Identification and Characterization of Potential Impurities of

Dec 23, 2013 - (9) This drug is currently being marked under the brand name of MULTAQ. The study toward the identification, synthesis, and ..... All t...
4 downloads 10 Views 446KB Size
Download PDF
Communication pubs.acs.org/OPRD

Identification and Characterization of Potential Impurities of Dronedarone Hydrochloride M. Mahender,†,‡ M. Saravanan,† Ch. Sridhar,† E. R. R. Chandrashekar,† L. Jaydeep Kumar,† A. Jayashree,‡ and Rakeshwar Bandichhor†,* †

Research and Development, Dr. Reddy’s Laboratories Ltd., Baachupalli, Hyderabad 500072, Andhra Pradesh, India Centre for Chemical Sciences & Technology, IST, Jawaharlal Nehru Technological University, Hyderabad 500085, Andhra Pradesh, India

‡

S Supporting Information *

best of our knowledge, and this impurity profiling study will be of immense importance for process development chemists to understand the source of potential impurities during the synthesis of 1 (Scheme 1). During the analysis of different laboratory batches of Dronedarone, six unknown impurities with area percentages ranging from 0.02% to 0.15% were detected by a simple gradient HPLC method (Figure 1). To commercialize an active pharmaceutical ingredient (API), it is mandatory for the manufacturer to identify and characterize all the unknown impurities that are present in API at a level of even below 0.05%.10 In this context, a comprehensive study has been undertaken to identify, synthesize (Figure 2), and characterize all the six impurities present in the laboratory batches of Dronedarone hydrochloride using spectroscopic and spectrometric techniques.

ABSTRACT: Six potential process related impurities were detected during the impurity profile study of an antiarrhythmic drug substance, Dronedarone (1). Simple high performance liquid chromatography and liquid chromatography−mass spectrometry methods were used for the detection of these process impurities. Based on the synthesis and spectral data (MS, IR, 1H NMR, 13C NMR, and DEPT), the structures of these impurities were characterized as 5-amino-3-[4-(3-di-nbutylaminopropoxy)benzoyl]-2-n-butylbenzofuran (impurity I); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide (impurity II); N-(2-butyl-3-(4-(3(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-1-chloromethanesulfonamide (impurity III); N-{2-propyl-3-[4-(3dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide (impurity IV); N-(2-butyl-3-(4-(3(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)formamide (impurity V); and (2-butyl-5-((3(dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3(dibutylamino)propoxy)phenyl)methanone (impurity VI). The synthesis and characterization of these impurities are discussed in detail.

■

■

RESULTS AND DISCUSSION A typical HPLC chromatogram of a laboratory batch of Dronedarone (Figure 1) was recorded as described in the Experimental Section, and the target impurities under study were marked as impurity I (retention time (RT): 5.408 min), impurity II (RT: 33.738 min), impurity III (RT: 34.657 min), impurity IV (RT: 20.553 min), impurity V (RT: 22.157 min), and impurity VI (RT: 13.159 min). The LC-MS compatible method described in the Experimental Section was used to detect all the impurities, and the structures are shown in Table 1 of the Supporting Information. The spectroscopic data of impurities I−IV were compared with those of Dronedarone. In addition to this, spectral data of impurities V and VI were compared with those of impurity I for better visualization of all the impurities at a glance.

INTRODUCTION

Antiarrhythmic agents1−3 are drug substances that are used to suppress abnormal rhythms of the heart, such as atrial fibrillation (AF), atrial flutter (AF), ventricular tachycardia (VT), and ventricular fibrillation (VF). To date, numerous drug candidates are available worldwide to treat arrhythmia disease. Among the antiarrhythmic drugs in current use, Dronedarone hydrochloride,4−8 a novel benzofuran derivative, is most effective due to its multiple pharmacological actions on cardiac ion channels. Dronedarone hydrochloride, chemically known as N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran5-yl}methanesulfonamide hydrochloride, has been developed by Sanofi-Aventis to overcome the iodine-associated adverse effects of the commonly used antiarrhythmic drug Amiodarone.9 This drug is currently being marked under the brand name of MULTAQ. The study toward the identification, synthesis, and characterization of impurities in Dronedarone hydrochloride was not reported in the literature to date, to the © 2013 American Chemical Society

