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A-0831-2401.Pdf Published online: 2019-09-20 Original Article Thieme Zhang Chaowei et al. Identification, Characterization and HPLC … Drug Res 2019; 00: 00–00 Identification, Characterization and HPLC Quantification of Process-Related Impurities in Bepotastine Besilate Bulk Drug Authors Chaowei Zhang1, Chengqun Han1, Lili Sun2, Jinlong Yu1, Qiaogen Zou1 Affiliations ABSTRacT 1 School of Pharmaceutical Sciences, Nanjing Tech Bepotastine besilate (here after referred to as BTST), chemically University, Nanjing, P. R. China known as ({d (S) 4 [4 [(4 chlorophenyl) (2 pyridyl) methoxy] piperi- 2 College of Biotechnology and Pharmaceutical Engineering, dino} butyric acid monobenzene sulphonate), is a second-gen- Nanjing Tech University, Nanjing, P. R. China eration antihistamine drug. To the best of our knowledge, no studies concerning the isolation or identification of process-re- Key words lated impurities have been reported so far. The current study drug research, chemistry, anti-inflammatory drugs reports the development and validation of a stability-indicating RP-HPLC method for the separation and identification of 5 po- received 16.05.2018 tential impurities in bepotastine besilate. In this experiment, the accepted 04.01.2019 structures of 3 process-related impurities were found to be new compounds. They were characterized and confirmed by NMR Bibliography and MS spectroscopy analyses. These 3 new compounds were DOI https://doi.org/10.1055/a-0831-2401 proposed to be (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-piperi- Published online: 20.9.2019 dinebutanoic acid,(Imp-A); 4-[(S)-(4-chlorophenyl)-2-pyridinyl- Drug Res 2020; 70: 12–22 methoxy]-1- piperidinebutyric acid, N-oxide (Imp-B) and (S)-4- © Georg Thieme Verlag KG Stuttgart · New York [(4- chlorophenyl)-2-pyridinylmethoxy]-1-piperidylethane ISSN 2194-9379 (Imp-C). In addition, an efficient optimized chromatographic method was performed on a Shimadzu Inertsil C8–3 column Correspondence (150 mm × 4.6 mm, 3 μm) to separate and quantify these 5 im- Professor, Dr. Qiaogen Zou purities. It was using 15 mmol ammonium formate buffer in Nanjing Tech University water (pH adjusted to 3.8 with formic acid) and acetonitrile as 5 Xinmofan Road the mobile phase in gradient mode. The method was developed 210009 Nanjing to separate and quantify these 5 impurities obtained in the range Jiangsu Province of 0.05–0.75 μg/mL. It was validated and proven to be selective, China accurate and precise and suitable. It is the first publication of Tel.: + 86/025/83206 648, Fax: + 86/025/83217 546 identification and characterization data of the 3 new com- [email protected] pounds. It is also the first effective HPLC method for separation and quantification of all of process-related impurities in bepo- tastine besilate. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Introduction cytotoxin protein. BTST can also cause infiltration of inflammatory Bepotastine besilate, chemically known as ({d (S) 4 [4 [(4 chloro- parts and inhibit the production of activated eosinophils IL-5. [2– phenyl) (2 pyridyl) methoxy] piperidino} butyric acid monobenzene 3] sulphonate), is a second-generation antihistamine drug. As a po- Bepotastine besilate can inhibit the infiltration of eosinophils tent and long-acting histamine H(1) receptor antagonist and with into peripheral tissues, so that tulipamustine is effective against platelet activating factor antagonist effects, BTST has a high-level nasal mucosal inflammation than existing drugs. In addition, be- selectivity and has no affinity for 5-HT2, α1, α2 receptor.[1] Exper- potastine besilate rarely passes through the blood-brain barrier, iments on human peripheral blood mononuclear cells showed that which means it has almost no sedative effect. It acts on anticholin- the anti-allergic effect of this compound may be related to inter- ergic effect and antihistamines separately. With excellent pharma- leukin-5 mediator. BTST can quickly and effectively inhibit 3 major codynamic effects and clinical effects, it has extremely small ad- symptoms of allergic rhinitis: sneezing, runny nose and stuffy nose. verse reactions, which makes it better than terfenadine, cetirizine, BTST can inhibit eosinophil infiltration, while eosinophils releasing epipitabine. So the clinical application has broad prospects.