Assay of some non-steroidal anti-inflammatory drugs with ammonium hexanitratocerate (IV) reagent

i n t e r n a t i o n a l j o u r n a l o f c h e m i c a l a n d a n a l y t i c a l s c i e n c e 4 ( 2 0 1 3 ) 1 1 5 e1 1 9

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Original Article

Assay of some non-steroidal anti-inflammatory drugs with ammonium hexanitratocerate (IV) reagent Vinod Kumar, Brijesh Kumar Singh, Ishwar Chandra Shukla* Department of Chemistry, University of Allahabad, Allahabad 211002, India

article info

abstract

Article history:

In the present paper we have reported a simple and convenient titrimetric method for

Received 2 March 2013

determination of non-steroidal anti-inflammatory drugs (NSAIDs) e.g. aceclofenac, diclofe-

Accepted 18 March 2013

nac sodium, ibuprofen, mefenamic acid and nimesulide in pure form and in their pharma-

Available online 9 April 2013

ceutical preparations such as acecloren (Tab), aclofen (Tab), voveran (Tab), diclomax (Inj), brufen (Tab), norswell (Tab), meftal (Tab), mef-T (Tab), nicip-DT (Tab) and dolamide (Tab)

Keywords:

with ammonium hexanitratocerate (AHC) reagent. It is a versatile oxidizing agent of cerium

NSAIDs

(IV) and is being widely used as an oxidant for several classes of organic compounds. During

Pharmaceuticals

estimation it was noted that the excipients present in pharmaceutical preparations do not

Ammonium hexanitratocerate (IV)

interfere. The value of percentage error, coefficient of variation (CV) and standard deviation

Oxidizing agent

(SD) prove the method to be precise and reproducible. To establish authenticity of the

Titration

method, recovery experiments were also carried out by standard drug addition method. Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights reserved.

1.

Introduction

Cerium (IV) compounds have proved to be versatile reagents capable of oxidizing almost every oxidizable functional group.1 Extensive work has lead to the development of a good number of such oxidants like cerium mischmetal,2 cerium ammonium sulphate,3,4 cerium sulphate,5,6 cerium nitrate,7 cerium fluoride,8 cerium chloride,9,10 cerium oxide,11,12 cerium metal,13 cerium carbonate14 and cerium acetate.15 There is no general method reported in Indian Phamacopoeia.16 In Indian Pharmacopoeia aceclofenac, diclofenac sodium, ibuprofen and mefenamic acid are determined by infrared absorption spectrophotometry, while ibuprofen is also determined by thin layer chromatography. There is no any method given for determination of nimesulide in Indian Pharmacopoeia.

Industrial demands have led many workers to search for more ideal oxidants with a number of specifications including: lower cost, higher yields, better selectivity, milder neutral conditions, easier preparations, high solubility, less toxicity and short reaction times. Among the above mentioned reagents, AHC has an edge over others for rendering easy manipulation and sharp end points. Therefore we have selected ammonium hexanitratocerate (AHC) as an oxidizing reagent for our study. NSAIDs are mainly used the treatment of osteoarthritis and rheumatoid arthritis, arthritis of systemic lupus erythematosus, musculoskeletal trauma, minor aches and pains, dysmenorrhoeal, psoriasis and other seronegative spondyloarthropathies. Aceclofenac works on cytokine inhibitor and helps in blocking the action of cyclooxygenase which also involved in the production of prostaglandins, cause pain,

* Corresponding author. Tel.: þ91 (0) 532 2506858. E-mail addresses: [email protected], [email protected] (I.C. Shukla). 0976-1209/$ e see front matter Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcas.2013.03.007

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swelling and inflammation. Diclofenac sodium is one of the most widely prescribed NSAID for its analgesic and antiinflammatory indications and used for the treatment of relieve pain, stiffness and swelling caused by several types of arthritis including osteoarthritis and rheumatoid arthritis. Ibuprofen shaved superior results compared to a placebo in the prophylaxis of Alzheimer disease. It decreases inflammation (swelling) and uterine contractions by a still unknown mechanism. Mefenamic acid is an NSAID used to treat pain including menstrual pain and it decreases inflammation (swelling) and uterine contractions by a still unknown mechanism. Nimesulide is used to treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoeal in adolescents and adult above 12 years old. Because of great medicinal value of these compounds their estimation has widely been studied. Most of the above methods involve sophisticated instruments and complicated techniques. In the present paper we describe a simple and convenient method for the determination of above NSAIDs with ammonium hexanitratocerate (IV) reagent. The method is applicable in all the pharmaceutical laboratories.

