IJCT 13(4) 353-359

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Journal of Chemical TechnologyVol. 13, July 2006, pp. 353-359

Sensitive bromatometric methods for the assay of metaprolol tartrate

in dosage forms

K Basavaiah1*, B C Somashekar1 & V Ramakrishna21Department of Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India

2Department of Pharmaceutical Chemistry, Govt. College of Pharmacy, Bangalore 560 027, IndiaEmail: [email protected]

Received 25 July 2005; revised received 12 April 2006; accepted 1 May 2006

One titrimetric and two spectrophotometric methods are described for the determination of metaprolol tartrate (MPT)

using bromate-bromide mixture and two dyes, methyl orange and indigo carmine, as reagents. In titrimetry, an acidified

solution of MPT is reacted with a known excess of bromate-bromide mixture and after a pre-determined time, the unreactedbromine is determined by iodometric titration. The spectrophotometric methods involve the addition of a known excess of

bromate-bromide mixture to MPT in acidic medium followed by determination of the residual bromine by reacting withfixed amount of either methyl orange and measuring the absorbance at 520 nm (Method A) or indigo carmine and measuringthe absorbance at 610 nm (Method B). In all the methods, amount of bromine reacted corresponds to the amount of MPT.

The working conditions of the methods have been optimised. Titrimetry allows the determination of MPT in 2.5 - 7.5 mgrange and the calculations are based on a 1:1(MPT : KBrO3) reaction stoichiometry. In the spectrophotometric methods,

Beers law is valid over the concentration ranges 0.5 -5.0 and 1.5 - 15.0 g mL-1 MPT for method A and method B,

respectively. Method A with a molar absorptivity of 8.17 104L mol-1 cm-1 is more sensitive than method B ( = 2.70 104L mol-1 cm-1). The limits of detection and quantification are reported for both the methods. The methods could usefully be

applied to routine quality control of tablets containing MPT. No interference was observed from common pharmaceuticaladjuvants. Statistical comparison of the results with those obtained by an established UV-spectrophotometric methodshowed excellent agreement and indicated no significant difference in accuracy and precision. The reliability of the methodswas further ascertained by recovery studies.

Keywords:Metaprolol tartrate, Assay, Bromate-bromide, Dyes, Dosage forms

IPC Code: A61K9/08

Beta blockers have been in clinical use for over 30

years and have an accepted role in the treatment of

high blood pressure, the secondary prevention of

myocardial infarction and in the treatment of

arrhythmias. Metaprolol tartrate (MPT), () -

(isopropylamino-3-[4-(2-methoxyethyl) phenoxy]-2-

propanol tartrate (Fig. 1), is known as a cardio

selective beta adrenergic receptor blocker1. Nearly

200 articles have appeared since the early 1980s

describing the detection and determination of thisdrug using a variety of analytical techniques, but a

large number of them are devoted to the analysis of

biological samples. The drug is official in the United

States Pharamcopoeia2 which describes a non-

aqueous titrimetric procedure for bulk drug and a high

performance liquid chromatographic method for assay

in tablets. For the determination of this drug in dosage

forms, several techniques including UV-

spectrophotometry3-6, near infrared spectroscopy7,

fluorimetry8,9, AAS10,11, liquid chromatography12,

high performance liquid chromatography13-16, high

performance thin layer chromatography17, gas

chromatography-mass spectroscopy18, densitometry19,

ion-selective electrode based potentiometry20, and

voltammetry21 have been reported. But most of the

above techniques are tedious, time-consuming and

difficult to perform besides involving expensive

instrumental setup, and are applicable for assay in

combined dosage forms.

Fig 1Structure of MPT

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INDIAN J CHEM. TECHNOL., JULY 2006354

From a pharmaceutical analysis stand point, it is

highly desirable if the assay methods are simple, rapid

and affordable by small-scale industrial laboratories,

without a compromise on the requirements ofsensitivity, selectivity, and accuracy and precision. In

this respect, titrimetry and spectrophotometry

continue to be used in industrial quality control

laboratories because of their low cost, versatility of

applications and ease of operation. However, there is

only one report22 on the titrimetric determination of

MPT and the method uses metavanadate as the

oxidimetric reagent which is performed in high H2SO4

concentration.

