Development and Validation of a Separation and Quantification Method for Residual Solvents in Active Substances by Headspace Gas Chromatography
Keywords:
Analytical validation, Flame Ionization Detection, Gas chromatography, Headspace, Residual solvents.Abstract
The main objective was to develop and validate a method to assaying simultaneously nine residual solvents mentioned in the guidelines of the International Conference on Harmonization (ICH) Q3C: toluene, methanol, ethanol, acetone, propan-2-ol, ethyl acetate, tetrahydrofuran, dichloromethane and acetonitrile. Chromatographic separation was achieved on DB-624 column (30 m × 0.53 mm, 1.8 ?m), nitrogen carrier gas and flame ionization detector. We have optimized the carrier gas flow, programming oven temperature and the split ratio. We have opted for the dimethyl sulfoxide as dissolution solvent. The developed method was validated for linearity, precision, accuracy and specificity and then applied for the research and quantification of residual solvents levels in two drug substances. Excellent results were obtained. The developed method proved to be simple, producing symmetric peak shape, good resolution and reasonable retention time for solvents elution before seventeen minutes, specific, precise and linear in the range from the reporting level limit of quantification to 120% of the limit value, with a correlation coefficient greater than 0.999. The use of n-butyl acetate as internal solvent has improved the linearity and precision, compensating for the occurring variability. The quantification of residual solvents levels in two drug substances nefopam and enoxaparin, did not exceed the amount specified by the ICH guidelines.Thus, our method can be applied for the routine quantification of residual solvents levels in different active substances, for pharmaceutical companies and research laboratories.
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[2] C.Witschi, E.Doelker. “Residual solvents in pharmaceutical products: acceptable limits, influences on physiocochemical properties, analytical methods and documented values”. Eur J Pharm Biopharm, vol. 43, pp. 215-42, 1997.
[3] S. Nojavan, A. Ghassempour, Y. Bashour, MK. Darbandi,SH. Ahmadi.“Determination of residual solvents and investigation of their effect on ampicillin trihydratecrystal structure”. J Pharm Biomed Anal, vol. 36, pp. 983-88, 2005.
[4] JC. Berridge. “Impurities in drug substances and drug products: new approaches to quantification and qualification”. J Pharm and Bio Ana, vol.14, pp.7-12, 1995.
[5] MD. Argentine, PK. Owens, BA. Olsen.“Strategies for the investigation and control of process-related impurities in drug substances”. Adva Drug Deliv Rev, vol.59, pp.12-28, 2007.
[6] L’adoption pour l’ICH ligne directrice : présence d’impuretés dans les nouvelles substances médicamenteuses–ICH thème Q3A (R) ; [cited 2003 Septembre 25]. Available:
http://publications.gc.ca/collections/Collection/H49-175-2003F.pdf/
[7] International Conference on Harmonization of Technical Requirements for Registration of pharmaceuticals for Human Use. ICH Harmonized tripartite guideline Q3A (R2). Impurities in new drug substances; [cited 2006 October 25]. Available :
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf/
[8] International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. ICH Harmonized tripartite guideline Q3B (R2). Impurities in new drug products; [cited 2006 June 2]. Available :
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3B_R2/Step4/Q3B_R2__Guideline.pdf/
[9] International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. ICH Harmonized tripartite guideline. Impurities: Guidelines for residual solvents Q3C (R5); [cited 2011 February 4]. Available: https://www.pmda.go.jp/files/000156308.pdf/
[10] JE. Haky, TM. Stickney. “Automated gas chromatographic method for the determination of residual solvents in bulk pharmaceuticals”. J. Chromatogr, vol.321, pp.137–44, 1985.
[11] ID. Smith, DG. Waters. “Determination of residual solvent levels in bulk pharmaceuticals by capillary gas chromatography”. Analyst, vol.116, pp.1327–31, 1991.
[12] F. Ruchatz, P. Kleinebudde, BW. Muller. “Residual solvents in biodegradable microparticles: determination by a dynamic headspace gas chromatographic method”. Int. J. Pharm, vol.142, pp.67–73, 1996.
[13] RJ. Markovich, S. Ong, J. Rosen. “Quantitation of the residual solvent naphtha in a pharmaceutical soft gelatin capsule product by equilibrium headspace gas chromatography”. J. Chromatogr. Sci; vol.35: pp.584–92,1997.