2.1.7.

2.

Methods

mg of sample ¼

2.1.

Reagent and solutions

2.1.1.

Ammonium hexanitratocerate solution (0.1 M)

Where, M ¼ molecular weight of sample, N ¼ normality of ferrous ammonium sulphate solution, B ¼ volume of ferrous ammonium sulphate for blank, S ¼ volume of ferrous ammonium sulphate for sample, n ¼ Stoichiometry of the reaction. The determinations were done with varying sample size (i.e. 1e10 mg) but for convenience, results have been shown only with 1, 3 and 5 mg sample size (Table 1). For testing quantitative validity of the recommended method, standard deviation (SD) and coefficient of variation (CV) were also calculated for each sample size. At least nine determinations were carried out and the average results were noted. To justify the validity of the proposed method, recovery experiments were carried out by the standard drug addition method (Tables 2e6). A known amount of the pure compound was taken and to this, varying amounts of the pharmaceutical preparations of the same compounds were added. The total amount of the sample was found by the usual method.

13.70 g of ammonium hexanitratocerate (IV) was weighed accurately and dissolved in 0.5 N nitric acid in a 250 mL volumetric flask.

2.1.2.

Ferrous ammonium sulphate solution (0.025 M)

2.4508 g of ferrous ammonium sulphate was accurately weighed and dissolved in distilled water in the presence of 10 mL of 4 M H2SO4 in a 250 mL volumetric flask.

2.1.3.

Ferroin indicator (0.001 M)

Solution was prepared by diluting 0.025 M ferroin (1, 10-phenanthroline ferrous sulphate complex) solution with distilled water.

2.1.4.

Sulphuric acid solution (4 M)

Solutions were prepared by diluting concentrated sulphuric acid (37 N) with distilled water.

2.1.5.

Injection solution

As described above the contents of the injection equivalent to 100 mg of the pure sample were taken and dissolved as usual to get a concentration of 1 mg/mL.

2.1.8.

Procedure

Aliquots containing 1e5 mg of the samples were taken in 100 mL stoppered conical flask followed by the addition of 5 mL AHC reagent. The reaction mixture was shaken well and allowed to react for required reaction time (10e15 min) at room temperature (25e30  C). After the reaction was over it was quenched by adding 10 mL of 4 M sulphuric acid. The unconsumed Ce (IV) was titrated against 0.025 M ferrous ammonium sulphate solution using two drops of ferroin indicator (0.001 M). A blank experiment was also performed under identical conditions using all the reagents except the sample. The amount of the sample was calculated by the following expression. On the basis of percentage error the value of SD and CV were also calculated (Table 1). In the case of pharmaceutical preparation the same procedure was applied. For each experiment, the amount of the compound was calculated by following expression:

% Recovery ¼

M  N ðB  SÞ n

P P P Nð XYÞ  ð XÞð YÞ  100 P 2 P 2 Nð X Þ  ð XÞ

Sample solution (1 mg/mL)

Accurately weighed (100 mg) pure samples as well as pharmaceutical preparation of aceclofenac, diclofenac sodium, ibuprofen, mefenamic acid and nimesulide were dissolved in min. amount of water in a 100 mL volumetric flask and then made up to the mark with distilled water to give a concentration of 1 mg/mL. While diluting the solution every care was taken to keep the solution homogeneous.

Where, N ¼ SN ¼ total number of observations, X ¼ amount of drug added, Y ¼ Amount of drug obtained by calculation. Standard deviation (SD) was calculated by the expression given below:

2.1.6.

On the basis of the value of SD, the value of coefficient of variation (CV) was calculated by the following expression:

Tablet solution

Twenty tablets of a particular sample were crushed to a fine powder and powder equivalent to 100 mg of sample was taken in 100 mL volumetric flask and dissolved similarly. No residue was noted in any of the samples.

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2  2  2 X1  X þ X2  X               Xn  X SD ¼ ðn  1Þ

CV ¼

SD  100 X

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Table 1 e Determination of some NSAIDs in pure form and in their pharmaceutical preparations with (0.1 M) ammonium hexanitratocerate (IV) reagent. S. no.