MPT has rendered itself to analysis by visible

spectrophotometry through several chemical

reactions. Nitration of MPT to produce a yellow

derivative in H2SO4 medium was introduced as a

quantitative method by Sanghavi and Vyas23.

Formation of a yellow colour on reacting the drug

with iron(III) chloride24in HCl medium has been the

basis of assay in pharmaceutical preparations. Ersoy

and Kocaman25have used bromothymol blue as ion-

pair reagent for the sensitive determination of MPT.

Based on a similar reaction but using benzyl orange as

a chromogenic reagent, a quantitative assay method

has been proposed by Vujic et al.26. A stable greenish

- yellow chromophore resulting from the reaction of

MPT with 1-fluoro-2,4-dinitro benzene (FDNB) in

tetraborate - HCl medium was used by Shingbal and

Bhangle27. In a method presented by one of the same

authors

28

, MPT was reacted with acetaldehyde andchloranil in the presence of Ag2O to produce a blue

chromogen measurable at 680 nm. There are two

reports on the use of charge-transfer complex

reactions employing 4-chloro-7-nitro-2,1,3-

benzoxadiazole (NBD-Cl)29 and tetracyano ethylene

(TCNE) or chloranilic acid(CAA)10 as - acceptors

for the determination of MPT. A method10 has been

proposed whereby the chelate formed with copper(II)

in the presence of CS2 was extracted into isobutyl

methyl ketone before absorbance measurement. Other

method determining MPT involved the formation of

copper(II)dithiocarbamate complex

11

by derivatisationthe secondary amino group of the drug with CS2and

CuCl2 before extracting into chloroform, and

measurement. But, most of the currently available

spectrophotometric methods suffer from one or the

deficiency such as poor sensitivity, narrow linear

range of response, stringent experimental conditions

like heating or extraction step, and/or use of

expensive chemicals (Table 1).

In the present study, two techniques, titrimetry and

spectrophotometry have been employed for the assay

of MPT using bromate-bromide mixture as the

Table 1Comparison of the existing spectrophotometric methods with the proposed methods for MPT

Sl No. Reagent/s used* max,nm Linear range, g ml-1 Remarks Ref.

1 KNO3 440

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BASAVAIAH et al.: SENSITIVE BROMATOMETRIC METHODS FOR THE ASSAY OF METAPROLOL TARTRATE 355

oxidimetric reagent and methyl orange and indigo

carmine as the spectrophotometric reagents. The

methods, when applied to the assay of MPT in dosage

forms, have been found to be convenient and are freefrom difficulties encountered in many of the existing

methods.

Experimental ProcedureReagents and materials

A Systronics Model 106 digital spectrophotometer

provided with matched 1-cm quartz cells was used for

all absorbance measurements. All chemicals used

were of analytical reagent grade and distilled water

was used to prepare all solutions. Bromate-bromide

mixture (510-3 M KBrO3 - 5010-3 M KBr) was

prepared by dissolving accurately weighed 0.8 g ofKBrO3 (Sarabhai M Chemicals, Baroda, India) and

