SPECTROPHOTOMETRIC DETERMINATION OF CARISOPRODOL IN PURE AND PHARMACEUTICAL FORMS USING TRIPHENYL METHANE DYES
HTML Full TextSPECTROPHOTOMETRIC DETERMINATION OF CARISOPRODOL IN PURE AND PHARMACEUTICAL FORMS USING TRIPHENYL METHANE DYES
M. Ravi 1, T . Veeraiah 1* and Ch.Venkata Ramana Reddy 2
Department of Chemistry 1, SAP College, Vikarabad-501101, Ranga Reddy Dist. Telangana, India
Department of Chemistry 2, JNTUH College of Engineering, Kukatpally Hyderabad-500 085, Telangana, India
ABSTRACT: New simple and sensitive extractive spectrophotometric methods have been developed and described for the determination of carisoprodol in pure form and in pharmaceutical formulations. The developed methods involve formation of coloured chloroform extractable ion-pair complexes of carisoprodol with triphenyl methane dyes viz., bromocresol green (BCG), bromothymol blue (BTB) and bromophenol blue (BPB) in acidic medium. The extracted complexes showed absorbance maxima at 420, 417 and 413 nm with use of BCG, BTB and BPB respectively. The stoichiometry of the complex in three cases is found to be 1:1. Beer’s law is obeyed in the concentration ranges: 2.5-25, 2.5-30 and 3.0-30μg/ml with BCG, BTB and BPB respectively. The effect of concentration of dye, pH and interference of excipients have been studied and optimized. The limits of detection and quantification have been determined for all the three methods. These methods have been validated as per the guidelines of International Conference on Harmonization (ICH) and have been applied to the determination of carisoprodol in commercial tablets and results of analysis were validated statistically through recovery studies. Thus the newly developed methods are accurate, efficient and stable.
Keywords: |
Spectrophotometry,
carisoprodol, bromocresol green, bromothymol blue, bromophenol blue, ion-pair complex,
ICH validation
INTRODUCTION: Carisoprodol, chemically, N-isopropyl-2-methyl - 2 – n – propyl - 1, 3-propanedioldicarbamate (Fig. 1), is a centrally acting muscle relaxant, with analgesic properties, making it a popular drug of abuse, whose chief application is in the treatment of acute muscular spasm associated with craniomandibular disorder, lumbago, sciatica, and other lower back syndromes 1, 2. Carisoprodol is a pharmaceutical active agent and structurally related to its metabolite, meprobamate 3. Carisoprodol is marketed as a muscle relaxant and dispensed by prescription under the trade name of Soma.
Carisoprodol produces weak anticlolinergic, antipyretic and analgesic effects 4. The effect of carisoprodol, which includes sedation, loss of balance, confusion and increased reaction time are similar to those of alcohol, benzodiazepines and other CNS depressants and well documented to decrease human performance and adversely affect driving effect 5.
FIG. 1: STRUCTUE OF CARISOPRODOL
Clinicians have reported a possible withdrawal syndrome consisting of insomnia, nausea, vomiting, tremors and anxiety in patients who discontinue the use of carisoprodol 6 and in at least one case, withdrawal has been mistaken for a psychotic disorder 7. The abuse of carisoprodol has increased substantially in many areas in the United States 8, 9 and there have been recommendations to place it into the Controlled Substances Act as a scheduled drug 10.
Several methods, such as Titrimetry 11, GC12, 13, 14, LC-MS 15, 16 GC-MS17, 18, IR Spectrometry 19, Visible absorbance densitometry 20 are available in the literature for the determination of carisoprodol. Carisoprodol and its metabolite, meprobamate present in oral fluid were determined using solid-phase extraction and liquid chromatography with tandem mass spectral detection 21. Validation of a new homogeneous immunoassay for the detection of carisoprodol in urine 22 and method development and validation of carisoprodol and its impurities by UV-HPLC 23 were also reported.