Sample

1

Aceclofenac (Pure Sample)

A

Acecloren (Tab) (Indoco Warren)

B

Aclofen (Tab) Ind-Swift Diclofenac sodium (Pure Sample)

2

A

B

3

Voveran (Tab) Novartis Diclomax (Inj) Torrent Ibuprofen (Pure Sample)

A

Brufen (Tab) Abott Pharma

B

Norswell (Tab) Zy. Cadilla Mefenamic acid (Pure Sample)

4

A

Meftal (Tab) Blue Cross

B

Mef-T (Tab) Ind-Swift

5

Nimesulide (Pure Sample)

A

Nicip-DT (Tab) Cipla

B

Dolamide (Tab) Ranbaxy

Aliquots taken (mL)

Amount presenta (mg)

Reaction time (min)

Molecularity

Amount obtained by calculationb (mg)

Error (%)

SD

CV

1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00 1.00 3.00 5.00

0.983 2.949 4.915 0.971 2.913 4.855 0.926 2.778 4.630 0.991 2.973 4.955 0.936 2.808 4.680 0.948 2.844 4.740 0.965 2.895 4.825 0.903 2.709 4.515 0.918 2.754 4.590 0.977 2.931 4.885 0.919 2.757 4.595 0.899 2.697 4.495 0.958 2.874 4.790 0.924 2.772 4.620 0.932 2.796 4.660

10 10 10 10 10 10 10 10 10 5 5 5 5 5 5 5 5 5 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

0.973 2.928 4.894 0.961 2.892 4.831 0.916 2.760 4.609 0.981 2.951 4.932 0.926 2.784 4.651 0.938 2.826 4.722 0.955 2.878 4.811 0.894 2.691 4.496 0.908 2.737 4.573 0.967 2.908 4.858 0.909 2.735 4.573 0.890 2.677 4.472 0.948 2.855 4.768 0.914 2.751 4.596 0.922 2.775 4.636

1.02 0.71 0.43 1.03 0.72 0.49 1.08 0.65 0.45 1.01 0.74 0.46 1.01 0.86 0.62 1.05 0.63 0.38 1.04 0.59 0.29 1.00 0.66 0.42 1.09 0.62 0.37 1.02 0.78 0.55 1.08 0.80 0.48 1.00 0.74 0.51 1.04 0.66 0.46 1.08 0.76 0.52 1.01 0.75 0.52

0.0048 0.0034 0.0035 0.0044 0.0034 0.0026 0.0048 0.0036 0.0029 0.0076 0.0051 0.0035 0.0042 0.0038 0.0026 0.0018 0.0030 0.0028 0.0025 0.0028 0.0023 0.0026 0.0029 0.0031 0.0034 0.0032 0.0025 0.0027 0.0027 0.0031 0.0013 0.0011 0.0015 0.0020 0.0026 0.0032 0.0024 0.0022 0.0030 0.0025 0.0026 0.0031 0.0026 0.0018 0.0030

0.4933 0.1161 0.0715 0.4579 0.1176 0.0538 0.5240 0.1304 0.0629 0.7441 0.1728 0.0710 0.4536 0.1365 0.0559 0.1919 0.1062 0.0593 0.2618 0.0973 0.0478 0.2908 0.1078 0.0690 0.3744 0.1169 0.0547 0.2792 0.0928 0.0638 0.1430 0.0402 0.0328 0.2247 0.0971 0.0716 0.2532 0.0771 0.0629 0.2735 0.0945 0.0674 0.2820 0.0649 0.0688

Tab ¼ tablet, Inj ¼ Injection. a In each sample nine estimations were done. b Average of nine determinations.

Where, X ¼ average value of amount obtained by calculations, X1, X2- - - -Xn ¼ amount obtained by calculations in different observations, n ¼ number of observations.

3.