6 g of KBr (Indian Drugs and Pharmaceuticals Ltd,

Hyderabad, India) in water and diluting to 1 litre in a

calibrated flask, and the reagent was used in

titrimetric work. A 0.03 M sodium thiosulphate

solution was prepared by dissolving about 7.45 g of

compound (Sisco Chem Industries, Mumbai, India) in

1 litre of water and standardized30. A 10% potassium

iodide solution was prepared by dissolving 10 g of

salt (Merck Chemicals, Mumbai,India) in 100 mL of

water. To prepare 1% starch indicator 1 g of soluble

starch (S. d. Fine Chem., Mumbai, India) was madeinto paste in water and poured into 100 mL boiling

water, boiled for 1 min and cooled. A stock standard

solution of bromate-bromide equivalent to 1000 g

mL-1 KBrO3 containing 10-fold excess of KBr was

prepared by dissolving 100 mg of KBrO3and 1 g of

KBr in water and diluting to 100 mL with water in a

calibrated flask. This was diluted appropriately to get

10 and 30 g mL-1 KBrO3solutions for method A and

method B, respectively. A stock solution equivalent to

500 g mL-1 methyl orange was prepared by

dissolving 58.8 mg of the dye (S. d. Fine Chem.,

Mumbai, India, dye content 85%) in water anddiluting to 100 mL in a calibrated flask, and filtered

using glass wool. It was diluted 10-fold to get 50 g

mL-1dye solution for use in method A. stock solution

containing 1000 g mL-1 indigo carmine was first

prepared by dissolving 111 mg of dye (S. d. Fine

Chem., Mumbai, India, dye content 90 %) in water

and diluting to 100 mL in a calibrated flask, and

filtered. A working concentration of 200 g mL-1dye

solution was obtained by 5-fold dilution with water

for method B. A 5 M hydrochloric acid was prepared

by diluting 112 mL of concentrated acid (S. d. Fine

Chem., Mumbai, India, Sp gr 1.18) to 250 mL with

water. This was further diluted to 2M with water.

Pharmaceutical grade MPT certified to be 99.7 %pure was gifted by Astra - Zeneca, Bangalore, India,

and used as received. A stock standard solution

containing 1 mg mL-1 drug solution was prepared by

dissolving 250 mg of pure drug in water diluting to

the mark with water in a 250 mL calibrated flask. This

solution was used in titrimetric work and the same

was diluted stepwise to yield working concentrations

of 10 and 30 g mL-1 for spectrophotometric

investigations.

Methods

Titrimetry

A 10 mL aliquot of pure drug solution containing2.5-7.5 mg of MPT was accurately measured and

transferred into a 100 mL Erlenmeyer flask. The

solution was acidified by adding 5 mL of 2 M

hydrochloric acid. Ten mL of bromate-bromide

reagent (510-3 M w. r. t. KBrO3) was pipetted into

the flask, the flask was stoppered, the contents mixed

and let stand for 10 min with occasional swirling.

Finally, 5 mL of 10 % potassium iodide solution was

added, and the liberated iodine was titrated against

0.03 M thiosulphate solution using starch as indicator

towards the end point. A blank titration was

performed, and the amount of drug in the measuredaliquot was calculated from the amount of KBrO3

reacted with drug.

Spectrophotometric method A

Different aliquots (0.5, 1.0.5.0 mL) of

standard 10 g mL-1 MPT solution were accurately

measured into a series of 10 mL calibrated flasks by

means of a micro burette and the total volume was

adjusted to 5 mL by adding water. To each flask were

added, 2 mL of 5 M hydrochloric acid and 1 mL of

bromate-bromide reagent (10 g mL-1 w. r. t KBrO3)

in succession. The flasks were stoppered immediately,contents mixed, and allowed to stand for 5 min with

occasional shaking. Lastly, 1 mL of 50 g mL-1

methyl orange solution was added to each flask, the

volume was diluted to the mark with water, mixed

well and absorbance measured at 520 nm against a

reagent blank after 10 min.

Spectrophotometric method B

Varying aliquots (0.5-5.0 mL) of standard 30 g

mL-1 MPT solution were accurately transferred into a

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series of 10 mL calibrated flasks by means of a micro

burette, and the total volume was brought to 5 mL by

adding water. Two mL 5 M hydrochloric acid and

1.5 mL of bromate-bromide reagent (30 g mL

-1

w. r.t KBrO3) were added to each flask, the flasks were

immediately stoppered, the contents mixed well and

let stand for 10 min with occasional shaking. Then,

1 mL of 200 g mL-1 indigo carmine solution was

added to each flask, the volume was completed to themark with water, mixed well and the absorbance of

each solution was measured at 610 nm against a

reagent blank after 10 min.