Simultaneous determination of carisoprodol and aspirin in human plasma using liquid chromatography – tandem mass spectrometry in polarity switch mode was carried out by Sreenivasulu et al 24. Carisoprodol and its metabolites were determined quantitatively in equine urine and serum by the same method 25. Thorough literature survey revealed that carisoprodol was identified and determined in tablets by liquid chromatography / mass spectrometry 26. Development and evaluation of carisoprodol tablets with improved dissolution efficiency using solid dispersion technology was reported 27. Formulation of carisoprodol topical gel along with its evaluation was also recently reported 28. Reports on kinetic analysis of non-isothermal carisoprodol reaction in nitrogen atmosphere 29 and diazotization of carisoprodol as skeletal muscle relaxant by derivatization spectrometry 30 are also available in the literature.
The chemical structure of carisoprodol molecule offers a lot of scope for the development of new methods for its determination with better sensitivity, specificity, precision and accuracy. The reported methods including chromatographic techniques require expensive experimental set-up and are not affordable in every laboratories for routine analysis. Spectrophotometry is considered as the most convenient analytical technique because of its inherent simplicity, low cost and wide availability in most quality control laboratories. Because of its physiological significance, the quantitative determination of carisoprodol attracted the attention of analytical chemists and almost all analytical methods have been applied to accomplish the purpose. However methods on spectrophotometric determination of this drug involving ion-pair complexes with common and versatile acidic dyes viz., bromocresol green (BCG), bromothymol blue (BTB) and bromophenol blue (BPB) are not reported yet. This prompted the authors to develop extractive spectrophotometric methods for the determination of carisoprodol using above mentioned dyes.
In this paper we report three simple and sensitive extractive spectrophotometric methods for the assay of carisoprodol. These methods are based on ion-pair complexation of drug with dyestuffs such as BCG, BTB and BPB and subsequent extraction into chloroform and to measure the absorbance of colour complex. The proposed methods have the advantages of speed and simplicity besides being accurate and precise and can be adopted by the pharmaceutical laboratories for industrial quantitative analysis.
MATERIAL AND METHODS: Carisoprodol was procured from Srini Pharmaceuticals Limited, Hyderabad as a gift sample. The dyestuffs viz., BTB, BPB, BCG (AR grade) supplied by SD Fine Chemicals Ltd. Mumbai, were used without any further purification. The dyestuffs were used as 0.025% solutions in doubly distilled water. Sodium acetate-hydrochloric acid buffers 31 of pH 2.5, 2.8 and 3.5 were prepared by mixing 50ml of 1.0M sodium acetate solution with calculated volume of 1.0 M HCl solution and diluted to 250 ml with doubly distilled water. The pH of each solution was adjusted to an appropriate value with the aid of a pH meter. Chloroform (HPLC grade) supplied by SD Fine Chemicals Ltd. Mumbai was used throughout the work.
The spectra (Fig. 2A, 2B and 2C) of ion-pair complexes have been recorded on Elico double beam SL 210 spectrophotometer using quartz cells of 10 mm path length. An Elico model Li-120 pH meter was used for pH measurement.
Calibration curve: Different aliquots of drug solution were transferred into 125ml separating funnel. To this 5ml of buffer (pH 2.5, 2.8 and 3.5), 5ml of dye were added and total volume was made up to 20ml with water. 10ml of chloroform was added and the contents were shaken for 5min. The two layers were allowed to separate for 5min. The organic layer was separated and absorbance of yellow colored solution which is stable at least for 3 hrs is measured at 420nm against blank similarly prepared. The same procedure of analysis is followed either for assay of pure drug or for dosage form. The calibration graphs (Fig. 3) are linear over the concentration ranges and are within the permissible range. The optical characteristics and statistical data for the regression equation of the proposed methods are presented in Table 1.