Results and discussion

It was found that the stoichiometric ratio between AHC reagent and NSAIDs varies. Different stoichiometric ratio is

obtained in different NSAIDs such as Acetazolamide (1:2), Diclofenac Sodium (1:2), Ibuprofen (1:2), Mefenamic Acid (1:4) and Nimesulide (1:4) in pure form and in their pharmaceutical preparations. The ratio remains constant even under varying reaction conditions i.e. change in reaction time, concentration of the reagent, reaction medium, reaction temperature etc. It was observed that all the compounds studied need 15 min to complete the reaction except Aceclofenac and Diclofenac sodium which require only

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Table 2 e Recovery studies of aceclofenac by standard drug addition method. S. no. 1 2 3 4

Number of observations (N )

Amount present (Pure) (mg)

Amount of drug added (mg) X

Total amount of drug obtained by calculation (mg)

Amount of drug obtained by calculation (mg) Y

XY

X2

Recovery (%)

3 3 3 3 P N ¼ 12

0.983 0.983 0.983 0.983

0.984 1.978 2.981 3.982 P X ¼ 9.925

1.965 2.972 3.980 4.979

0.975 1.980 2.963 3.960 P Y ¼ 9.878

0.959 3.916 8.833 15.769 P XY ¼ 29.477

0.968 3.912 8.886 15.856 P 2 X ¼ 29.662

99.50

Table 3 e Recovery studies of diclofenac sodium by standard drug addition method. S. no. 1 2 3 4

Number of observations (N )

Amount present (Pure) (mg)

Amount of drug added (mg) X

Total amount of drug obtained by calculation (mg)

Amount of drug obtained by calculation (mg) Y

XY

X2

Recovery (%)

3 3 3 3 P N ¼ 12

0.911 0.911 0.911 0.911

0.986 1.970 2.975 3.983 P X ¼ 9.914

1.986 2.979 3.977 4.980

0.991 1.969 2.965 3.977 P Y ¼ 9.902

0.977 3.879 8.821 15.840 P XY ¼ 29.517

0.972 3.881 8.851 15.864 P 2 X ¼ 29.568

99.81

Table 4 e Recovery studies of ibuprofen by standard drug addition method. S. no. 1 2 3 4

Number of observations (N )

Amount present (Pure) (mg)

Amount of drug added (mg) X

Total amount of drug obtained by calculation (mg)

Amount of drug obtained by calculation (mg) Y

XY

X2

Recovery (%)

3 3 3 3 P N ¼ 12

0.965 0.965 0.965 0.965

0.985 1.972 2.960 3.985 P X ¼ 9.902

1.980 2.969 3.973 4.982

0.990 1.967 2.974 3.973 P Y ¼ 9.904

0.975 3.879 8.803 15.832 P XY ¼ 29.489

0.970 3.889 8.762 15.880 P 2 X ¼ 29.501

99.94

Table 5 e Recovery studies of mefenamic acid by standard drug addition method. S. no. 1 2 3 4

Number of observations (N )

Amount present (Pure) (mg)

Amount of drug added (mg) X

Total amount of drug obtained by calculation (mg)

Amount of drug obtained by calculation (mg) Y

XY

X2

Recovery (%)

3 3 3 3 P N ¼ 12

0.977 0.977 0.977 0.977

0.960 1.915 2.880 3.838 P X ¼ 9.593

1.972 2.969 3.978 4.983

0.958 1.908 2.855 3.813 P Y ¼ 9.532

0.918 3.654 8.222 14.634 P XY ¼ 27.428

0.922 3.667 8.294 14.730 P 2 X ¼ 27.613

99.32

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Table 6 e Recovery studies of nimesulide by standard drug addition method. S. no. 1 2 3 4

Number of observations (N )

Amount present (Pure) (mg)

Amount of drug added (mg) X

Total amount of drug obtained by calculation (mg)

Amount of drug obtained by calculation (mg) Y

XY

X2

Recovery (%)

3 3 3 3 P N ¼ 12

0.958 0.958 0.958 0.958

0.958 1.913 2.865 3.820 P X ¼ 9.556

1.982 2.980 3.971 4.960

0.944 1.892 2.840 3.795 P Y ¼ 9.471

0.904 3.619 8.137 14.497 P XY ¼ 27.157

0.918 3.660 8.208 14.592 P 2 X ¼ 27.378

99.22

5 min. By the allowing more reaction time (more than 10e15 min) there is no improvement in the results. A lesser reaction time (less than 5 min) than the described limit gives higher percentage of error because of incomplete reaction. The effect of concentration of ammonium hexanitratocerate reagent (0.01e0.16 M) was also studied and it was found that the recommended concentration (0.10 M) was suitable for accurate and concordant results. Effect of variation in reaction temperature was studied. The reactivity of the sample is very slow at ice cold temperature but increases with the rise in temperature up to room temperature (25e30  C). Beyond this temperature, no improvement over the results has been noticed. On the basis of available literature and stoichiometry, a possible course of reaction may also be suggested. Since the isolation and identification of final reaction product was not possible, it is assumed that the NSAIDs were oxidized to their corresponding oxidized products.

