New titrimetric and spectrophotometric methods for ...

Articles Indian Journal of Chemical Technology Vol. 10, July 2003, pp. 355-362

New titrimetric and spectrophotometric methods for the determination of promethazine theoclate using metavanadate K Basava iah

* & V S Charan

Department of Chemistry, University of Mysore, Manasagangotri , Mysore 570 006, India

Received I April 2002; revised received 31 December 2002; accepted 10 Apri/2003

Four new methods (titrimetric and spectrophotometric, two each) which are accurate, precise and rapid are described for the determination of promethazine theoclate in bulk form and in tablets. The titrimetric methods are based on the oxidation of the drug by metavanadate in acidic condition followed by determination of the unreacted oxidant by titration with iron(II) ammonium sulphate (Method A) or titration of the vanadium(IV) formed, with cerium(IV) sulphate (Method B). The spectrophotometric procedures are also based on the oxidation of the drug with metavanadate followed by the estimation of unreacted oxidant after complexing with chromotropic acid and measuring the absorbance at 420 DID (Method C) or estimation of the vanadium(IV) formed, by reacting it with ferriin and measuring the resulting ferroin at 510 DID (Method D). Method A and Method B are applicable over the ranges 1-20 and 5-12 mg, respectively. Calculations in both methods are based on the reaction stoichiometry of 1:2 (drug: metavanadate). In spectrophotometry, Beer's law is obeyed over the ranges 0.0-125.0 and 10.0-60.0 J.l.g mL" 1 for method C and method D, respectively and the corresponding molar ab'Sorptivity values are 2.64x103 and 5.33x103 L mor 1 cm·I, respec.tively. The methods were successfully applied to the determination of promethazine theoclate in avomine tablets, and the results obtained were in the range of 97.73-102.24% of declared content with a relative standard deviation of 1.51-2.22%.

Promethazine theoclate (PMT) is an antihistamine H 1 receptor antagonist. It is primarily an antihistamine with additional sedative and antiemetic actions. PMT is used in the treatment of nausea and vomiting associated with migraine labyrinthine disorders and radiation therapy. Not many methods are found in the literature for the determination of PMT. Davidson 1 has determined the drug in tablets by difference spectrophotometric method. A condensation reaction involving PMT and formaldehyde in strong H 2 S04 medium at 4-5°C and subsequent measurement at 551 nm has also been reported 2 . Recently a flow-injection method with cerium(IV) oxidation of the drug and measurement of the coloured radical cation has been described by Martinez and Garcia 3 . In the present work, a combination of redox property and complexing ability of metavanadate has been exploited for developing four procedures for the determination of PMT. In two methods (A and C), the drug is oxidized by a known excess of metavanadate and after the reaction is judged to be complete, the unreacted oxidant is either backtitrated (A) or determined by spectrophotometry by complexing with

*For correspondence (E-mail: basavaiahk @yahoo.co.in ; Fax : 0091 -82 1-42 1263)

chromotropic acid (C). In the pther two procedures (Methods B and D), a large excess of metavanadate is employed to oxidize PMT, and the reduced form of the oxidant vanadium(IV), is determined either by titrimetry with cerium(IV) or by spectrophotometry by reacting the vanadium(!\') with ferriin. The spectrophotometric procedures are based on reactions at room temperature compared to 4-5 °C required in the reported procedure 2 , and use a si mple spectrophotometer for measurement, whereas the flow injection method involves an expensive experimental set-up which is not always easily available. Both procedures employ mild working conditions and are based on measurement of coloured species which are stable for several months unlike the un stable condensation product2 or radical cation 3 . The additional advantage is the long and dyn am ic concentration ranges of applicability in comparison with narrow ranges of 10.0-60.0 and 10.3-31.3 J.,lg mL·' for reported methods2.3 .

Experimental Procedure Apparatus A Systronic model 106 digital spectrophotometer provided with 1-cm matched glass cells was used for absorbance measurements.

