Isolation, Synthesis and Characterization of Rosiglitazone Maleate Impurities

Transcription

1 I: ; CDE ECJA E- Chemistry Vol. 5, o.3, pp , July 2008 Isolation, ynthesis and Characterization of Rosiglitazone Maleate Impurities IGAMETTY RADA KRIA, MADAVA VEKATA AGA BRAMEWAR RA, TIRMALARAJU ATYAARYAA RAJU, VURIMIDI IMABIDU # and GATA MAE REDDY * Research and Development, Dr. Reddy s Laboratories Ltd., Integrated Product and Development, Unit-III, Plot o. 116, V Co-p. Ind. Estate, Bollaram, Jinnaram, Medak Dist ; A P, India # Institute of ciences and Technology, Center for Environmental ciences, J..T. University, Kukatpally, yderabad , India Dr. Reddy s communication o. DRL-IPD-IPM reddyghanta@yahoo.com Received15 ovember 2007; Accepted 2 January 2008 Abstract: Three unknown impurities in rosiglitazone maleate 1 bulk drug at level below 0.1% (ranging from 0.05 to 0.1%) were detected by simple reverse phase high performance liquid chromatography. These impurities were preliminarily identified with LC-M and characterized by the mass number of the impurities. Different experiments were conducted and finally synthesized and characterized the unknown impurities. Keywords: Rosiglitazone, Drug, Impurities, ynthesis, PLC and LC-M Introduction Rosiglitazone maleate 1, is an anti diabetic drug, which is a choice of non insulin dependent diabetes mellitus (IDDM) 1-5, during the process development of rosiglitazone maleate 1, three unknown impurities were identified in the analysis of different batches whose percentage area ranged from 0.05 to 0.1% by PLC. A comprehensive study has been carried out to isolate or to prepare and characterize those impurities, due to the importance of the stringent requirement of regulatory authorities and all the impurities should be at the levels of >0.1% must identified and characterized. The present paper aims to isolate or prepare impurities and characterization. Experimental amples The investigated samples of Rosiglitazone maleate bulk drug material were prepared in Dr. Reddy s Laboratories Ltd., Active Pharmaceutical Ingredient, yderabad, India.

2 Isolation, ynthesis of Rosiglitazone Maleate Impurities 563 igh performance liquid chromatography (PLC) An in-house LC isocratic method was developed for the analysis of rosiglitazone maleate and its impurities, where a column (Inertsil D 3V, 250 x 4.6 mm, 5 µ) with a mobile phase consisting of buffer (4.14 g of sodium dihydrogen phosphate in 1000 ml of water, adjusted the p to 6.2 with diluted sodium hydroxide), and acetonitrile in the ratio of 50:50 (v/v) with a flow rate of 1.0 ml/min, UV detection at 245 nm was used. This LC method was able to detect all these impurities. Liquid chromatography-mass spectrometry (LC-M) LC-M/M compatible method was developed for the analysis of Rosiglitazone maleate and its impurities, where a column (Inertsil D 3V 250 X 4.6 X 5.0 µ) with a mobile phase consisting of 0.01M ammonium acetate (p=6.0) adjusted with dilute acetic acid and acetonitrile in the ratio of 65:35, with a flow rate of 1.0 ml/min, UV detection at 280 nm was used. This LC method was able to detect all the impurities. The mass spectrum of impurities was recorded on AB-4000 Q-trap LC-M/M mass spectrometer. Mass spectrometry The electro spray ionization and M-M studies were performed on AB-4000 LC-M/M mass spectrometer. The positive and negative electro spray M data was obtained by switching the capillary voltage between n+5000 and -4500V respectively. MR spectroscopy The 1 MR experiments of rosiglitazone maleate were done at 400 Mz and 100 Mz on Varian Mercury plus 400 Mz FT MR pectrometer and similar experiments for impurities 1, 2 and 3 were performed on Gemini-2000 (200 Mz) in DM-d 6. The 1 chemical shift values were reported on the δ scale in ppm relative to TM (δ=0.00ppm) and the chemical shift values were reported relative to CDCl 3 (δ=77.00ppm) and DM-d 6 (δ=39.50ppm) as internal standards respectively. DEPT spectra revealed the presence of methyl and methane groups as positive peaks and methylenes as negative peaks. FT IR spectroscopy The IR spectra were recorded in the solid state as KBr dispersion medium using Perkin Elmer pectrum ne FT IR spectrophotometer. ynthesis of impurities ynthesis of impurity 1 (desmethyl impurity) To a mixture of 2-chloropyridine, (2, 40.0 g, mol) and 2-aminoethanol (3, 48.2 g, mol) heated to C and maintained for h, the reaction was monitored by TLC, after completion of the reaction, cool to C, added saturated sodium chloride solution (~ 98 ml), and extracted with toluene (4 x 50 ml), the combined organic layer was distilled, yielded 14 g of crude 4, proceeded to next step with out further purification. The crude compound 4 (10 g), potassium tert- butoxide (29.5 g), and DMF (30 ml) were stirred for 10 h at C temperature, after completion of the reaction (monitored by TLC) water (500 ml) was added and stirred for 2-4 h, the obtained solid was filtered and washed with water suck dry for h, the wet material was taken into the RBF, added thiazolidine-2,4- dione (6, 5.5 g, mol), benzoic acid (0.6 g), piperdine (0.5 g), toluene (82.0 ml) were heated to azotropically reflux for 4-8 h, cool to C filtered the solid and washed with toluene, obtained compound 7, dried at C, yield 7.0 g.

