 (2.36) 2.62 (6.26)

C 5 99.41 0.46 0.21 — — — —

Official

PCPM

6 97.69 0.88 0.77 4.06 (2.36) 1.38 (6.26)

A 6 99.52 1.12 1.25 2.09 (2.26) 2.23 (6.26)

B 4 99.97 0.82 0.67 1.40 (2.26) 1.20 (6.59)

C

5 100.71 0.75 0.56 — — — —

Official

6 98.26 0.65 0.42 3.05 (2.26) 2.33 (6.26)

A

FPH

6 99.04 0.76 0.58 0.66 (2.26) 3.22 (6.26)

B

4 99.63 0.71 0.50 0.97 (2.36) 2.80 (6.59)

C

5 99.26 0.43 0.18 —

Official

6 98.84 1.05 1.10

A

TPPM

6 98.65 0.28 0.08

B

4 100.66 0.70 0.49

C

K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66 65

66

K. Basa6aiah, G. Krishnamurthy / Talanta 47 (1998) 59–66

respect of the direct titration, hence, there are no significant differences between the proposed and BP methods with respect to accuracy and precision.

4. Conclusion In conclusion, the results of the titrations indicate that the proposed methods are simpler than and superior to many existing methods and do not require special working conditions. The chloramine-T method [29] is not suitable for micro determination. In the perchloric acid method [30], the medium has to be scrupulously anhydrous. This is inconvenient in practice and even trace amount of water will affect the results. As the reagent is unstable, the N-bromosuccinimide method of Pathak et al. [31] is unreliable. The complexometric method [3] involves the filtration of the complex before titrating the unreacted metal. Thermometry [5] requires an expensive experimental set up. Hence, the proposed methods can be recommended for the routine determination of phenothiazines in their pure form and in their preparations. Besides, owing to the stability of the solid reagent and reasonable stability of its solution, hexacyanoferrate(III) can be used for routine analysis.

Acknowledgements The authors are grateful to the Quality Control Managers of Sarabhai Chemicals, and RhonePoulenc, India, for gifts of the pure drug samples.

References [1] A.S. Horn, Dopamine receptors, in: C. Hansch (Ed.), Comprehensive Medicinal Chemistry, vol. 3, Pergamon Press, Oxford, 1990, pp. 287–288. [2] The British Pharmacopoeia, HMSO, London, 1993, pp. 552, 1079, 1080, 546, 1074, 1076, 291, 920. [3] M. Gajewska, Chem. Anal. 18 (1973) 651.

.

[4] V.I. Tkach and N.G. Timoshenko, Farm. Zh. (Kiev) 2 (1988) 79; Anal. Abstr. 50(10E) (1988) 54. [5] U.M. Abbasi, M. Siddiqui, M.I. Bhangas, J. Chem. Soc. Pak. 13 (1991) 242. [6] Z. Feher, I. Kolbe, E. Pungor, Fresenius’ Z. Anal. Chem. 332 (1988) 345. [7] K. Basavaiah, P.G. Ramappa, Indian J. Pharm. Sci. 50 (1989) 231. [8] S.M. Golabi, M. Showkati-Shishevan, Talanta 38 (1991) 1253. [9] J. Blazek, Cslka Farm. 15 (1966) 200. [10] M.I. Walash, M. Rizk, A.-M. Abou-ouf, F. Belal, Analyst 108 (1983) 626. [11] L. Long, Y. Zhang, Yaowu Fenxi Zarhi, 15 (1995) 45; Anal. Abst. 57(2G) (1995) 175. [12] H. Mehgrub, M.A. Korany, H. Abdine, E.M. AbdelHady, Anal. Lett. 24 (1991) 1797. [13] P. Ryclovsky, I. Nemcova, Cesk Farm. 38 (1989) 241; Anal. Abstr. 52(6E) (1990) 34. [14] A. Mounsey, D. Strachan, F.T. Rowell, V. Rowell, J.D. Tyson, Analyst 121 (1996) 955. [15] D. De Orsi, L. Gagliardi, D. Tonelli, J. Pharm. Biomed. Anal. 14 (1996) 1635. [16] Z.Q. Zhang, Z.G. Chen, H. Zhang, Microchem. J. 53 (1996) 282. [17] F.A. Mohamed, Anal. Lett. 28 (1995) 2491. [18] I.L. Zhuravleva, M.B. Terenina, R.V. Golovnya, M.A. Filiminova, Khim.-Farm. Zh. 5 (1993) 58; Anal Abstr. 56(9G) (1994) 2. [19] J.L. Lopez Paz, A. Townshend, Anal. Commun. 33 (1996) 31. [20] M.S. Mehrous, M.M. Abdel-Khalek, M.E. Abdel-Hamid, Talanta 32 (1985) 651. [21] F.A. Aly, F. Belal, M.I. Walash, J. Pharm Biomed. Anal. 12 (1994) 955. [22] A. Kojlo, H. Puzanowska-Tarasiewicz, Anal. Lett. 26 (1993) 593. [23] J. Bessett, R.C. Denny, G.H. Jaffery and J. Mendham, Vogel’s Text Book of Quantitative Inorganic Analysis, 4th ed., Longman, Harlow, 1987, p.385. [24] J. Bessett, R.C. Denny, G.H. Jaffery and J. Mendham, Vogel’s Text Book of Quantitative Inorganic Analysis, 4th ed., Longman, Harlow, 1987, p.375. [25] J. Karpinska, B. Starczewska, H. PuzanowskaTarasiewicz, Anal. Sci. 12 (1996) 161. [26] F. Mohr, Annalaus 105 (1958) 60. [27] F. Feigl, Spot Tests, Elsevier, Amsterdam, 1954, pp. 170, 273. [28] C. Channegowda, S.M. Mayanna, Indian Drugs 31 (1994) 574. [29] I.C. Shukla, J. Inst. Chem. (India) 62 (1990) 159. [30] J. Blazek, M. Pinkasova, Cslka Farm. 23 (1974) 3. [31] V.N. Pathak, I.C. Shukla, S.R. Shukla, Talanta 29 (1982) 58.

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