In either method, a standard graph was prepared by

plotting the absorbance as a function of concentrationof MPT. The concentration of the unknown was read

from the calibration graph or deduced from therespective regression equation derived from the

Beers law data.

Method for tablets

Twenty tablets were weighed and powdered. An

amount of powder equivalent to 100 mg of MPT was

accurately weighed into a 100 mL calibrated flask,

60 mL of water added and shaken for 20 min. Then,

the volume was diluted to the mark with water, mixed

well and filtered using a Whatmann No. 42 filter

paper. A suitable aliquot was then analysed by

titrimetry. The tablet extract (1000 g mL-1MPT) was

diluted with water to obtain working concentrations of

10 and 30 g mL-1for analysis by spectrophotometric

methods.

Results and Discussion

The acidified solution of bromate and bromide

behaves as an equivalent solution of bromine and has

been widely used for the determination of many

organic and inorganic substances31,32. The present

methods make use of oxidising/brominating ability,

and bleaching action of in situgenerated bromine.

Method developmentTitrimetry

Direct titration of MPT with in situ generated

bromine was not successful. However, the reaction

between the two was found to occur when the two

were allowed to stand for some time, thus enabling

the indirect titrimetric determination of MPT. Hence,

several factors like nature of acid and its

concentration, reaction time, and the excess of reagent

were optimized. Reproducible and stoichiometric

results were obtained when 0.24 to 0.56 M

hydrochloric acid concentration was maintained.

Hence, 0.4 M acid concentration for the

bromination/oxidation step and the iodometric back

titration was used in the assay. Reaction was completein 10 min and yielded stoichiometry of 1:1 (MPT :

KBrO3), and contact times up to 20 min had no effect

on the stoichiometry of the reaction. A constant

molar-ratio was obtained when excess of reagent was

not more than 2 times the theoretical amount. Under

the optimum conditions, 2.5 - 7.5 mg of MPT could

be determined with good accuracy and precision with

reaction stoichiometry of 1:1.

Spectrophotometric methods

The ability of bromine to effect

oxidation/bromination of MPT and bleach the

colour of methyl orange and indigo carmine dyeshas been used for the indirect spectrophotometric

assay of MPT. In both methods, the drug was

reacted with a measured excess of in situgenerated

bromine in acid medium and the unreacted bromine

was determined by reacting with either methyl

orange or indigo carmine followed by absorbance

measurement at 520 or 610 nm. In either method,

the absorbance increased linearly with increasing

concentration of MPT.

MPT, when added in increasing amounts to a fixed

amount of bromine, consumed the latter and there

occurred a concomitant fall in its concentration. Whena fixed amount of either dye was added to decreasing

amounts of bromine, a concomitant increase in the

concentration of dye resulted. This was observed as a

proportional increase in absorbance at the respective

maxwith increasing concentration of MPT and Beers

law is obeyed in the concentration range given in

Table 2.

Preliminary experiments were performed to

determine the maximum concentration of each dye

spectrophotometrically, and these were found to be 5

and 20 g mL

-1

for methyl orange and indigocarmine, respectively. A bromate concentration of 1.0

g mL-1 (in the presence of excess KBr) was found to

destroy the red colour due to 5 g mL-1 methyl orange

whereas in the case of 20 g mL-1 indigo carmine,

4.5 g mL-1 KBrO3 was sufficient to bleach the blue

colour in acid conditions. Hence, different amounts of

MPT were reacted with 1.0 mL of 10 g mL-1 KBrO3

in method A and 1.5 mL of 30 g mL-1 KBrO3 in

method B before determining the residual bromine as

described under the respective procedures.

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Hydrochloric acid was the ideal medium for

oxidation/bromination reaction as well as the

determination of residual bromine by using either dye.