FIG. 3: CALIBRATION GRAPHS FOR CARISOPRODOL-BCG, BTB, & BPB ION-PAIR COMPLEXES
Procedure for the assay of pure drug:
Five different solutions of pure drug in the range of calibration curve were selected and the recovery experiments were performed. The recoveries and their relative standard deviations are tabulated in Table 2.
Procedure for the assay of dosage forms:
Ten tablets of Soma 250mg each are powdered and dissolved in doubly distilled water and stirred thoroughly, filtered through a Whatman No. 42 filter paper. This solution was transferred into 100 ml standard volumetric flask and diluted with doubly distilled water as required. Different solutions of drug in the range of calibration curve were chosen and the assay was estimated using the calibration curve. The results of the recovery experiments are tabulated in Table 3.
TABLE 1: OPTICAL CHARACTERISTICS AND STATISTICAL ANALYSIS FOR THE REGRESSION EQUATION OF THE PROPOSED METHODS
Parameters | Extraction methods withb | ||
BCG | BTB | BPB | |
λmax (nm) | 420 | 417 | 413 |
Beer’s law limit (μg ml-1) | 2.5-25 | 2.5-30 | 3.0-30 |
Molar absorptivity (L mol-1 cm-1) | 18225 | 20540 | 23630 |
Formation constant, K, M-1 | 1.55x106 | 1.61x106 | 1.71x106 |
Sandell sensitivity (μg cm-2) | 0.0168 | 0.0162 | 0.0142 |
Slope (specific absorptivity), b | 0.0595 | 0.0615 | 0.0702 |
Intercept (a) | 0.0068 | -0.0235 | -0.0211 |
Correlation coefficient (r) | 0.998 | 0.999 | 0.999 |
Standard deviation of intercepts (% n=6) | 0.0043 | 0.0081 | 0.0112 |
Limit of detection, μgml-1 | 0.2384 | 0.4346 | 0.5234 |
Limit of quantification, μgml-1 | 0.7226 | 1.3170 | 1.5954 |
Regression equationa | Y=0.0595C±0.0068 | Y=0.0615C±0.0235 | Y=0.0702C±0.0211 |
aWith respect to Y=bc+a, where C is the concentration (μg ml-1) and Y is absorbance
bSix replicate samples
TABLE 2: APPLICATION OF PROPOSED METHODS FOR THE ANALYSIS OF CARISOPRODOLE IN PURE FORM
Taken | Proposed methods | Reference | |||||
(μg ml-1) | Found (μg ml-1) | Recovery (%) | methodRecovery (%) | ||||
BCG | BTB | BPB | BCG | BTB | BPB | ||
5 | 5.08 | 4.98 | 5.05 | 101.6 | 99.6 | 101.0 | 99.8 |
10 | 10.15 | 9.98 | 9.96 | 101.5 | 99.8 | 99.6 | 101.2 |
15 | 15.15 | 14.95 | 15.25 | 101.0 | 99.66 | 101.66 | 101.5 |
20 | 19.95 | 20.12 | 19.85 | 99.75 | 100.6 | 99.25 | 101.12 |
25 | 24.98 | 25.25 | 25.15 | 99.92 | 101.0 | 100.6 | 101.25 |
99.98 | |||||||
101.25 | |||||||
99.96 | |||||||
RSD (%) | 0.8686 | 0.6293 | 0.9892 | 0.7039 | |||
Mean±SD | 100.75±0.8712 | 100.13±0.6301 | 100.42±0.9934 | 100.75±0.7092 | |||
t-test | 0.3098 | 0.1849 | 0.4944 | ||||
F-test | 0.6626 | 1.2667 | 0.5096 |
TABLE 3: APPLICATION OF PROPOSED METHODS FOR THE ANALYSIS OF CARISOPRODOL IN PHARMACEUTICAL FORM
Taken | Proposed methods | Reference | |||||
(μg ml-1) | Found (μg ml-1) | Recovery (%) | Method | ||||
Soma 250mg | BCG | BTB | BPB | BCG | BTB | BPB | Recovery (%) |
4 | 3.96 | 4.06 | 4.05 | 99.0 | 101.25 | 101.25 | 98.98 |
8 | 7.98 | 8.02 | 8.02 | 99.75 | 100.25 | 100.25 | 101.25 |
12 | 12.04 | 12.04 | 11.95 | 100.33 | 100.33 | 99.58 | 99.92 |
