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Vol.4, No.4 (2011), 784-789 ISSN: 0974-1496 CODEN: RJCABP http://www.rasayanjournal.com ASSAY OF ATOMOXETINE HYDROCHLORIDE IN BULK AND ITS SOLID DOSAGE FORMS BY VISIBLE SPECTROPHOTOMETRY USING TWO AROMATIC ALDEHYDES K. Raghubabu*1, L. Santhi Swarup1, B. Kalyana Ramu2, M.Narayanarao3 and C.Ramdas3 1 Department of Engineering Chemistry, AU College of Engineering (A), Andhra University, Visakhapatnam -530003(AP) India 2 Department of Chemistry, Maharajah s College (Aided& Autonomous), Vizianagaram-535002 (AP) India. 3 M/s Tychy Industries, R&D Division, Hyderabad, (AP) India *E-mail: drraghualways@yahoo.co.in ABSTRACT Two simple and sensitive visible spectrophotometric methods (A and B) have been developed for the determination of Atomoxetine hydrochloride in bulk and solid dosage forms. Methods (A and B) are based on the reaction of drug with aromatic aldehydes such as Vanillin or Para dimethyl amino Benzaldehyde (PDAB) in the presence of sulphuric acid in non aqueous medium and formed colored condensation products with an absorption maximum of 560nm for method A and 600nm for method B. The Beer s law obeyed in the concentration range of 1-5 g/ml for method A and 10-50 g/ml for method B. The proposed methods are validated with respect to accuracy, precision, linearity and limit of detection. The suggested procedures are successfully applied to the determination of the drug in pharmaceutical preparation, with high percentage of recovery, good accuracy and precision. The results of analysis have been validated statistically by repeatability and recovery studies. The results are found satisfactory and reproducible. These methods are applied successfully for the estimation of atomoxetine hydrochloride in tablet or capsule form without the interference of excipients. Keywords: ADHD, Beer s Law, Condensation reactions, Determination, PDAB, Vanillin. 2011 RAS YAN. All rights reserved. INTRODUCTION The Atomoxetine hydrochloride (ATH) (Fig.1) is the first non-stimulant choice drug for symptomatic treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor (NRI). It is chemically known as (R)-N-methyl-3-phenyl-3-(o-tolyloxy) propan-1-amine hydrochloride base (1:1) 1- 2. H3C O N CH3 .HCl H Fig.-1: Showing the chemical structure of ATH ASSAY OF ATOMOXETINE HYDROCHLORIDE K. Raghubabu et al. Vol.4, No.4 (2011), 784-789 In the literature, several analytical techniques like HPLC 3-8, LC-MS-MS 9, HPTLC10, Chemiluminescence 11 and UV 12-13 have been reported for its determination in plasma and capsule dosage forms. A survey of literature has not revealed any visible spectrophotometric methods for estimation of ATH in bulk drug and formulations. For routine analysis, simple, rapid and cost effective visible spectrophotometric methods are required and preferred. So the authors have made some attempts in developing visible spectrophotometric methods and succeeded in developing two methods (A&B) using aromatic aldehydes 14-15 such as vanillin (method A) or PDAB (method B) in the presence of sulphuric acid in non aqueous medium and colored condensation products are formed and stable for 30 minutes. The proposed methods for ATH determination have many advantages over other analytical methods due to its rapidity, lower cost and environmental safety. Unlike HPLC, HPTLC procedures, the instrument is simple and is not costly. Economically, all the analytical reagents are inexpensive and available in any analytical laboratory. The proposed methods report a new for the determination of ATH in pharmaceuticals. These methods can be extended for the routine assay of ATH formulations. EXPERIMENTAL A Shimadzu UV-Visible spectrophotometer 1601 with10mm matched quartz cells was used for all spectral measurements. All the chemicals used were of analytical grade. Pure ATH drug was obtained as a gift sample from M/s Tychy Industries, Hyderabad (AP). Axepta-25mg tablets and Attentrol-25mg capsules were purchased from local market. Sulphuric acid (14M), Vanillin (BDH, 0.4%, w/v 2.63x 102 M); PDAB (E. Merck, 0.1% w/v 6.31x 10-3M) in methanol was prepared. Preparation of standard drug stock solution About 100mg of ATH was dissolved in 100ml of methanol to get 1mg/ml stock solution. It was further diluted with the same solvent to get working standard solution (50 g/ml) for method A and (200 g/ml) for method B. Preparation of Sample solution About 20 tablets were pulverized and the powder equivalent to 100mg of ATH was weighed, dispersed in 25ml of IPA, sonicated for 30 minutes and filtered through Whatman filter paper No.41.The filtrate was evaporated to dryness and the residue was dissolved in 100 ml of methanol (1mg/ml). It was used as stock sample solution and was further diluted with the same solvent to get working standard solutions. Fig.