Articles Reagents and solutions All chemicals used were of analytical reagent grade and double distilled water was used throughout the study. A 0.05 M sodium metavanadate solution was prepared by dissolving - 3 g of reagent (S.D. Fine Chern. Ltd. India) in water and diluting to 500 mL and standardized using iron(II) ammonium sulphate4. After standardization, the solution was diluted to 0.02 M and 250 ~J.g mL·' for use in titrimetry (Method A) and spectrophotometry (Method C), respectively. Cerium(IV) sulphate (0.05 M) was prepared by dissolving 20.2 g of the reagent (Loba-Chemi) in 0 .5 M H2S04 and diluting to 500 mL with the same acid and standardized using iron(II) solution 4 . It was then diluted to get 0.02 M solution for use in titrimetric work (Method B). N-phenylanthranilic acid (NPA) indicator (0.1%) was prepared by dissolving the requisite amount in alcohol. Ferroin indicator was prepared by dissolving 1.485 g of 1,10-phenanthroline in 100 mL of 0.025 M ferrous sulphate. Ferriin reagent was prepared by dissolving 0.16 g of iron(III) ammonium sulphate and 0.198 g of 1,10phenanthroline base in 2 mL of 1 M HCI and diluting to 100 mL with water. Chromotropic acid reagent (0. 1%) was prepared by dissolving 0.1 g of acid in water and diluting to 100 mL. Aqueous solutions of HzS04 (10 M), CH 3COOH (10 M), ammonia (1:1) and hydroxylammonium chloride (5%) were perpared in the usual way. AR grade acetone was used in titrimetric work (Method B) . Pharmaceutical grade PMT was procured from Rhone-Poulenc, India and used without further purification. A stock standard solution containing 2 mg mL·' of PMT was prepared by dissolving 200 mg of sample in a few drops of 0.1 M HCl and diluting to 100 mL with water. The solution was kept in an amber coloured bottle and stored in a refrigerator. This was diluted to get 500 and 250 !J.g mL-1 solution for spectrophotometric methods C and D, respectively.

General Methods Method A Reaction stoichiometry The reaction stoichiometry was examined by allowing 1-20 mg of the sample dissolved in 0.1 MHCl to react with a known amount of metavanadate solution. The reaction was allowed to proceed for 5 min, after which the excess of metavanadate was back-titrated with iron(ll) ammonium sulphate using NPA indicator. The value of n, the number of moles 356

Indian J. Chern. Techno!., July 2003

of metavanadate required to react with each mole of drug was calculated using the equation, volume of meta vanadate solution x molarity of meta vanadate solution

n=----~--------------------

volume of drug solution x

molarity of drug solution and results obtained are presented in Table 1.

Method A 10 mL aliquot of drug solution containing 1-20 mg of PMT was pipetted into a 100 mL titration flask and was acidified by adding 5 mL of I 0 M H2S04. Then, 10 mL of 0.02 M metavanadate was added by means of a pipette, the contents were mixed well and kept aside with occasional shaking. After ensuring the complete oxidation of the drug as indicated by the complete disappearance of the red colour of the radical cation (5 min), the unreacted metavanadate was titrated with 0 .02 M iron(II) ammonium sulphate solution using 2 drops of NPA indicator. A blank titration was performed simultaneously, and the amount of the drug in the aliquot was calculated usi ng the equation: Amount(mg)

= (B-S) x R x 249.5

... (1)

where B

=

volume of iron(II) solution used in the blank titration, mL

S

=

volume of iron(II) solution used in the sample titration, mL

R

=

molarity of iron(II) ammonium sulphate solution

Method B Reaction stoichiometry Before applying the reaction to the quantitati ve determination of PMT, the stoichiometry of the reaction was determined by treating an aliquot of the drug solution containing 5-12 mg PMT with an unmeasured excess of metavanadate solution in acid conditions, and determining the amount of vanadium(IV) formed, by titration with cerium(IV) sulphate solution under the specified condition of indicator and catalyst. Then usi ng the equation,