[14] JY. Zhu, XS. Chai. “Some recent developments in headspace gas chromatography”. Curr. Anal. Chem, vol.1, pp.79-83, 2005.
[15] Monograph 2.4.24 “Identification and control of residual solvents”, in: European Pharmacopeia, 8th ed., Tome I. Strasbourg, 2014.
[16] V. Balarm. “Recent advances in the determination of elemental impurities in pharmaceuticals status, challenges and moving frontiers”. Trac trends in Analytical chemistry, vol.80, pp.83-95, 2016.
[17] CR. Lee, C. Nguyen Van Dau, AM. Krastulovi?. “Artefact formation in the determination of residual solvents according to a method of the European Pharmacopeia”. International Journal of pharmaceutics, vol.195 (1-2), pp.159-169, 2000.
[18] CF. Poole. The essence of chromatography. Amsterdam: Elsevier, 2003.
[19] HM. McNair, JM. Miller. Basic gas chromatography, 2nd edition, 2009.
[20] T. Maciej, N. Jacek, S. Wies?aw. “Analytical procedure for quality control of pharmaceuticals in terms of residual solvents content: challenges and recent developments”. Trends in Analytical Chemistry, vol.80, pp.328-44, 2016.
[21] C. Cheng, S. Liu, BJ. Mueller, Z. Yan. “A generic static headspace gas chromatography method for determination of residual solvents in drug substance”. J Chromatography A, vol.1217, pp.6413-21, 2010.
[22] MR. Siddiqui, R. Singh, A. Bhatnagar, J. Kumar, M. Chaudhary (2013). “Determination of residual solvents in docetaxel by headspace gas chromatography”. Arabian Journal of chemistry, [in press]. Available: http://dx.doi.org/10.1016/j.arabjc.2013.09.014.
[23] International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. ICH Validation of analytical procedures: text and methodology Q2 (R1); [updated 2005, November; cited 1994 October 27]. Available:
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf/
[24] International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. ICH guidance for industry, Q2B. Validation of analytical procedures: Methodology; 1996.
[25] GA. Shabir. “Validation of high-performance liquid chromatography methods for pharmaceutical analysis. Understanding the differences and similarities between validation requirements of the US Food and Drug administration, the US Pharmacopoeia and the International Conference on Harmonization”. J. Chromatogr. A, vol.987, pp.57- 66, 2003.
[26] J. Caporal-Gautier, J.M. Nivet. Guide de validation analytique, Rapport d’une commission SFSTP, Méthodologie. S.T.P Pharma pratiques, vol.2 (4), pp.205-26, 1992.
[27] V. Anil Kuamar, G. Aravind, I. Srikanth, A. Srinivasarao, Ch. Dharma Raju. “Novel analytical method development and validation for the determination of residual solvents in amlodipine besylate by gas chromatography”. Der Pharma Chem; vol.6, pp.2228-38, 2012.
[28] S. R. Clécio. “Development and validation of headspace gas chromatographic method for determination of residual solvents in five drug substances”. Int J pharm Sci Invent; vol.2, pp.36-41, 2013.
[29] B. Sivasaikiran, Y. Nayudamma Chowdary, V. Sreelakshmi, S.K. Shrivastava, S. Pugazhendhy. “Development ad validation of a headspace gas chromatographic method for determination of residual solvents in bosentan monohydrate”. Int J Pharm Tech Res, vol.6, pp.421-7, 2014.
[30] EM. Antolin, YB. Quiñónez, VG. Canavaciolo, ER. Cruz. “Validation of an analytical method for quality control of residual solvents (n-hexane and acetone) in D-002: new active ingredient from beeswax”. J Pharm Biome Anal, vol.47, pp.646-50, 2008.
[31] K. Urakami, A. Higashi, K. Umemoto, M. Godo. “Matrix media selection for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography”. J Chromatogr A, vol.1057, pp.203-10, 2004.
[32] C.M. Teglia, M. Montemurro, M.M. De Zan, M.S. Cámara. “Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals”. J pharm Anal, vol.5, pp.269-306, 2015.
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Published
2018-03-14
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Louati, K., Sayadi, M., & Safta, F. (2018). Development and Validation of a Separation and Quantification Method for Residual Solvents in Active Substances by Headspace Gas Chromatography. American Scientific Research Journal for Engineering, Technology, and Sciences, 41(1), 57–75. Retrieved from https://asrjetsjournal.org/index.php/American_Scientific_Journal/article/view/3892
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