■

FORMATION AND CONTROL OF IMPURITIES Impurity I. Impurity I (8) is the starting material for the synthesis of 9, during the course of the reaction, 8 is subjected to oxalate salt hydrolysis followed by mesylation of the resulting free base compound with methanesulfonyl chloride to afford crude 9. Aqueous workup followed by isolation of 9 from hexanes facilitated the complete removal of impurity I, as it has more solubility in hexanes. Received: May 19, 2013 Published: December 23, 2013 157

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162

Organic Process Research & Development

Communication

Scheme 1. Synthesis of Dronedarone Hydrochloride

Impurity II. During the mesylation of 8, the choice of base and selection of suitable temperature are crucial to control the formation of impurity II. The usage of organic bases in the presence of dichloromethane as selected solvent led to the formation of >10% of impurity II and its formation varying depending upon the basicity of the reaction mixture. However, the formation of impurity II was controlled to less than 0.3% during the reaction using sodium bicarbonate as a base and it is washed off to an extent less than 0.01% during the isolation of Dronedarone (9) from hexanes. Impurity III. Chloromethanesulfonyl chloride is one of the potential impurities in methanesulfonyl chloride. During the mesylation of 8, the presence of chloromethanesulfonyl chloride participates in the mesylation reaction and leads to the formation of impurity III. As it has no solubility in hexanes, the downstream isolation process is unsuccessful to eliminate this impurity. Being the removal of impurity III from 9 is highly challenging, we controlled the chloromethanesulfonyl chloride impurity in methanesulfonyl chloride with a limit of not more than 0.05%. Impurity IV. Starting material 2 is known to contain a small amount of 2-n-propyl-5-nitrobenzofuran as an impurity. This compound follows the same sequence as described for the API synthesis (Scheme 1) and leads to the formation of impurity IV in 9. Impurity IV is an analogue of 9, and hence, the downstream process is unsuccessful to eliminate this impurity, as it has similar structural properties. As we had learned that the removal of impurity IV from 9 is difficult, we controlled the potential impurity of 5-nitro-2-propylbenzofuran in 2 with a limit of not more than 0.1%. Impurity V. Impurity V is formed as a result of competitive reaction of amine 8 with ammonium formate during the catalytic hydrogenation of nitro derivative 7. As ammonium formate assisted hydrogenation is a simple and mild (no over reduced products) and allowed us to perform the reaction without hydrogen gas pressure conditions, we opted to use the catalytic transfer hydrogenation rather than conventional

hydrogenation. Impurity V is a thermodynamically controlled impurity, and its rate of formation is increasing exponentially with the function of increase in temperature. By conducting the reduction reaction below 55 °C, we controlled the impurity V to a negligible level in the reaction, and furthermore, it washed off completely during the oxalate salt formation. Impurity VI. During the catalytic hydrogenation of nitro derivative 7, the presence of chloro compound 6 as an impurity in 7 reacted with the resulted amine product 8 to afford impurity VI. Like impurity V, the formation of impurity VI is controlled less than 0.2% by conducting the reaction below 55 °C. In addition to the aforementioned impurities (impurities I to VI), all the other intermediates (4, 5, and 7) were controlled to a not detected level in Dronedarone. Structure Elucidation of Dronedarone and Its Impurities. The ESI mass spectrum of Dronedarone exhibited a protonated molecule peak at m/z 557.3 (M + H)+ in positive ion mode, indicating the molecular mass of this impurity to be 556.3, which corresponds to the molecular formula C13H44N2O5S. The IR spectrum displayed characteristic absorptions at 3184 cm−1 (sulfonamide NH), 2956 cm−1 (aromatic C−H), 1626 cm−1 (CO), and 1329 and 1144 cm−1 (SO2). The presence of a quaternary carbon signal at δ 190.4 ppm in the 13C NMR spectrum is evident for the presence of the CO group. The DEPT spectrum displayed twelve negative signals due to twelve methylene groups, and eleven positive signals due to four methyl groups and seven methine groups, and the remaining eight signals correspond to eight quaternary carbons. The 1H NMR spectrum displayed aromatic proton signals at δ [7.79 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.26 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H)] and the rest of the aliphatic signals at δ [4.10 (t, J = 6.0 Hz, 2H), 2.92 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 7.2 Hz, 4H), 1.95 (m, 2H), 1.72 (m, 2H), 1.4−1.2 (m, 10H), 0.89 (t, J = 7.2 Hz, 9H)]. Based on the above spectral data, the molecular formula of Dronedarone was confirmed as 158

