Skip to main content
SpringerLink
Log in

Identification and Characterisation of Rucaparib Degradation Products and Their Comparison with Known Impurities

  • Original
  • Published:
Chromatographia Aims and scope Submit manuscript

Abstract

A reversed-phase HPLC (high-performance liquid chromatographic) method is employed to identify and quantify the degradation impurities and related substances of Rucaparib (RCB), API bulk drug. There is no literature available that elucidates degradation phenomenon of RCB. Thus, the present study focuses on understanding the degradation phenomenon of RCB. The chromatographic separation is achieved within 25 min run time, where Zorbax Bonus RP column is used with a gradient elution of trifluoroacetic acid–ACN–water as the mobile phase. In this study, various forced degradation conditions such as photolysis, hydrolysis, oxidation, and thermal degradation were employed on RCB. Oxidative, basic, and acidic stress conditions showed a significant impact on degradation compared to thermal and photolysis. LC–MS technique was used for the characterization of degradation products and the plausible pathways of fragmentation were proposed. Qualified reference standards were used to quantify the stressed samples and the mass balance was found close to 99.5% (w/w) considering the response of the degradants to be equivalent to RCB. Results of this investigation confirmed the efficacy of the proposed novel method to determine drug stability of RCB, and ICH guidelines were also considered to authenticate our results.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Qaseem A, Snow V, Sherif K et al (2007) Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians. Ann Intern Med 146:511

    Article  PubMed  Google Scholar 

  2. Yancik R, Ries LG, Yates JW (1986) Ovarian cancer in the elderly: an analysis of surveillance, epidemiology, and end results program data. Am J Obstet Gynecol 154:639

    Article  CAS  PubMed  Google Scholar 

  3. Swisher EM, Lin KK, Oza AM et al (2016) Articles Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 18:1–13

    Google Scholar 

  4. Balasubramaniam S, Beaver JA, Horton S, Fernandes LL, Tang S, Horne HN, Liu J, Liu C, Schrieber SJ, Yu J, Song P, Pierce W, Robertson KJ, Palmby TR, Chiu HJ, Lee EY, Philip R, Schuck R, Charlab R, Banerjee A, Chen XH, Wang X, Goldberg KB, Sridhara R, Kim G, Pazdur R (2017) FDA approval summary: Rucaparib for the treatment of patients with deleterious BRCA mutation—associated advanced ovarian cancer. Clin Cancer Res 23:7165–7170

    Article  CAS  PubMed  Google Scholar 

  5. Ihnen M, zu Eulenburg C, Kolarova T et al (2013) Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor Rucaparib for the treatment of sporadic human ovarian cancer. Mol Cancer Ther 12:1002–1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Plummer R, Lorigan P, Steven N et al (2013) A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 71:1191–1199

    Article  CAS  PubMed  Google Scholar 

  7. Pieper AA, Verma A, Zhang J, Snyder SH (1999) Poly(ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci 20:171–181

    Article  CAS  PubMed  Google Scholar 

  8. Herceg Z, Wang Z (2001) Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110

    Article  CAS  PubMed  Google Scholar 

  9. Dantzer F, Schreiber V, Niedergang C et al (1999) Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81:69–75

    Article  CAS  PubMed  Google Scholar 

  10. Lord CJ, Ashworth A (2013) Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 19:1381–1388

    Article  CAS  PubMed  Google Scholar 

  11. Thompson D, Easton D (2001) Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jenner ZB, Sood AK, Coleman RL (2016) Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 12:1439–1456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Drew Y, Ledermann J, Hall G et al (2016) Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer 114:723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sparidans RW, Durmus S, Schinkel AH et al (2014) Liquid chromatography–tandem mass spectrometric assay for the PARP inhibitor rucaparib in plasma. J Pharm Biomed Anal 88:626–629

    Article  CAS  PubMed  Google Scholar 

  15. Ramesh T, Nageswara Rao P, Nageswara Rao R (2014) LC–MS/MS characterization of forced degradation products of zofenopril. J Pharm Biomed Anal 88:609

    Article  CAS  PubMed  Google Scholar 

  16. International Council for Harmonisation (2003) Stability testing of new drug substances and products Q1A(R2). In: The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use

  17. ICH (2003) Stability testing: photostability testing of new drug substances and products Q1B. Int Conf Harmon 24:4

    Google Scholar 

  18. Biswas KM, Castle BC, Olsen BA et al (2009) A simple and efficient approach to reversed-phase HPLC method screening. J Pharm Biomed Anal 49:692–701

    Article  CAS  PubMed  Google Scholar 

  19. Mallet CR, Lu Z, Mazzeo JR (2004) A study of ion suppression effects in electrospray ionization from mobile phase additives and solid-phase extracts. Rapid Commun Mass Spectrom 18:49–58

    Article  CAS  PubMed  Google Scholar 

  20. García MC (2005) The effect of the mobile phase additives on sensitivity in the analysis of peptides and proteins by high-performance liquid chromatography–electrospray mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 825:111–123

    Article  CAS  Google Scholar 

  21. Apffel A, Fischer S, Goldberg G et al (1995) Enhanced sensitivity for peptide-mapping with electrospray liquid-chromatography mass–spectrometry in the presence of signal suppression due to trifluoroacetic acid-containing mobile phases. J Chromatogr A 712:177–190

    Article  CAS  PubMed  Google Scholar 

  22. Guan K, Palmer DC (2006) Effects of trifluoroacetic acid concentrations in mobile phases on HPLC retention of zwitterionic and weakly basic triazole derivatives. J Liq Chromatogr Relat Technol 29:415

    Article  CAS  Google Scholar 

  23. ICH (2005) ICH Topic Q2 (R1) validation of analytical procedures: text and methodology. In: International conference on harmonization

Download references

Acknowledgements

The authors thank the Director, National Institute of Technology, Warangal for providing research facilities and the MHRD, Government of India for providing the financial assistance. Thippani Ramesh wishes to thank the management of Mylan Laboratories Ltd. for supporting this work.

Funding

There was no funding for this work.

Author information

Authors and Affiliations

  1. Department of Chemistry, National Institute of Technology, Warangal, India

    Babji Palakeeti, K. Vijendar Reddy, Ramaiah Konakanchi, Pothuraju Nageswara Rao & K. Vengatajalabathy Gobi

  2. Mylan Laboratories, Jubilee Hills, Hyderabad, Telangana, India

    Tippani Ramesh

Authors
  1. Babji Palakeeti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tippani Ramesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Vijendar Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramaiah Konakanchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pothuraju Nageswara Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Vengatajalabathy Gobi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pothuraju Nageswara Rao.

Ethics declarations

Conflict of interest

Author Babji palakeeti declares that he has no conflict of interest. Author Dr. Tippani Ramesh declares that he has no conflict of interest. Author Vijender Reddy K declares that he has no conflict of interest. Author Ramaiah Konakanchi declares that he has no conflict of interest. Dr. K. Vengatajalabathy Gobi declares that he has no conflict of interest. The corresponding author Prof. Pothuraju Nageswara Rao declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with animals performed by any of the authors. This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Palakeeti, B., Ramesh, T., Reddy, K.V. et al. Identification and Characterisation of Rucaparib Degradation Products and Their Comparison with Known Impurities. Chromatographia 82, 591–604 (2019). https://doi.org/10.1007/s10337-018-3669-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10337-018-3669-z

Keywords

Search

Navigation