Drug Res (Stuttg) 2020; 70(01): 12-22
DOI: 10.1055/a-0831-2401
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Identification, Characterization and HPLC Quantification of Process-Related Impurities in Bepotastine Besilate Bulk Drug

Chaowei Zhang
1   School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, P. R. China
,
Chengqun Han
1   School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, P. R. China
,
Lili Sun
2   College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, P. R. China
,
Jinlong Yu
1   School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, P. R. China
,
Qiaogen Zou
1   School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, P. R. China
› Author Affiliations
Further Information

Publication History

received 16 May 2018

Publication Date:
20 September 2019 (online)

Abstract

Bepotastine besilate (here after referred to as BTST), chemically known as ({d(S)4[4[(4chlorophenyl) (2pyridyl) methoxy] piperidino} butyric acid monobenzene sulphonate), is a second-generation antihistamine drug. To the best of our knowledge, no studies concerning the isolation or identification of process-related impurities have been reported so far. The current study reports the development and validation of a stability-indicating RP-HPLC method for the separation and identification of 5 potential impurities in bepotastine besilate. In this experiment, the structures of 3 process-related impurities were found to be new compounds. They were characterized and confirmed by NMR and MS spectroscopy analyses. These 3 new compounds were proposed to be (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid,(Imp-A); 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-1- piperidinebutyric acid, N-oxide (Imp-B) and (S)-4-[(4- chlorophenyl)-2-pyridinylmethoxy]-1-piperidylethane (Imp-C). In addition, an efficient optimized chromatographic method was performed on a Shimadzu Inertsil C8–3 column (150 mm×4.6 mm, 3 μm) to separate and quantify these 5 impurities. It was using 15 mmol ammonium formate buffer in water (pH adjusted to 3.8 with formic acid) and acetonitrile as the mobile phase in gradient mode. The method was developed to separate and quantify these 5 impurities obtained in the range of 0.05–0.75 μg/mL. It was validated and proven to be selective, accurate and precise and suitable. It is the first publication of identification and characterization data of the 3 new compounds. It is also the first effective HPLC method for separation and quantification of all of process-related impurities in bepotastine besilate.

 
  • References

  • 1 Hussar DA, Abbas CA. New drugs: Asenapine, iloperidone, and bepotastine besilate. Journal of the American Pharmacists Association 2010; 50: 107-110 doi: 10.1331/JAPhA.2010.10505
  • 2 Choi YK, Chung YH, Nam YS. et al. UPLC-MS/MS method for determination of bepotastine in human plasma. Journal of Chromatographic Science 2014; 52: 886-893 doi: 10.1093/chromsci/bmt135
  • 3 Cho KH, Choi HG. Development of novel bepotastine salicylate salt bioequivalent to the commercial bepotastine besilate in beagle dogs. Drug Development and Industrial Pharmacy 2013; 39: 901-908 doi: 10.3109/03639045.2012.717295
  • 4 Tashiro M, Duan XD, Kato M. et al. Brain histamine H(1) receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with (11)C-doxepin. British Journal of Clinical Pharmacology 2008; 65: 811-821 doi: 10.1111/j.1365-2125.2008.03143.x
  • 5 Lee BM, Lee JD, Lim DS. et al. Comparison of efficacy and bioequivalence between bepotastine/nicotinate and bepotastine/salicylate of antihistamine drugs. Toxicology Letters 2014; 229: S102-S102 doi: 10.1016/j.toxlet.2014.06.375
  • 6 Kida T, Fujii A, Sakai O. et al. Bepotastine besilate, a highly selective histamine H-1 receptor antagonist, suppresses vascular hyperpermeability and eosinophil recruitment in in vitro and in vivo experimental allergic conjunctivitis models. Experimental Eye Research 2010; 91: 85-91 doi: 10.1016/j.exer.2010.04.006
  • 7 Yang QJ. bepotastine besilate. Chinese Journal of Medicinal Chemistry 2010; 20: 159-159
  • 8 Narasimha RK, Nagaraju Ch.V.S., Rajan ST. et al. Stability indicating HPLC method for the quantification of bepotastine besilate and its related substances. Der Pharma Chemica 2014; 6: 343-351
  • 9 Ha TH, Suh KH, Leet GS. A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist. Bulletin Of the Korean Chemical Society 2013; 34: 549-552 doi: 10.5012/bkcs.2013.34.2.549
  • 10 Xia J, Yu Z, Wang H. A New Synthetic Method of Bepotastine Besilate. Chinese. Journal of Pharmaceuticals 2016; 47: 8-10