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162

Organic Process Research & Development

Communication

Figure 1. (a) HPLC chromatogram of the Dronedarone laboratory sample. (b) HPLC chromatogram of the Dronedarone laboratory sample spiked with six impurities.

at m/z 635.3 (M + H)+, indicating the molecular mass of this impurity to be 634.3, which is 78 amu more than that of Dronedarone. In the IR spectrum, the characteristic absorption peak at 3184 cm−1 assigned to the sulfonamide NH function of Dronedarone disappeared, which indicates that the NH function could be further mesylated, and it had been confirmed by the 1H NMR spectrum, which displayed a singlet signal at δ 3.37 ppm with six proton integration. These observations are further supported by the appearance of two methyl carbon signals at δ 41.6 ppm in the 13C and DEPT (positive signal) spectrum. Based on the above spectral data, the molecular formula of impurity II could be deduced as C32H46N2O7S2, and the corresponding structure was characterized as N-(2-butyl-3(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N(methylsulfonyl)methanesulfonamide. Structure Elucidation of Impurity III. The positive ESIMS spectrum of impurity III exhibited a protonated molecule peak at m/z 591.3 (M + H)+ with chlorine abundance indicating the molecular mass of this impurity to be 590.3, which is 34 amu more than that of Dronedarone. The isotopic abundance with a 3:1 ratio is characteristic of the presence of a single chlorine atom in impurity III. The IR spectrum displayed characteristic SO2 (1348 and 1154 cm−1) and CO (1623 cm−1) absorptions. In 1H NMR spectrum, a singlet signal

C13H44N2O5S and the corresponding structure was characterized as N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide.4 Structure Elucidation of Impurity I. The ESI-MS spectrum of impurity I showed a protonated molecule peak at m/z 479.3 (M + H)+, indicating the molecular mass of this impurity to be 478.3, which is 78 amu less than that of Dronedarone (M − SO2Me). The IR spectrum was devoid of SO2 functional absorption and displayed the characteristic primary amine absorptions at 3453 and 3365 cm−1, besides the CO absorption at 1637 cm−1. In the 1H NMR spectrum of this impurity, the broad singlet signal appearing at δ 3.57 ppm with two proton integration is evidence for the presence of aromatic primary amine protons, whereas while a singlet signal at δ 2.92 ppm corresponding to the methyl proton of the sulfonamide function assigned to Dronedarone was absent, it was further confirmed by the 13C and DEPT spectra, which displayed a shortage of methyl carbon signals (positive signal) at δ 38.9 ppm. Based on the above spectral data, the molecular formula of impurity I was confirmed as C30H42N2O5 and the corresponding structure was characterized as 5-amino-3-[4-(3di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran. Structure Elucidation of Impurity II. The ESI-MS spectrum of impurity II displayed a protonated molecule peak 159

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162

Organic Process Research & Development

Communication

Figure 2. Synthesis of impurities II, III, IV, V, and VI.