The reaction between MPT and bromine (in situ) wasunaffected when 1.0 -5.0 mL of 5 M hydrochloric

acid was used in about 8 mL. Hence, 1 mL was used

for both steps in the assay procedures. For

quantitative reaction between MPT and bromine (in

situ), a contact time of 10 min was found sufficient in

both methods and constant absorbance readings were

obtained when contact times were extended up to 30

min. The standing time of 5 min was necessary for the

bleaching of dye colour by the residual bromine. The

measured colour was stable for several hours even in

the presence of reaction product.

Quantation parameters

A linear correlation was found between absorbance at

max and concentration of MPT in the ranges given in

Table 2 in both the methods. The graphs obeyed Beers

law and can be described by the regression equation:

Y = a + bX

(where Y = absorbance; a = intercept; b = slope and X

= concentration in g mL-1 ) obtained by the method

of least squares. Correlation coefficients, intercepts

and slopes for the calibration data are summarized in

Table 2. Sensitivity parameters such as apparentmolar absorptivity and Sandell sensitivity values, and

the limits of detection and quantification are also

presented in Table 2 and speak of the excellent

sensitivity of the proposed methods.

Method validation

Assay precision and accuracy

Intra-day and inter-day precision were assessed

from the results of seven replicate analyses on pure

drug solution. The mean values and the relative

standard deviation (RSD) values for replicate analyses

at three different levels (amounts/concentrations) are

compiled in Table 3. To evaluate the inter-day

precision, anaysis was performed over a period of five

days preparing all solutions afresh each day. The

accuracy of the methods was determined bycalculating the percentage deviation observed in the

analysis of pure drug solution and expressed as the

percent relative error (RE). Table 3 summarises the

intra-day precision and accuracy data for the assay of

MPT in pure drug solution by the proposed methods,

which were within 3%. The inter-day precision was

less than 4%.

Application to analysis in dosage forms

The Indian pharmaceutical industry has at present 4

different brands of tablets in 25, 50 and 100 mg doses.

Three brands of tablets were assayed by the proposed

methods, and the results are summarized in Table 4.The results obtained were compared with those

obtained by the established UV-spectrophotometric

methods5which consisted of the measurement of the

absorbance of tablet extract in 0.1 M HCl at 224 nm.

A close agreement between the results obtained by the

proposed methods and the reference method interms

of accuracy and precision was obtained as found from

the Students t-value and F-value.

Table 3Intra-day precision and accuracy

Titrimetry Method A Method B

MPT

taken,mg

MPT

found,mg

Range,

mg

Relative

error, %

RSD,

%

MPT

taken, gmL-1

MPT

found, gmL-1

Range, g

mL-1

Relative

error, %

RSD, % MPT

taken, gmL-1

MPT

found, gmL-1

Range, g

mL-1

Relative

error, %

RSD,

%

3.0 3.03 0.12 1.0 0 2.25 1.50 1.48 0.017 1.33 2.41 3.0 2.95 0.028 1.67 2.54

5.0 5.01 0.35 0.20 2.59 3.00 2.92 0.029 2.67 1.35 6.0 5.91 0.093 1.50 1.947.0 6.97 0.04 0.43 1.84 4.50 4.40 0.070 2.22 2.36 12.0 11.78 0.049 1.83 2.24

Mean value of seven determinationsRSD.Relative standard deviation

Table 2 Quantitative parameters of spectrophotometric

methods

Parameters Method A Method B

max (nm) 520 610

Beers law limits (g mL-1) 0.5 - 5.0 1.5 - 15.0

Molar absorptivity (l mol-1cm-1) 8.17 104 2.70 104

Sandell sensitivity (g cm-2) 0.0084 0.025

Limit of detection (g mL-1) 0.054 0.15

Limit of quantification (g mL-1) 0.165 0.47

Regression equation (Y)

Slope (b) 0.11 0.04Intercept (a) 0.012 -6.7 104Correlation coefficient (r) 0.9989 0.9988

Y=a + bX where Y is the absorbance and X concentration in

g mL-1.

