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Development and validation of the GC method for quantitative determination of semi-volatile solvents in pharmaceutical substance Bosentan

Elżbieta U. Stolarczyk ,  Aleksandra Groman ,  Wojciech Łuniewski 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland

Abstract
Bosentan is an active substance in the orphan drugs used to treat pulmonary artery hypertension (PAH). It is a dual endothelin receptor antagonist (ERA) with the affinity for both receptors of the A and B: endothelin-A (ETA) and endothelin-B (ETB). Under normal conditions, ETA or ETB receptors cause constriction of the pulmonary blood vessels. By blocking this interaction, bosentan decreases pulmonary vascular resistance [1].

The new gas chromatography method with direct-injection for quantitative determination of residual semi-volatile solvents such as acetic acid, dimethyl sulfoxide (DMSO) and ethylene glycol in bosentan - the pharmaceutical active substance has been developed and validated. The optimization of the method consisted in the selection of experimental conditions that allowed to meet the requirements for this procedure, including:
  • The appropriate level of detection limit (LOD) of analytes, in particular for ethylene glycol,
  • The stability of determination - decomposition peak of Bosentan were observed depending on the temperature of the injector,
  • The appropriate specificity of the method between all solvents used in the synthesis of Bosentan
  • The appropriate range of the determination which includes 10 -120 % of specified limits of residual solvents. According to the Guideline Q3C (R5) 11 [2] acceptable limits (maximum allowable limit) of ethylene glycol is 620 ppm, acetic acid 5000 ppm and DMSO 5000 ppm in respect to sample preparation.
The developed method was validated according to the requirement of ICH (International Conference of Harmonization) validation guidelines Q2R1 [3]. Specificity, precision, accuracy, linearity, limits of detection and quantitation and robustness were determined and excellent results were obtained.

Acknowledgements:

The study was supported by European Union under European Regional Development Fund No. UDA-POiG.01.03.01-14-062/09-00 “Innovative technologies of cardio-vascular medicines of special therapeutic and social importance”.


References:
  1. http://www.ema.europa.eu/docs/pl_PL/document_library/EPAR__Product_ Information/human/000401/WC500041597.pdf
  2. ICH Harmonised Tripartite Guideline (2011) Guideline for residual solvents (1997) Q3C(R5)
  3. ICH Harmonised Tripartite Guideline (2006) Validation of Analytical Procedures: Text and Methodology (1994) Q2(R1)
 

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Presentation: Poster at IX Multidyscyplinarna Konferencja Nauki o Leku, by Elżbieta U. Stolarczyk
See On-line Journal of IX Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2014-03-14 10:36
Revised:   2014-05-02 19:20