-2: Absorption spectra of ATH-VN-H+ ASSAY OF ATOMOXETINE HYDROCHLORIDE Fig.-3: Beer s Law plot of ATH-VN/H+ 785 K. Raghubabu et al. Vol.4, No.4 (2011), 784-789 Assay: Method A Aliquots of standard drug solution in methanol (0.2 - 1.0ml, 50 g/ml) were placed in a series of 10ml calibrated tubes and volume of each test tube adjusted to 3.0ml with methanol. To each of these test tubes 1.0 ml of Vanillin (2.63x 10-2M) and 1.0 ml of concentrated sulphuric acid (14M) were added, while cooling under a tap with constant shaking and kept in water bath at 60 c for 10min. cooled and diluted to the mark with methanol. The absorbance was measured at 560nm (Fig.2 showing absorption spectra) against the reagent blank within 10 minutes. The amount of drug in a sample was computed from Beer s law plot (Fig.3). Method B Aliquots of standard drug solution in methanol (0.5ml - 2.5 ml, 200 g/ml) were placed in a series of 10ml calibrated tubes and volume of each test tube adjusted to 3.0ml with methanol. To each of these test tubes 1.0 ml of PDAB(6.31x 10-3M) and 1.0 ml of concentrated sulphuric acid (14M) were added, while cooling under a tap with constant shaking and kept in water bath at 60 c for 10min. cooled and diluted to the mark with methanol. The absorbance was measured at 600nm (Fig.4 showing absorption spectra) against the reagent blank within 10 minutes. The amount of drug in a sample was computed from Beer s law plot (Fig.5). Fig.-4: Absorption spectra of ATH-PDAB-H+ Fig.-5: Beer s Law plot of ATH-PDAB/H+ RESULTS AND DISCUSSIONS Optimum operating conditions used in the procedure were established by adopting variation of one variable at a time (OVAT) method. The effect of various parameters such as time, volume and strength of reagents and acid solution and solvent for final dilution of the colored species were studied. The optical characteristics such as Beer s law limits, Sandell s sensitivity, molar extinction coefficient, percent ASSAY OF ATOMOXETINE HYDROCHLORIDE 786 K. Raghubabu et al. Vol.4, No.4 (2011), 784-789 relative standard deviation (calculated from the six measurements containing 3/4th of the amount of the upper Beer s law limits) were calculated for all the methods and the results are summarized in table1.Regression characteristics like standard deviation of slope (Sb), standard deviation of intercept (Sa), standard error of estimation (Se),% range of error (0.05 and 0.01 confidence limits) were calculated for both the methods and are shown in Table-1. Table-1: Optical Characteristics , precision and accuracy of proposed methods. Parameter max Beer s law limit( g/ml) Sandell s sensitivity( g/cm2/0.001 abs. unit) Molar absorptivity (Litre/mole/cm) Correlation coefficient Regression equation (Y)* Intercept (a) Slope(b) %RSD % Range of errors(95% Confidence limits) 0.05 significance level 0.01 significance level Method A 560 1-5 Method B 600 10-50 0.007557 0.135747 38617.51 2149.741 0.998 0.998 0.006 0.011 0.129 0.774 0.831 1.275 0.007 0.821 0.862 1.315 *Y = a + b x, where Y is the absorbance and x is the concentration of ATH in g/ml Table-2: Analysis of Atmoxetine Hydrochloride in pharmaceutical formulations by proposed and reference methods. Method *Formulation s Labeled Amount (mg) A Batch-1 25 Batch-2 25 Batch-1 25 Batch-2 25 B Found by Proposed Methods **Amount t F found SD 24.98 0.247 2.405 0.036 25.13 1.84 2.697 0.022 24.83 0.375 1.09 0.05 24.87 0.541 2.167 0.085 Found by Reference Method SD #% Recovery by Proposed Method SD 24.97 0.056 24.98 0.036 24.97 0.056 24.98 0.036 99.92 0.145 100.05 0.088 99.31 0.2004 99.473 0.339 * Different batches from two different companies (Batch-1: Axapta tablets, Batch 2: Attentrol capsules) **Average Standard deviation of six determinations, the t- and F-values refer to comparison of the proposed method with reference method (UV). Theoretical values at 95% confidence limits t =2.57 and F = 5.05. # Recovery of 10mg added to the pre-analyzed sample (average of three determinations). Reference method (reported UV method) using 0.1M HCl ( max=270nm). Commercial formulations containing ATH were successfully analyzed by the proposed methods. The values obtained by the proposed and reference methods for formulations were compared statistically by the t-and F-test and found not to differ significantly. As an additional demonstration of accuracy, recovery experiments were performed by adding a fixed amount of the drug to the pre-analyzed formulations at three different concentration levels. These results are summarized in Table-2.The ingredients usually ASSAY OF ATOMOXETINE HYDROCHLORIDE 787 K. Raghubabu et al. Vol.4, No.4 (2011), 784-789 present in formulations of ATH did not interfere with the proposed analytical methods. Among the four aromatic aldehydes (vanillin, PDAC, PDAB and anisaldehydes) tried, all of them responded. But, Vanillin and PDAB were preferred as they were found to be better sensitivity in the assay of ATH. These methods can be extended for the routine assay of ATH formulations. Chemistry of colored species In proposing the nature of colored species formation with vanillin(method A) or PDAB (method B) to form schiff base as ATH possess aliphatic seconadary amine group. The formation of colored species The formation of colored species with these reagents may be assigned through above analogy as shown in Scheme-1 for methods A and B. CONCLUSIONS The reagents utilized in the proposed method are normal cost and readily available and the procedure does not involve any critical reaction conditions or tedious sample preparation. The proposed analytical methods are validated as per ICH guide lines and possess reasonable precision, accuracy, simple; sensitive and the proposed methods report a new for the determination of ATH in pharmaceuticals. ACKNOWLEDGEMENTS The authors are very much thankful to the m/s Tychy Industries, Hyderabad. Andhra Pradesh (India) for providing gift sample of the drug and also thanks to the University authorities for providing necessary facilities. R R HO C=O H + + N H 2S O 4 CH3 H H HO CH=N + MeO MeO ATH V a n il i o n CH3 R C H-N O C H3 MeO C o lo r e d s p e c i e s R R ( C H 3 )2. N C=O + H H PDAB + N H 2S O 4 C H3 ( C H 3)2. N CH=N + C H3 H ATH H3C R + M e2N O C H-N C H3 R= C o lo re d s p e c ie s Scheme-1 REFERENCES 1. J. Spencer, V. Baranov, the Journal of Clinical Psychiatry, 67(3), 415(2006). 2. S. Prasad, C. Steer. , Pediatric Drugs, 10(1), 39(2008). ASSAY OF ATOMOXETINE HYDROCHLORIDE 788 K. Raghubabu et al. Vol.4, No.4 (2011), 784-789 3. C. Patel, M. Patel, Journal of Chromatography B, 850, 356(2007). 4. S.K. Patel, N.J. Patel, J AOAC Int., 93(4), 1207(2010). 5. S. Sudhir Kamat, Vishal B. Choudhari, Vinayak T. Vele and Swarup S. Prabhune, Chromatographia, 67(1-2), 143(2008). 6. G. Wei G, Li. Webinar, G. Guinin, Zhang. Jun, Journal of Chromatography B, 854 (1-2), 128 (2007). 7. X.Y. Zhang, K.S. Bi, D.Su, Z.B. Liue, L.Y. Jiang, X.H.Chen, Fenxi Ceshi Xuebao , 29(8), 817(2010) 8. F. Peter, A. Bernard, Journal of Pharmaceutical and Biomedical Analysis, 46, 431(2008). 9. H. John, L. Richard, Journal of Pharmaceutical and Biomedical Analysis, 38, 720-733(2005). 10. K. Hemalatha, D. Satyanarayana, Asian Journal of Chemistry, 20(7), 54(2008). 11. H.D.Wang, H.P.Lu, Y.J. Wu, L.B. Qu, Yaowu Fenni Zazhi, 27(3), 348(2007). 12. Paras N. Raveshiya and Hetal R. Prajapati., Journal of Pharmacy Research, 4(6), 1720(2011). 13. S.K. Koradia, P.T. Shah, R.R. Rana, S.S. Vaghani, S. Pandey and N.P. Jivani, Asian J. Research Chem., 2(3), 258(2009) . 14. D. Gowri Sankar, C.S.P. Sastry, M. Narayana Reddy, Indian Drugs, 28(6), 269(1991). 15. F.G. Singleton, C.B. Pollard, J. Am. Chem. Soc., 63(1), 240(1941). 16. United States Pharmacopoeia, in: Validation of compendial methods, 26th ed. Pharmacopoeial convention Inc., Rockville, MD, 2439(2003) 17. ICH, Q2(R1), Harmonized Tripartite Guideline, Validation of Analytical procedures Text and methodology, International conference on Harmonization(ICH), Geneva, (2005). [RJC-848/2011] International Journal of Chemical, Pharmaceutical Chemical, Environmental and Pharmaceutical Research www.ijcepr.com ISSN: 2229-3892(Print); ISSN: 2229-5283(Online) [Abstracted in : Chemical Abstracts Service , American Chemical Society, USA and CAB(I) , UK] ________________________________________________________________________________________________________ ijCEPr widely covers all fields of Chemical, Environmental and Pharmaceutical Research. Manuscript Categories: Full-length paper, Review Articles, Short/Rapid Communications. Manuscripts should be addressed to: E-mail: ijcepr@gmail.com Water: Research & Development [Water R&D] www.waterrnd.com ISSN: 2249-2003 [Abstracted in : Chemical Abstracts Service, USA and CAB(I) , UK] ________________________________________________________________________________________________________ WaterR&D is an international Research Journal, dedicated to Water . It is a truly interdisciplinary journal on water science and technology. It ll showcase the latest research related to Water in the field of chemistry, physics, biology, agricultural, food, pharmaceutical science, and environmental, oceanographic, and atmospheric science. It includes publication of reviews, regular research papers, case studies, communications and short notes. Manuscript Categories: Full-length paper, Review Articles, Short/Rapid Communications. Manuscripts should be addressed to: E-mail: waterrd@gmail.com ASSAY OF ATOMOXETINE HYDROCHLORIDE 789 K. Raghubabu et al.

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