appeared at δ 2.92 ppm with three proton integration corresponding to the methyl proton of the methane sulfonamide function in Dronedarone being shifted downfield, which appeared at δ 4.40 ppm with two proton integration. These observations suggested that impurity III contains a chloromethane sulfonamide function and its mass is matched well with the protonated mass observed in the mass spectrum. This was further substantiated by the DEPT spectrum, which displayed a methylene carbon signal (negative signal) at δ 68.4 ppm instead of a methyl carbon signal (positive signal) at δ 38.9 ppm. Based on the above spectral data, the molecular formula of impurity III could be deduced as C31H43ClN2O5S and the corresponding structure was characterized as N-(2butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5yl)-1-chloromethanesulfonamide. Structure Elucidation of Impurity IV. The positive ESIMS spectrum of impurity IV exhibited a protonated molecule peak at m/z 543.3 (M + H)+, indicating the molecular mass of this impurity to be 542.3, which is 14 amu less than that of Dronedarone. The IR spectrum showed typical SO2 (1337 and 1156 cm−1), CO (1638 cm−1), and NH (3258 cm−1) function absorptions. The 1H NMR spectrum of this impurity displayed a shortage of two proton signals at δ 1.3−1.2 ppm, and the rest of the signals appeared with the same chemical shift and with the same number of protons as Dronedarone.

Based on this observation and synthetic methodology, it was confirmed that the second position of the benzofuran ring moiety attached with an n-propyl group instead of an n-butyl group. These predictions are further supported by the shortage of one methylene carbon signal at δ 30.0 ppm in the 13C and DEPT (negative signal) spectrum. Based on the above spectral data, the molecular formula of impurity IV could be deduced as C30H42N2O5S and the corresponding structure was characterized as N-{2-propyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide. Structure Elucidation of Impurity V. The ESI-MS spectrum of impurity V exhibited a protonated molecule peak at m/z 507.4 (M + H)+ in positive ion mode, indicating the molecular mass of this impurity to be 506.4, which is 28 amu more than that of impurity I. The IR spectrum displayed characteristic amide CO absorption at 1691 cm−1 and keto CO absorption at 1636 cm−1. This was further supported by the 13C NMR spectrum which displayed quaternary carbon signals at δ 190.2 and 159.3 ppm characteristic of amide and keto carbons, respectively. These spectral data revealed that the amine function of impurity I could be formylated. Based on the synthetic methodology and the above spectral data, the molecular formula of impurity V could be deduced as C31H42N2O4 and the corresponding structure was characterized 160

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162

Organic Process Research & Development

Communication

(ppm) relative to TMS as internal standard. 13C and DEPT spectra were recorded on Varian Mercury plus 200 MHz FTNMR using CDCl3 as a solvent; the chemical shifts are reported in δ (ppm) relative to CDCl3 as internal standard. FT-IR Spectroscopy. The IR spectra were recorded in the solid state as KBr powder dispersions using a Spectrum-One FT-IR spectrometer (PerkinElmer, Boston, MA, USA). Synthesis of Impurities. Synthesis of Impurity I. Impurity I is the intermediate of Dronedarone, and it was prepared as per the synthesis shown in Scheme 1. The presence of this impurity was confirmed by coinjection with Dronedarone in the HPLC. Synthesis of Impurity II. To a stirred solution of impurity I (6.0 g, 0.012 mol) and chloroform (60 mL) was added triethylamine (10.2 mL, 0.10 mol), and the resulting reaction mixture was heated to 55 °C. Methanesulfonyl chloride (1.8 mL, 0.03 mol) was added at 55 °C, and the reaction mixture was stirred for 1.5 h. The reaction mixture was allowed to cool to 25−35 °C, followed by quenching with saturated aqueous sodium bicarbonate solution (48 mL). The layers were separated, followed by concentrating the organic layer to dryness in vacuo. The residual product thus obtained was purified through column chromatography using ethyl acetate and hexanes (1:4, v/v) as eluent to afford impurity II with 98.7% purity and 80% yield. Synthesis of Impurity III. To a stirred solution of impurity I (10.0 g, 0.015 mol) and dichloromethane (70 mL) was added sodium bicarbonate (2.55 mL, 0.03 mol), and the resulting reaction mixture was heated to 37 °C. Chloromethanesulfonyl chloride (1.6 mL, 0.03 mol) was added at 37 °C and stirred for 4 h. The reaction mixture was allowed to cool to 25−35 °C and then quenched with saturated aqueous sodium bicarbonate solution (60 mL). The layers were separated, and the organic layer thus obtained was concentrated to dryness in vacuo. To the resulting residual product was added hexane (100 mL), and the resulting mixture was stirred at 25 °C for 8−10 h. The separated product was filtered and dried under vacuum at 35 °C to afford impurity III with 96.0% purity and 82.6% yield. Synthesis of Impurity IV. Impurity IV is a lower analogue of Dronedarone, and it was prepared from 2-n-propyl-5-nitrobenzofuran instead of 2-n-butyl-5-nitrobenzofuran as per the synthesis shown in Scheme 1. Synthesis of Impurity V. To a stirred solution of impurity I (10 g, 0.02 mol) and toluene (50 mL) was added formic acid (1.4 mL, 0.03 mol), and the reaction mixture was heated to reflux for 3 h. The reaction mixture was allowed to cool to 25 °C followed by washing with water (50 mL) and then concentration to dryness to afford impurity V with 95.3% purity and 91.0% yield. Synthesis of Impurity VI. To a stirred solution of impurity I (3.6 g, 0.007 mol) and isopropanol (36 mL) was added 1chloro-3-di-n-butylaminopropane (1.7 g, 0.008 mol) and potassium carbonate (1.0 g, 0.008 mol). The resulting reaction mixture was heated at 75 °C for 12−14 h and then allowed to cool to 25 °C. The undissolved material was filtered off, followed by concentration of the filtrate mother liquors to dryness in vacuo. The residual product thus obtained was purified through column chromatography using ethyl acetate and hexanes (1:4, v/v) as eluent to afford impurity VI with 90.2% purity and 98.5% yield.

