Skip to main content
SpringerLink
Log in

Identification and synthesis of potential impurities of bilastine drug substance

  • Original Paper
  • Published:
Chemical Papers Aims and scope Submit manuscript

Abstract

Bilastine is a new, well-tolerated, nonsedating H1 receptor antihistamine. Herein, we describe the synthesis of four new potential impurities of bilastine, namely 2-[4-(2-(4-(1-(2-methoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl) phenyl]-2-methylpropanoic acid (2) (methoxyethyl bilastine), 2-[4-(2-(4-(1-(2-(2-ethoxyethoxy)ethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoic acid (3) ((2-ethoxyethoxy)ethyl bilastine), 2-amino-2-methylpropyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoate (4) (2-amino-2-methylpropyl ester of bilastine or bilastine open-ring ester) and 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl] piperidine-1-yl) ethyl) phenyl]-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylpropanamide (5) [N-(1-hydroxy-2-methyl-2-propanyl)amide of bilastine or bilastine open-ring amide]. Each (2, 3, 4 and 5) is an observed process-related impurity with a possible significant impact on the quality of the drug product. This work is useful for generic pharmaceutical industry for making impurity reference standards. Pharmacopeia is not available for bilastine; hence, the control of these impurities in the API below the threshold level is essential as per International Conference on Harmonization (ICH) recommendations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Scheme 3
Scheme 4
Fig. 3
Fig. 4
Scheme 5

Similar content being viewed by others

Abbreviations

DCM:

Dichloromethane

DIPEA:

N,N-diisopropylethylamine

TBAB:

Tetrabutylammonium bromide

NaCl:

Sodium chloride

MTBE:

Methyl tertiary-butyl ether

EDC·HCl:

N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

Na2CO3 :

Sodium carbonate

DMAP:

4-Dimethylaminopyridine

NaOH:

Sodium hydroxide

HCl:

Hydrochloric acid

H2SO4 :

Sulfuric acid

Boc2O:

Di-tert-butyl dicarbonate (Boc anhydride)

References

  • Bousquet J, Cauwenberge PV, Khaltaev N (2001) Allergic rhinitis and its impact on asthama. J Allergy Clin Immunol 108(5):S147-334. https://doi.org/10.1067/mai.2001.118891

    Article  CAS  PubMed  Google Scholar 

  • Carter NJ (2012) Bilastine in allergic rhinitis and urticaria. Drugs 72(9):1257–1269. https://doi.org/10.2165/11209310-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  • Collier SJ, Wu X, Poh Z, Rajkumar GA, Yet L (2011) Alternative synthesis of bilastine. Synth Commun 41:1394–1402. https://doi.org/10.1080/00397911.2010.486506

    Article  CAS  Google Scholar 

  • Ding HX, Liu KK-C, Sakya SM, Flick AC, O’Donnell CJ (2013) Synthetic approaches to the 2011 new drugs. Bioorg Med Chem 21:2795–2825. https://doi.org/10.1016/j.bmc.2013.02.061

    Article  CAS  PubMed  Google Scholar 

  • International Conference on Harmonization (ICH) Guidelines Q3A (R2): Impurities in New Drug Substances (2006).

  • Kaizhong M, Xin H (2017) Bilastine compound and preparation method. CN Patent: 104530002B

  • Lee C-H, Khoo J-H, Kwon K-C, Ju H (2013) Process for preparation of 2-methyl-2 phenylpropionic acid derivatives and novel intermediate compounds. US Patent: 8367704B2

  • Lei W, Ke L, Qian W, Weifeng L (2014) Preparation method of 2-(4-haloethyl) phenyl-2-methylpropionate and method for synthesizing bilastine. CN Patent: 102675101B

  • Lian L, Hua Y, Zhanxiao (2015) 2-phenylpropionate derivative and preparation method and use thereof. CN Patent: 105017211A

  • Liwei X, Limin D, Ning W, Dunchao T, Dechao Z, Dalong Z, Ke W (2016) Preparation method of bilastine. CN Patent: 104177331B

  • Orjales A, Rubio V, Bordell M (2004) Benzimidazole derivatives with antihistaminic activity. EP Patent: 0818454B

  • Pawankar R, Canonica GW, Holgate ST, Lockey RF (2011–2012) World Allergy Organization (WAO) white book on allergy: executive summary [online]. Available from https://www.worldallergy.org/publications/wao_white_book.pdf. Accessed 18 Aug 2021.

  • Ridolo E, Montagni M, Bonzano L, Incorvaia C, Canonica GW (2015) Bilastine: new insight into antihistamine treatment. Clin Mol Allergy 13:1. https://doi.org/10.1186/s12948-015-0008-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rongli Z, Xuan C, Chunguang S, Hongxin W (2014) Bilastine crystal formation and preparation method thereof. CN Patent: 103788062A

  • Srinivasan TR, Sajja E, Ghojala VR (2014) Novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl} ethyl) phenyl]-2-methylpropanoic acid. WO Patent: 2014188453A2

  • Tie L, Sufeng M, Qiqiang Y (2013) Preparation method of bilastine. CN Patent: 103214455A

  • Validation of Analytical Procedures, Text and Methodology Q2 (R1): (2006).

  • Wedi B (2008) Urticaria. J Dtsch Dermatol Ges 6(4):306–317. https://doi.org/10.1111/j.1610-0387.2008.06661.x

    Article  PubMed  Google Scholar 

  • Wolthers OD (2013) Bilastine: a new nonsedating oral H1 antihistamine for treatment of allergic rhinoconjunctivitis and urticaria. Biomed Res Int. https://doi.org/10.1155/2013/626837

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuenan Z, Qiqiang Y, Sufeng M, Jinmin W (2013) Method for preparing bilastine. CN Patent: 103351380A

  • Zezula J, Hajicek J (2014) A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates. WO Patent: 2014026657A2

  • Zhen L, Chenggang Y, Yufa Y (2016) Preparation method of bilastine. CN Patent: 106146459A

Download references

Acknowledgements

The authors gratefully acknowledge Aurobindo Pharma Limited for supporting the work. The authors are also thankful to the Chemical Research Department and Analytical Research Department for the support and cooperation.

Author information

Authors and Affiliations

  1. Chemical Research Department, APL Research Centre-II, Aurobindo Pharma Ltd, Telangana State, Survey No. 71 & 72, Indrakaran Village, Kandi Mandal, Sangareddy District, 502329, India

    T. Purendar Reddy, Nageshwar Dussa, Srinivas Mamidi, Mahesh Panasa & Ramadas Chavakula

  2. Department of Engineering Chemistry, A. U. College of Engineering (A), Andhra University, Visakhapatnam, Andhra Pradesh, 530003, India

    T. Purendar Reddy & M. Padma

Authors
  1. T. Purendar Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nageshwar Dussa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Srinivas Mamidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahesh Panasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramadas Chavakula
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Padma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Purendar Reddy.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 10994 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reddy, T.P., Dussa, N., Mamidi, S. et al. Identification and synthesis of potential impurities of bilastine drug substance. Chem. Pap. 76, 4137–4145 (2022). https://doi.org/10.1007/s11696-022-02157-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11696-022-02157-5

Keywords

Search

Navigation