3 564 G. MAE REDDY et al. The above compound 7(6.0 g), acetic acid and water mixture 100 ml (8:2) and wet palladium carbon (10 g) under hydrogen pressure 2.0 kg/cm in hydrogenation rector for 12 h, the reaction mass was filtered through hyflow, washed with acetic acid and p was adjust to 6-7 with caustic lye, followed by extracted with dichloromethane (60 ml), the organic layer was distilled completely and product was isolated in isopropyl alcohol, yield 2.5 g, mass m/z 344, IR (KBr): 3333,1698, 1 MR: 12.0(1), (1), (1), (2), (2), (1), (2), (2), (3), (1). ynthesis of impurity 1 (dimer impurity) To a solution of 5-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-benzylidene}-thiazolidine- 2,4-dione (8, 300 g, mol) in TF (1010 ml), cool the reaction mass to -5 to 0 C and slowly added L-slectride (186 ml) using dropping funnel at -5 to 0 C the reaction maintained for 40 minutes, then reaction was further cooled -10 C and added 10% aqueous sodium hydroxide (338 ml) solution, followed by 27% hydrogen peroxide solution (84 ml) was added. The solvent was distilled below 0 C and p was adjusted to 7 with 2M Cl solution (370 ml), the reaction mass was extracted with dichloromethane (3 x 150 ml), the separated organic layer was distilled completely, the crude was purified by column chromatography using dichloromethane and methanol as eluents, yield 4.0 g with 98% purity by PLC, mass m/z 712, IR (KBr): 3434, 2927, 1753, 1702; 1 MR: 7.94(1), 7.9(1), 7.37(1), (4), (2), (4), (2). ynthesis of impurity 2 (succinate impurity) A mixture of Rosiglitazone maleate (1, 10 g) and water (2 ml) were heated to C for 120 h with out stirring, the reaction mass cooled to C scratched 8.4 grams. Take this material and methanol (160 ml) heat to C, stirred for minutes and cool to C, filter the solid and dried at C, yield 3.9 g with 99% purity by PLC, M : m/z 473, IR(KBr): 3547, 3422 and 1755,1715; 1 MR: 4.97(dd,1), 3.05(dd,1), 3.38(m,1), 7.15(d,1), 6.86(d,1), 4.11(t,2), 3.89(t,2), 3.06(s,3), 8.07(d,1), 6.56(t,1), 7.50 (t,1) 6.65(d,1), 5.07(t,1), 2.65(d,1), 3.02(m,1). Figure 1. Blend chromatogram of rosiglitazone and its impurities Table 1. IR and mass spectral data of impurities 1, 2 & 3..o. compound IR cm -1 M 1 Impurity (), 2927() 1753(C=), 1702 (C=) protonated molecular ion +ve E m/z = Impurity (), 3422() protonated molecular ion 1755(C=), 1715 (C=) 3 Impurity (), 1698() 1753(C=), 1702 (C=) +ve E m/z = 473 protonated molecular ion +ve E m/z = 344

4 Isolation, ynthesis of Rosiglitazone Maleate Impurities 565 Table 2. 1 MR spectral date of impurities 1,2&3.o. Impurity 1 Impurity 2 Impurity 3 ppm ppm ppm Results and Discussion In our approach based on the mass information from LC-M we have proposed structures and synthetic schemes (1-3) for the impurities. We have also designed different experiment and synthesized these compounds and characterized. The isolated compounds RRT s are matching with of unknown impurities. The same impurities were enriched from the filtrates of the isolated compounds, by keeping compound stability at variable temperatures. ynthesis of rosiglitazone impurities Toluene F C + 2 Cl DMF/ t BuK C Pd/C, Ac Impurity 1 (Desmethyl Rosiglitazone) cheme 1 L-slectride C 3 C3 8 cheme 2 Impurity 2 (Dimer impurity) 6 7 3C

5 566 G. MAE REDDY et al. C 3 Rosiglitazone Maleate (1). C C water C 3 Impurity 3 (succinate impurity) C C cheme 3 Conclusion The results from various physio-chemical techniques confirm the structures of three impurities of Rosiglitazone maleate 1. Based on the through analytical and the sequence of preparations, the structures of three impurities were established with well characterization. Acknowledgement We thank the management of Dr. Reddy s laboratories Ltd. for supporting this work. Cooperation extended by all college of Analytical Research and Development division is gratefully acknowledged. References 1. Barrie C C C, Michael A C, Grahem P C, Peter T D, David, Richard M., Carolyn A L, tephen A and Peter L, J. Med. Chem. 1994, 37, DeFronzo R A, Ferrannini E and Koivisto V, Am. J. Med 1983, 17, 74(1A) Meguro K and Fujita T, U , 1987; Chem. Abstr. 1986,105: Momose Y, Meguro K, Ikeda, atanaka C, i and ohda T, Chem. Pharm Bull. 1991, 39(6), Barrie C C C, Drake E, David, Curtis R, Catherine M, Richard M, Keith R J, John T and tefan R W, J. Chem. oc., Perkin Trans-1, 1994, 3319.

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