as N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)formamide. Structure Elucidation of Impurity VI. The ESI-MS spectrum of the impurity VI exhibited a protonated molecule peak at m/z 648.7 (M + H)+ in positive ion mode, indicating the molecular mass of this impurity to be 647.7, which is 91 amu more than that of impurity I. In the IR spectrum of this impurity, only one weak absorption peak appeared at 3423 cm−1 instead of two weak absorption peaks in impurity I. This suggested that the aromatic amine group could be monoalkylated with 1-chloro-3-di-n-butylaminopropane. Also, its molecular weight is matched well with the protonated molecular mass observed in the ESI mass spectrum, and this was further substantiated by the 1H NMR, 13C NMR, and DEPT spectra. Based on the synthetic methodology and the above spectral data, the molecular formula of impurity VI could be deduced as C41H65N3O3 and the corresponding structure was characterized as (2-butyl-5-((3-(dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone.

■

EXPERIMENTAL SECTION Materials and Reagents. The investigated sample, Dronedarone hydrochloride, was synthesized at DRL research and development centre, IPDO, Dr. Reddy’s Laboratories Ltd., A.P., India. HPLC grade acetonitrile, potassium dihydrogen phosphate, tetrabutylammonium hydrogen sulfate, and trifluoroacetic acid used in the analysis were purchased from Merck, Mumbai, India. Water used for preparing the mobile phase was purified using a Millipore milli-Q plus (Milford, MA, USA) purification system. NMR solvent CDCl3 was purchased from Cambridge Isotope Laboratories Inc., MA, USA. Formic acid, methanesulfonyl chloride, chloromethanesulfonyl chloride, and triethylamine used for the synthesis of impurities were purchased from Sigma-Aldrich, Hyderabad, India. High Performance Liquid Chromatography (HPLC). An in-house HPLC method was developed for the analysis of Dronedarone and its potential impurities (Agilent series 1100 with empower software, G1312A binary pump, G1314A variable wavelength detector, Waldbronn, Germany), where a column Inertsil C8-3 (150 mm × 4.6 mm, 3 μm) with a mobile phase consisting of A: 1.36 g of KH2PO4 and 3.39 g of TBAHS in 1000 mL of MQ water, B: acetonitrile and water (9:1, v/v), with a timed gradient program of T/%B: 0/35, 5/35, 15/40, 30/45, 35/50, 40/80, 45/90, 52/90, 54/35, 60/35 with a flow rate of 0.8 mL/min and UV detection at 288 nm was used. This HPLC method was able to detect all the impurities. Liquid Chromatography−Mass Spectrometry (LCMS). An in-house LC-MS method was developed for the analysis of Dronedarone and its potential impurities, where a column Inertsil C8-3 (150 mm × 4.6 mm, 3.5 μm) with a mobile phase consisting of A: 1.0 mL TFA in 1000 mL water, B: 1.0 mL TFA in acetonitrile and water (9:1, v/v), with a timed gradient program of T/%B: 0/35, 5/35, 15/40, 30/45, 35/50, 40/80, 45/90, 52/90, 54/35, 60/35 with a flow rate of 0.8 mL/min and UV detection at 288 nm was used. This LCMS method was able to detect all the impurities. Mass Spectrometry. The mass spectra were recorded on Schimadzu LCMS-QP8000 and Micromass LCT Premier XE mass spectrometers. NMR Spectroscopy. The 1H NMR spectra were recorded on a Varian Mercury plus 400 MHz FT-NMR spectrometer using CDCl3 as a solvent; the chemical shifts are reported in δ