[4–7] 12 Zhang C et al. HPLC Method For Bepotastine Besilate … Drug Res 2020; 70: 12–22 Bepotastine besilate tablet was developed by Tanabe Seiyaku from School of Pharmaceutical Sciences in Nanjing Tech University and Ube Industries in Japan, was approved in July 2000 and January (Nanjing, China). Starting material A (SMA; (S)-4-[(4-chlorophenyl)- 2002 for the treatment of allergic rhinitis and urticaria, eczema/ 2 pyridinylmethoxy]-Piperidine and starting material B (SMB; 1- dermatitis, prurigo and pruritus cutaneous in human patients. Bromo-3-(carboethoxy)-propane were purchased from Lianben A thorough literature survey revealed that most reports of be- Pharm-chemicals Tech. Co., Ltd. (Beijing, China). The purity of all potastine besilate are focused on synthesis and pharmacokinetics. substances was > 99 %. HPLC grade acetonitrile was purchased from Narasimha RK et al. described a HPLC method for the quantifica- Merck Ltd. (Darmstadt, Germany). Ammonium formate, formic tion of bepotastine besilate and its related substances.[8] They also acid, sodium hydroxide, hydrochloric acid, hydrogen peroxide studied on the forced degradation of bepotastine besilate. How- (30 %) and acetone were purchased from Aladdin Reagent Co., Ltd. ever, the study was not comprehensive enough. The impurities they (Shanghai, China). Double-distilled water was produced through a studied were not characterized, and 3 new impurities were found Milli-Q pure water system (Milford, MA, USA). The other chemicals during our synthesis. All the 3 impurities have never been identifi- were all of analytical grade. cated or characterizated before thus, a simple, sensitive, and effec- tive analytical method needs to be developed to monitor the levels HPLC instrumentation and methods of all possible impurities in BTST, from the initial production pro- Chromatographic studies were performed on an Agilent 1220 se- cess, to ensure its safety in the formulations. However, to the best ries HPLC (Palo Alto, CA), equipped with a binary gradient pump, of our knowledge, no studies concerning the formation or identi- degasser, variable wavelength detector, autosampler, and Chem- fication of these 3 new-found process-related impurities have been Station software. The peak homogeneity was studied by using Ag- reported so far. Several syntheses of BTST have been published ilent 1220 series DAD detector. The separation was performed on [7–10]; the route shown in ▶Fig. 1 for manufacturing BTST has a Shimadzu Inertsil C8–3 column(150 mm × 4.6 mm, 3 μm) (Tokyo, several advantages such as the use of low-cost materials, a simple Japan). Mobile phase A was ammonium formate buffer (15 mmol preparation process, and good yields [10]. Impurities inevitably with the pH adjusted to 3.8 using formic acid) mixed with 10 % ACN, form at the end of this process, and include unreacted starting ma- and phase B was ACN. terials, by-products, and intermediates. It is essential to carryout The HPLC gradient program was as follows: Time(min)/A:B (v/v); identification and structural elucidation of potential impurities in T0100/0, T1577.8/22.2, T1877.8/22.2, T2366.7/33.3, T33100/0, drug development. In this study, the potential process-related im- T40100/0. The UV detector wavelength was chosen at 220 nm. The purities of BTST were isolated and then analyzed by HPLC-UV–ESI–MS. flow rate was 1.0 mL/min, and the column temperature was main- The aims of the current research are as follows: (i) to propose tained at 25◦C. A water and acetonitrile mixture (70:30,v/v) was potential process-related impurities in bulk BTST by reference to used in the BTST samples preparing, which was at 1 mg/mL con- the synthetic methodology; (ii) to identify and elucidate the struc- centration. In this experiment, 10 μL of sample solution was inject- tures of these impurities by NMR and MS; (iii) to optimize LC con- ed into the HPLC system for analysis. ditions and develop an effective HPLC method for the quantitative determination of the potential impurities in BTST. LC–MS instrumentation and methods LC-MS analysis in this experiment was performed using an API4000 mass spectrometer (Milwaukee, WI, USA) equipped with an elec- Materials and Methods trospray ionization (ESI) source interface coupled to an Agilent 1200-LC system (Palo Alto, CA, USA). The HPLC gradient program Chemical and reagents was as follows: Time(min)/A:B (v/v); T0100/0, T1577.8/22.2, Bepotastine besilate and standards of 4-[(S)-(4-chlorophenyl)- T2577.8/22.2, T35100/0, T40100/0. And 10 μL of sample solution 2-pyridinylmethoxy]-1- Piperidinebutyric acid, ethyl ester (BT-01); was injected. The UV detector wavelength was chosen at 220 nm. (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-Piperidinebutanoic The column temperature was maintained at 25◦C.The flow rate acid,(Imp-A) ;4-[(S)-(4- chlorophenyl)-2-pyridinylmethoxy]-1- Pi- was maintained at 1 mL/min and was split at the column outlet to peridinebutyric acid,N-oxide (Imp-B) and (S)-4-[(4- chlorophenyl)- allow 0.2 mL of eluent to flow into the mass spectrometer. The MS This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2-pyridinylmethoxy]-1-piperidylethane (Imp-C) were obtained
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