16 | 15.96 | 15.95 | 16.08 | 99.75 | 99.68 | 100.5 | 99.85 |
20 | 20.02 | 20.05 | 19.85 | 100.1 | 100.25 | 99.25 | 101.05 |
100.25 | |||||||
99.98 | |||||||
101.48 | |||||||
99.75 | |||||||
RSD (%) | 0.5047 | 0.5633 | 0.7853 | 0.8154 | |||
Mean±SD | 99.78±0.5037 | 100.38±0.5655 | 100.16±0.7867 | 100.27±0.8177 | |||
t-test | 0.7511 | 0.5767 | 0.0648 | ||||
F-test | 0.3794 | 0.4781 | 0.9255 |
RESULTS AND DISCUSSION: Carisoprodol forms ion-pair complexes in acidic buffer with dyestuffs such as bromocresol green (BCG), bromothymol blue (BTB) and bromophenol blue (BPB) and these complexes are quantitatively extracted into chloroform. Ion-pair complexes of drug with BCG, BTB and BPB absorbed maximally at 420, 417 and 413 respectively (Fig. 2A, 2B and 2C). The reagent blank under similar conditions showed no absorption.
Carisoprodol molecule has two amide nitrogen atoms on both sides of the chain, one of which is alkylated as N-isopropyl amido group. The protonation takes place preferably on free amido nitrogen since the approach of dye molecule to drug molecule from N-alkylated amido side prevents the protonation to some extent due to steric factors. The sulphonic acid group present in BCG, BTB and BPB, undergoes dissociation in the pH range 1-5. The colour of such dyes is due to the opening of lactoid ring and subsequent formation of quinoid group. It is supposed that the two tautomers are present in equilibrium but due to strong acidic nature of the sulphonic acid group, the quinoid body must predominate. Finally the protonated carisoprodol forms ion-pairs with the dyestuffs which are quantitatively extracted into chloroform. The possible structure of ion-pair complex is proposed and given in Chart 1.
CHART 1: CARISOPRODOL – DYE ION-PAIR COMPLEXStoichiometry: In order to establish molar ratio between carisoprodol and dyestuffs used, the Job’s method of continuous variation32 has been applied. In this method, solutions of drug and dyestuff with identical molar concentrations (8 x 10-5M) were mixed in varying volume ratios in such a way that the total volume of each mixture was the same. The absorbance of each solution was measured and plotted against the mole fraction of the drug, [drug]/ [drug] + [dyestuff] (Fig.4).
This measurement showed that 1:1 complex was formed with each dyestuff. The formation constants33 were also estimated and found to be 1.55x 106, 1.61x 106 and 1.71x 106 K M-1 for complexes with BCG, BTB and BPB respectively.
FIG. 4: CONTINUOUS-VARIATIONS STUDY OF DRUG-DYE SYSTEMS
[Drug] = [Dye] = 8x10-5M
Optimization of the factors affecting the absorbance: The influence of pH on the ion-pair formation of carisoprodol with various dyestuffs has been studied using sodium acetate-hydrochloric acid buffer. The results are shown in Fig.5. It is evident that absorbance of complexes with BCG, BTB and BPB was found to be constant within the pH ranges 3.3-3.8, 2.6-3.0 and 2.3-2.7 respectively. Thus, all the absorbance measurements were made at pH 3.5, 2.8 and 2.5 with BCG, BTB and BPB respectively.