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Accuracy and validity of the methods were further

established by performing recovery experiments via

standard-addition technique. To a fixed amount of

drug in tablet powder (pre-analyzed), pure MPT was

added at three different levels and the total was found

by the proposed methods. Each test was repeated

three times. The recovery of pure MPT added to

formulations ranged from 97.60 - 102.50% (Table 5)

indicating that tablet excipients such as talc, starch,

acacia, stearate, alginate, lactose, calcium gluconateand calcium dihydrogen orthophosphate did not

interfere in the assay procedures.

Conclusions

Three simple, rapid and cost-effective methods for

the assay of metaprolol tartrate in bulk drug and tablet

dosage form have been developed and appropriately

validated. The titrimetric method is applicable over amicro scale and is independent of the experimental

variables that would often affect the accuracy and

precision. Unlike most of the existing

spectrophotometric methods, the proposed procedures

are free from stringent experimental conditions and

are characterized by long dynamic linear range of

response and high sensitivity, and infact, the methods

are one of the most sensitive ever reported for MPT.

Another significant advantage of the

spectrophotometric methods is that the measurement

is made at longer wavelengths where the interference

from co formulated substances is far less compared toshorter wavelengths used in most currently available

procedures. In addition, all the three methods have

demonstrated to be fairly accurate and precise, and

may be used as advantageous alternatives in industrial

quality control laboratories.

Acknowledgements

The authors wish to express their gratitude to theQuality Control Manger, Astra - Zeneca,

Bangalore, India for providing pure metaprolol

Table 4Assay results of dosage forms

Percent found* SDFormulation brand

name **

Nominal amount

(mg/tablet )Tirimetry Method A Method B Reference method

Betaloc 50 g100.10 1.41

t= 0.79

F= 3.27

101.20 1.39

t= 0.80

F= 3.17

99.98 0.87

t = 1.28

F= 1.24

100.65 0.78

100 g99.89 1.62

t= 0.48

F=2.84

101.30 1.42

t=1.35

F=2.18

102.30 0.93

t= 3.38

F= 1.06100.28 0.96

Metolar 100 g97.98 1.44

t= 1.84F= 1.81

98.50 1.33

t=1.24F= 1.54

98.14 1.77

t= 1.45F= 2.74

99.44 1.07

Metapro 50 g101.77 1.85

t= 1.47F= 4.42

99.20 1.73

t= 1.57F= 3.86

102.50 1.39

t = 2.78F= 2.49

100.50 0.88

* Mean value of five determinations

**Marketed by: a. AstraZenecab. ciplac. MicrovascularTabulated t-value at 95 % confidence level is 2.77

Tabulated F-value at 95 % confidence level is 6.39

Table 5Results of recovery studies

Titrimetry Method A Method B

Preparation

studies

Amount

of drug intablet, mg

Amount of

pure drugadded, mg

Total

found,mg

Recoveryof puredrug, %

Amount

of drug in

tablet, g

Amount of

pure drug

added, g

Total

found,

g


Amount

of drug in

tablet, g

Amount of

pure drug

added, g

Total

found,

g


3.912 1.0 4.92 101.00 9.85 10.00 20.10 102.50 24.53 30.0 53.81 97.60

3.912 2.0 5.93 100.75 9.85 20.00 29.90 100.25 24.53 60.0 85.37 101.40

Metolar

3.912 3.0 6.98 102.00 9.85 30.00 39.55 99.00 24.53 120.0 143.65 99.27

* Mean value of three determinations

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tartrate as gift. Two of the authors (BCS & VRK)

thank the authorities of the University of Mysore,

Mysore, for research facilities. VRK is thankful to

the Principal Secretary, Department of Health andFamily Welfare, Govt. of Karnataka, Bangalore, for

permission.

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