Basavaiah & Charan: Titrimetric and spectrophotometric methods for the determination of promethazine theocl ate

volume of cerium(IV) solution x molarity of cerium(IV) solution

n=----~--------~~------

volume of drug solution x molarity of drug solution the stoichiometry of the reaction was calculated and results are presented in Table 1. Method A 10 mL aliquot of standard drug solution equivalent to 5-12 mg of PMT was measured accurately into 100 mL conical flask followed by 2 mL of 10M H2S04. Then 10 mL of 0.05 M sodium metavanadate solution was added, the contents were mixed well and set aside for 5 min to ensure the complete oxidation of the drug. Finally 10 mL of acetone and 2 drops of ferroin indicator were added and the vanadium(IV) was titrated with cerium(IV) solution slowly near the equivalence point. The amount of drug in the aliquot was calculated using the equation:

Amount(mg)

= V x R x 249.5

where V

=

R

=

volume of cerium(IV) solution consumed molarity of cerium(TV) solution

Method C Varying aliquots (0.0 to 2.5 mL of 500 Jlg mL-1) of PMT solution were measured accurately into a series of 10 mL standard flasks by means of a microburette. The volume was adjusted to 3 mL by adding water. Then, 1 mL of 10 M H2S04 and 2.5 mL of 250 Jlg 1 mL- metavanadate solution were added, the contents were mixed well and the flasks were allowed to stand for 20 min to facilitate the oxidation of the drug. Finally, 0.5 mL of 0.1 % chromotropic acid and 1 mL of 5% hydroxylammonium chloride were added, diluted to the mark with water, mixed well and absorbance of each solution was measured at 420 nm against water as blank. MethodD Different aliquots of 250 Jlg tnL- 1 of standard PMT solution in the range 0.4 to 2.5 mL were transferred into a series of 10 mL calibrated flasks and the total volume was adjusted to 3 mL by adding requisite

Articles

volume of water. Then, 0.5 mL each of 10M H2S04 and 0.05 M metavanadate were added to each flask , the contents were mixed well and set aside for about 5 min to allow the oxidation of the drug to complete as shown by the formation of colourless solution. Lastly, 2 mL each of 10 M acetic acid and ferriin reagent were added followed by 2 mL of I : 1 ammonia after 5 min and diluted to the mark. The absorbance of each solution was measured at 510 nm after a standing time of 10 min against water as blank. For both spectrophotometric methods, a standard curve was prepared or a regression equation was evaluated. The concentration of the unknown solution was read from the calibration graph or computed from the regression equation.

Procedure for avo mine tablets Twenty tablets were weighed accurately and ground to a fine powder. A portion of the powder equivalent to 200 mg of the active component was weighed accurately into a 100 mL standard flask, 60 mL of water and 5 mL of 0.1 mL HCl were added and shaken thoroughly for about 20 min . Then the volume was made up to the mark with water, mixed well and filtered usi ng a quantitative filter paper. The first 10 mL portion of the filtrate was rejected and a suitable aliquot was then taken for analysis usi ng the titrimetric procedures A and B. The filtrate was appropriately diluted to get 500 and 250 Jlg mL-1 for spectrophotometric procedures C and D, respectively , and a suitable aliquot was subjected to analysis as described under general methods.

Results and Discussion PMT being a N-substituted phenothiazine derivative undergoes two-step oxidation, first to red coloured radical cation and then to colourless sulphoxide5 (Fig. 1) by metavanadate in H 2S04 medium, and in the process metavanadate is reduced to vanadium(IV). The proposed methods are based on the determination of either unreacted metavanadate or vanadium(IV), the reduced form of vanadium(V).

