Development and validation of gas chromatography methods for the control of volatile impurities in the pharmaceutical substance dutasteride
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Abstract
Dutasteride, N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is an active pharmaceutical ingredient (API) which inhibits the conversion of testosterone to dihydrotestosterone. Dutasteride as a 5-reductase inhibitor is useful for the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Because of a large variety of solvents and reagents used in the synthesis, it was necessary to develop new, sensitive and selective gas chromatography (GC) methods. The optimization of the methods consisted in selecting different types of sample injection and detection as well as optimization of experimental conditions that allowed to meet the appropriate range (10-120% of the specification limit) and suitable detection limits (LOD) of compounds. Significant differences in the volatility of these compounds forced the division into volatile solvents (methanol, acetonitrile, dichloromethane, ethyl acetate, heptane and toluene) analyzed with the use of the gas chromatography with headspace (GC-HS) and less volatile compounds (pyridine, dimethylformamide, 1,4-dioxane, acetic acid, ethylene glycol, 4-dimethylaminopyridine) analyzed with the use of gas chromatography with direct injection (GC-FID). Benzene, carbon tetrachloride and 1,2-dichloroethane are potential contaminants of toluene and dichloromethane, thus the control of these solvents was a limit test procedure. Due to the low specification limits for benzene (2 ppm), carbon tetrachloride (4 ppm) and 1,2-dichloroethane (5 ppm) it was neccesery to use gas chromatography with mass spectrometry detection (GC-MS).
All three new methods were validated according to the requirements of the ICH (International Conference on Harmonization) validation guideline Q2R1 and the guideline for residual solvents Q3C. Specificity, precision, accuracy, linearity, limits of detection and quantitation and robustness were determined and the results meeting the acceptance criteria were obtained.
Cite this as
2016. Development and validation of gas chromatography methods for the control of volatile impurities in the pharmaceutical substance dutasteride. PeerJ Preprints 4:e1836v1 https://doi.org/10.7287/peerj.preprints.1836v1Author comment
This is an Abstract submitted to the X MKNOL Conference.
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Competing Interests
The authors declare that they have no competing interests.
Author Contributions
Aleksandra Groman conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Elżbieta U. Stolarczyk conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Marta Jatczak conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Elżbieta Lipiec-Abramska contributed reagents/materials/analysis tools, wrote the paper, reviewed drafts of the paper.
Data Deposition
The following information was supplied regarding data availability:
The research in this article did not generate any raw data.
Funding
This work has been supported by The National Centre for Research and Development, Poland, grant no. INNOTECH-K2/IN2/65/182982/NCBR/13. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