4.

Interferences

Excipients like starch, calcium carbonate, sodium carbonate, cellulose, magnesium trisilicate, tricalcium phosphate and gum acacia if present in the pharmaceutical preparations do of tablets and other excipients in injection not interfere in the estimation.

Conflicts of interest All authors have none to declare.

Acknowledgements The authors are greatly thankful to Acto Pharmaceutical Laboratories Hyderabad and Blue Cross Laboratory Limited Mumbai, India for providing reference substance of NSAIDs as gift. The authors Vinod Kumar and Brijesh K. Singh are also thankful to University Grant Commission, New Delhi, India for providing financial assistance in the form of research fellowship.

references

1. Hwu JR, King KY. Versatile reagent ceric ammonium nitrate in modern chemical synthesis. Curr Sci. 2001;81:1043e1053. 2. Lannou MI, Helion F, Namy JL. Some uses of mischmetall in organic synthesis. Marie-Isabelle Lannou and Florence Helion. Tetrahedron. 2003;59:10551e10565. 3. Basavaiah K, Ramakrishna V, Kumar URA. Use of ceric ammonium sulphate and two dyes, methyl orange and indigo carmine, in the determination of lansoprazole in pharmaceuticals. Acta Pharmaceutica. 2007;57:211e220. 4. Sumathi T, Sundaram PS, Chandramohan G. A kinetic and mechanistic study on the silver (I)-catalyzed oxidation of Lalanine by cerium (IV) in sulfuric acid medium. Arabian J Chem. 2011;4:427e435. 5. Haiping L, Ning L, Sifu B. Effect of cerium sulfate on acidic electroless nickel deposition. J Rare Earths. 2006;24:180e184. 6. Song JY, Chung SH, Kim MS, et al. The catalytic decomposition of CF4 over Ce/Al2O modified by a cerium sulfate precursor. J Mol Catal A: Chem. 2013;370:50e55. 7. Khokra SL, Arora K, Mehta H, Aggarwal A, Yadav M. Common methods to synthesize benzothiazole derivatives and their medicinal significance: a review. Int J Pharm Sci Res. 2011;2:1356e1377. 8. Dorai AK, Selvasekarapandian S, Hellar N, Ayyasamy S, Muthusamy H. Electrical properties of cerium fluoride thin films. Ionics. 2010;16:481e486. 9. Wegehaupt FJ, Sener B, Attin T, Schmidline PR. Application of cerium chloride to improve the acid resistance of dentine. Achieves Oral Biol. 2010;55:441e446. 10. Conlon DA, Kumke D, Moeder C, Hardiman M, Hutson G, Sailer L. Insights into the cerium chloride-catalyzed Grignard addition to esters. Adv Syn Catal. 2004;346:1307e1315. 11. Shih CJ, Chen YJ, Hon MH. Synthesis and crystal kinetics of cerium oxide nanocrystallites prepared by co-precipitation process. Mat Chem Phy. 2010;121:99e102. 12. Heckert EG, Karakoti AS, Seal S, Self WT. The role of cerium redox state in the SOD mimetic activity of nanoceria. Biomaterials. 2008;29:2705e2709. 13. Rodrigues SMM, Nardini V, Constantino MG, Silva GVJD. Cerium metal- mediated Reformatsky-type reaction with ethyl bromosuccinate for the synthesis of novel paraconic acid analogs. Tetrahedron Lett. 2012;53:6136e6137. 14. Wu M, Zhang Q, Liu Y, Fang Q, Liu X. Hydrothermal preparation of fractal dendrites: cerium carbonate hydroxide and cerium oxide. Mat Res Bulletin. 2009;44:1437e1440. 15. Arii T, Taguchi T, Kishi A, Ogawa M, Sawada Y. Thermal decomposition of cerium (III) acetate studied with samplecontrolled thermogravimetricemass spectrometry (SCTGdMS). J Eur Ceramic Soc. 2002;22:2283e2289. 16. Indian Pharmacopoeia. New Delhi: Controller of Publication, Govt. of India, Ministry of Health and Family Welfare; 2008.