Method A PMT was found to be oxidized quantitatively to its sulphoxide by metavanadate in acid medium. The reaction was found to be slow in HCl and H3P04 media and was found to be rapid and quantitative in H2S04 medium. Under similar conditions of acid strength, the oxidation reaction took more than 30 min 357

Articles

Indian J. Chern. Technol., July 2003

cx:D

~~~ ~if~

R

R

I

PMT (colourless) +

~SX)

e~N I

#

I

Radical cation (coloured}

(X~X) I

R

R

l

H,O

OH

0

I

I

H"+ ~SX) '-":: ~N

I

!

#

I

R

o= sX) I

N

+W

~

I

R

Sulphoxide (colourless)

Fig. !- Reaction scheme for oxidation of PMT.

in the case of HCI and the reaction was found to be incomplete even after 60 min when H3P0 4 was used. Both media gave non-stoichiometric results under the specified conditions of standing time (5 min). A 5 mL vol ume of I 0 M H 2S04 in a total volume of about 25 mL was found to be adequate for both oxidation and backtitration steps. In the 1-20 mg range studied, 2 moles of vanadate were found to react with each mole of drug giving a stoichiometric ratio of 1:2 (PMT:oxidant ). A I 0 mL of 0.02 M meta vanadate was found suffi cient to cause oxidation of the drug in the studied range in a reasonable time of 5 min . Larger concentrati on of oxidant up to 0.05 M did not affect the stoichiometry and the results.

Method B Of the few titrimetric procedures 6-9 available for the determination of vanadi um(IY ), one useful and convenient procedure9 involves the titration with cerium(IY) in H2S04 medium using ferroin indicator and in the presence of acetone catalyst. Method B is based on the oxidation of PMT to sulphoxide by a large excess of vanadate in acid medium and the titration of resulting vanadium(IY) with cerium(IV) as described by Sriramam et a /.9 For the oxidation of the drug as well as the titration of vanadium(IV), a 2 mL of I 0 M H2S04 in an overall volume of about 25-30 mL was found optimum. Even in thi s method, the drug and metavanadate were found to react in a I :2 molar ratio. A 10 mL of 0 .05 M metavanadate solution was fo und adequate to effect the oxidation of the drug in the 5-12 mg range. Contact times up to 30 358

min had no effect on either the sto ichiometry or the results of assay. The relation between the drug amount and the titration end-point in both the methods was examined. The linearity between the two variables is apparent from the correlation coefficient of -0.9996 and 0.9985 for methods A and B, respectively, revealing that the reaction between PMT and metavanadate proceeds stoichiometrically in the ratio 1:2. In method B, the titration of vanadium(IV) should be performed slowly particularly towards the end-point with an interval of at least 20 s between two additions.

Method C In acidi c solutions, chromotropic acid was found to give a yellow coloured chromogen with metavanadate which is believed to be a complex 10 . Since metavanadate easily oxidizes PMT in acidic conditions, the colour reaction between metavanadate and chromotropic acid was used for the determi nati on of PMT in ppm level. In the present . study , a known amou nt of metavanadate was made to oxidize PMT to its sulphoxide in H2S04 medium and the unreacted oxidant was determined by complexing with chromotropic acid in the same acidic conditions employed to cause oxidation of the drug. PMT when added in increasi ng concentrations to a fixed concentration of metavanadate, consumes the latter and consequently there wi ll be a concomi tant fall in the concentmtion of metavanadate. This is observed as a proportional decrease in th e absorbance of the yellow colour with increasi ng concentration of PMT (Fi g. 2). The decreasing absorbance values at 420 nm were plotted against increasing concentration of PMT to obtain the calibration graph (Fig. 3). By a preliminary study it was found that Beer's law is obeyed up to 750 Jlg mL-1 of sodi um metavanadate under the specified ac id and reagent concentrations (Fig. 4 ). Hence different amounts of PMT were reacted with a fixed concentration (750 Jlg m.L-1) of the oxidant in the assay procedure. In this procedure two blanks were prepared. The reagent blank which contained the optimum concentration of all the reactants except PMT gave maximum absorbance. The other blank was prepared in the absence of metavanadate and PMT which showed negligible absorbance. Hence, all measurements were made against water. The yellow colour measured was found to be stable for several months.

Articles

Basavaiah & Charan: Titrimetric and spectrophotometric methods for the determination of promethazine theoclate

0.5 0.4

0.4

.

. -e

.. 0.3 •= .c ..... .c 0.2

;$ 0.3

u

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