■

CONCLUSION The process-related impurities (impurities I−VI) in the Dronedarone hydrochloride bulk drug were identified, 161

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162

Organic Process Research & Development

Communication

synthesized, and characterized by LC-MS, FT-IR, and NMR (1H, 13C and DEPT) techniques.

■

ASSOCIATED CONTENT

* Supporting Information S

All the structures, molecular weights, and retention times of the corresponding impurities are mentioned in Table 1. The 1H NMR, 13C NMR, and DEPT chemical shift values of Dronedarone and all impurities are given in Tables 2 and 3, and the FT-IR and mass spectral data are given in Table 4. This material is available free of charge via the Internet at http:// pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +91 9000770751. Fax: +91 40 44346285. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors gratefully acknowledge the management of Dr. Reddy’s Laboratories Limited, for allowing us to carry out the present work. The authors are also thankful to the colleagues of Process Research and Analytical Research Departments for their cooperation.

■

REFERENCES

(1) Vaughan Williams, E. M. Symp. Card. Arrhythmias 1970, 449− 472. (2) Bigger, J. T., Jr. Am. J. Cardiol. 1984, 5, 8B−16B. (3) Peter, M. D.; Kowey, R. Arch. Intern. Med. 1998, 158, 325−332. (4) Gubin, J.; Chatelain, P.; Lucchetti, J.; Rosseels, Inion, G. US Patent 5223510, 1993. (5) Fino, N.; Leroy, C. US Patent 6828448 B2, 2004. (6) Biard, M. US Patent 6846936 B2, 2005. (7) Gutman, A.; Nisnevich, G.; Yudovitch, L. US Patent 7312345 B2. 2007. (8) (a) Hivarekar, R. R.; Deshmukh, S. S.; Tripathy, N. K. Org. Process Res. Dev. 2012, 16 (4), 677−681. (b) Mali, A. C.; Ippar, S. S.; Bodke, M. B.; Patil, N. S.; Mathad, V. T. Org. Process Res. Dev. 2013, 17 (5), 863−868. (c) Mohanarangam, S.; Satyanarayana, B.; Elati, R. C.; Vijayabhaskar, B.; Pratap Reddy, P. J. Chin. Chem. Soc. 2011, 58, 841− 845. (9) Deltour, G.; Binon, F.; Tondeur, R.; Goldenberg, C.; Henaux, F.; Sion, R.; Deray, E.; Charlier, R. Arch. Int. Pharmacodyn. Ther. 1962, 139, 247−254. (10) ICH harmonized tripartite guideline, Impurities in New Drug Substances Q3A (R2), current step 4th version, October 25, 2006.

162

dx.doi.org/10.1021/op400190b | Org. Process Res. Dev. 2014, 18, 157−162