TABLE 4: INTERFERENCE STUDY
Sl. No. | Excipients | Tolerance limit(μg ml-1) |
1 | Microcrystalline cellulose | 98 |
2 | Starch | 145 |
3 | Lactose | 116 |
4 | Povidone | 62 |
5 | Silicon dioxide | 79 |
6 | Titanium dioxide | 53 |
FIG. 5: EFFECT OF pH
[Drug] = [8µg ml-1, [Dye] = 5ml of 0.025%
The effect of dyestuff concentrations was also studied by adding different volumes of dyestuff to a constant amount of carisoprodol (8µg ml-1). It is apparent from Fig.6 that the maximum absorbance, in each case, was found with 3.0ml of dyestuff, beyond which absorbance was constant. Thus, 5ml of each dyestuff was used for ion-pair formation throughout the experiment.
FIG. 6: INFLUENCE OF THE VOLUME OF 0.025% DYE
[Drug] = [8µg ml-1]
A systematic study of the effect of foreign species present along with carisoprodol on the determination of carisoprodol at 8 µg ml-1 levels was undertaken. This study was carried out by following the proposed procedures for a 10 ml sample system, by adding a known amount of foreign species to a carisoprodol solution of 8 µg ml-1. Table 4 summarizes the results obtained. However, the drug content from the powdered capsules was extracted into chloroform, which completely removes any interference by the common excipients found in formulations.
Validation of the proposed method:
All the three proposed methods have been validated in terms of guideline proposed by International Conference on Harmonization34 viz. selectivity, specificity, accuracy, precision, limits of calibration curve, LOD, LOQ, robustness, ruggedness and regression equation. The student t-test and variance F-test have been performed in comparison with a reference method. Table 1 summarizes the values for Beer’s law limits, molar absorptivity, regression equation, correlation coefficients, relative standard deviation and recoveries. To test the reproducibility of the proposed methods, six replicate determinations of 10µg ml-1 of carisoprodol were made. The coefficient of variation was found to be less than 1.2% for all the procedures. The proposed methods have been successfully applied to the determination of carisoprodol in pharmaceutical preparations. The performance order of the proposed methods is BCG > BTB > BPB. The results obtained and shown in Table 2 and Table 3 were compared to those obtained by a reference method 27 by means of t-test at 95% confidence level. In all cases, the average results obtained by proposed methods and reference method were statistically identical, as the difference between the average values had no significance at 95% confidence level.
CONCLUSION: Carisoprodol forms ion-pair complexes with acidic triphenylmethane dyes viz., bromocresol green, bromothymol blue and bromophenol blue in 1:1 proportion. These complexes are extractable into chloroform and offer a basis for assay of the drug. The developed methods are simple, sensitive, and reproducible and can be used for routine analysis of carisoprodol in pure and formulation forms.
ACKNOWLEDGEMENTS: The authors are grateful to Prof. G. Venkateshwarlu, Department of Chemistry, Osmania University, Hyderabad for helpful discussion and to Sri M. Ravindra Reddy, Chairman, Managing Committee & Sri P. Shivaprakash, Principal of SAP College Vikarabad for providing facilities. The authors are thankful to the UGC for financial assistance under Major Research Project.
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How to cite this article:
Ravi M, Veeraiah T and Reddy VR: Spectrophotometric Determination of Carisoprodol in Pure and Pharmaceutical Forms Using Triphenyl Methane Dyes. Int J Pharm Sci Res 2015; 6(7): 2936-43.doi: 10.13040/IJPSR.0975-8232.6(7).2936-43.
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Article Information
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2936-43
515
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English
Ijpsr
M. Ravi , T . Veeraiah * and Ch.Venkata Ramana Reddy
Department of Chemistry, SAP College, Vikarabad, Ranga Reddy Dist. Telangana, India
tadooru_veeraiah@rediffmail.com
21 November, 2014
24 January, 2015
20 March, 2015
10.13040/IJPSR.0975-8232.6(7).2936-43
01 July, 2015