Abstract
A simple, rapid and robust enantioselective method was developed and validated for the quantitation of OTX015 enantiomers [(−)-OTX015 and (+)-OTX015] with ultrahigh-performance liquid chromatography (UHPLC) as per ICH guidelines. The active [(−)-OTX015] and inactive [(+)-OTX015] enantiomers were resolved on a Chiralpak-IA column using methanol consisting of 0.1 % diethyl amine at a flow rate of 1.0 mL min−1. The resolution between the enantiomers was found to be more than 3.7 in the optimized method. The developed method was extensively validated and proven to be robust. The calibration curve for (+)-OTX015 showed excellent linearity over the concentration range of 10–100 µg mL−1. The limit of detection and the limit on quantitation for (+)-OTX015 were 5 and 10 µg mL−1, respectively. The recovery for (+)-OTX015 ranged between 100.7 and 102.5 % in the bulk drug sample of (−)-OTX015. The proposed method was found to be suitable and accurate for quantitative determination of (+)-OTX015 in bulk drug.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Noel JK, Iwata K, Ookie S, Sugahara K, Nakamura H, Daibata M (2013) Development of the BET bromodomain inhibitor OTX015. Mol Cancer Ther 12:C244
Garnier JM, Sharp PP, Burns CJ (2014) BET bromodomain inhibitors: a patent review. Expert Opin Ther Pat 24:185–199
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE (2015) Nature 23:1067–1073
Herait P, Dombert H, Thieblemont C, Facon T, Stathis A, Cunnigham D, Palumbo A, Vey N, Michallet M, Recher C, Rezai K, Preudhomme C (2015) BET bromodomain (BRD) inhibitor OTX015: Final results of the dose-finding part of a phase I study in hematologic malignancies. 13th International Congress on Targeted Anticancer Therapeutics 2015
Williams K, Lee E (1985) Importance of drug enantiomers in clinical pharmacology. Drugs 30:333–354
Tripathi KD (1993) Drug enantiomers: configuration and pharmacological implications. Ind J Pharmacol 25:73–77
Srinivas NR (2001) Impact of chirality I. A look in the mirror from a pharmacokinetic perspective. Ind J Pharm Sci 63:265–272
Bid HK, Phelps DA, Xiao L, Guttridge DC, Lin J, London C, Baker LH, Mo X, Houghton PJ (2016) The bromodomain BET inhibitor JQ1 suppresses tumor angiogenesis in models of childhood sarcoma. Mol Cancer Ther (ahead of print)
Bradner JE, Zuber J, Shi J, Vakoc CR (2011) WO 2011/143660 A2
ICH draft guidelines on validation of analytical procedure: definitions and terminology, Federal Register, IFPMA, Switzerland (1995) vol 60, pp 1260–1268
http://www.agilent.com/chem. Publication Number 5965-5900E. Enhanced diode array detector sensitivity and automated peak purity control
Acknowledgments
The authors would like to thank Dr. Saravanan Vadivelu and his team for the synthesis of the OTX015 enantiomers, and the analytical and DMPK department teams for their continuous support in completing this work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Financial Disclosure
The authors have no financial involvement with any organization with a financial interest discussed in the manuscript.
Conflict of Interest
The authors wish to declare that there are no conflicts of interests in the contents of the manuscript.
Ethical Approval
This article does not contain any studies with animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Balaji, N., Mullangi, R. & Kumar, A.S. Development and Validation of a Chiral Liquid Chromatographic Method for Quantitative Determination of (+)-OTX015 in (−)-OTX015. Chromatographia 79, 1317–1323 (2016). https://doi.org/10.1007/s10337-016-3138-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10337-016-3138-5