Research Journal of Pharmacy and Technology

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Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame Ionized Detection for the Determination of Residual Solvents in Letermovir API Synthesis


Affiliations
1 Vignan Institute of Pharmaceutical Technology, Beside VSEZ, Kapujaggarajupeta, Duvvada, Visakhapatnam-530049, India
2 K.L.E.F, Vaddeswaram, Guntur District-522502, Andhra Pradesh., India
     

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Residual solvent testing is an integral part of reference material certification. A gas chromatography / flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: ethyl acetate, MTBE, Toluene and isopropyl acetatein Letermovir API. HS-GC method in a simple and selective manner is delineated for the quantification and determination of Residual Solvents in Letermovir API. The separation of solvents along with drug on Chromatographic chamber was processed on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30 m × 0.32mm × 1.8μm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 10-50μg/ml for ethyl acetate, MTBE, Toluene and isopropyl acetate (r2>0.999) for the amount of solvent determined through sophisticated methods was in good agreement. The proposed methods were validated. The method of accuracy was assessed by recovery studies at three different levels.The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for ethyl acetate, MTBE, Toluene and isopropyl acetate. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of ethyl acetate, MTBE, Toluene and isopropyl acetate in Letermovir. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity (micrograms/mL) and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

Keywords

Letermovir, Head-Space GC, Residual solvents.
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  • Manfred M, Thomas S, Andreas U, Steffen W, Helga R-Schaeff, Holger Z, Peter L. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob. Agents Chemother. 2012;56(2):1135-37.

  • Thomas G, Guy H, Nicole E, Helga R-Schaeff, Holger Z, Peter L. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J. Virol. 2011;85(20):10884-93.

  • Peter L, Guy H, Tobias W, Judith B, Daniela P, Thomas G, Helga R-Schaeff, Holger Z. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob. Agents. Chemother. 2010;54(3):1290-97.

  • Steffen W, Holger Z, Peter L. In vitro drug combination studies of Letermovir (AIC246, MK-8228) with approved anti-human cytomegalovirus (HCMV) and anti-HIV compounds in inhibition of HCMV and HIV replication. Antimicrob. Agents. Chemother. 2015;59(6):3140-48.

  • International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Q3C (R4): Impurities: guideline for residual solvents, Step 4, July 1997.

  • (2) International Conference on Harmonization, Guidance on impurities: residual solvents. Fed. Regist. 62: 67377-88, 1997.

  • (3) USP <467>, General Chapter on Organic volatile impurities, United States Pharmacopeia, (USP 32-NF 27). Pharmacopoeia Convention Inc., Rockville, Maryland, August 2009.

  • (4) Residual Solvents (5.4), European Pharmacopoeia, Supplement 4.6, Directorate for the Quality of Medicines of the Council of Europe, Strasbourg, fourth edition, 2004, 3911.

  • Ramesh Babu J, Suhasini J, Vidyadhara S. Residual Solvents in Bendamustine Hydrochloride By Headspace Chromatography. Asian J. Pharm. Ana. 2018; 8(1):07-12.

  • Ali Ismail, Youssef Alahmad. Determination of ethanol and n-hexane residues in bulk rosuvastatin and atorvastatin and their dosage forms using HS-GC-MS developed method. Research J. Pharm. and Tech 2018; 11(11): 4829-4836.

  • Tentu NageswaraRao, T.B. Patrudu, Suneel Kumar. A, N. Krishna Rao, Karri Apparao. A New Analytical Method Validation and Quantification of Residual Solvents in Telmisartan Bulk Drug Product by Headspace gas Chromatographic Method. Research J. Science and Tech. 2018; 10(2):98-104.

  • Shoeb Alahmad, Mhd.Amer Almardini, Mahzia yahia. Validated HS-GC-FID Method for Determination of Residual Ethanol in. Solid Dosage Form. Research J. Pharm. and Tech. Feb. 2014; 7(2):184-187.

  • Ahrendt KA, Borths CJ, MacMillan DWC. New strategies for organic catalysis: the first highly enantioselective organocatalyticDiels−Alder reaction. J. Am.Chem. Soc. 2000;122:4243–4.

  • List B, Lerner RA, Barbas III CF. Proline-catalyzed direct asymmetric aldol reactions. J. Am.Chem.Soc.2000;122:2395–6.

  • MacMillan DWC. The advent and development of organocatalysis. Nature. 2008;455:304–8.

  • Marqués-López E, Herrera RP, Christmann M. Asymmetric organocatalysis in total synthesis – a trial by fire. Nat.Prod.Rep. 2010;27:1138–67.


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  • Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame Ionized Detection for the Determination of Residual Solvents in Letermovir API Synthesis

Abstract Views: 168  |  PDF Views: 0

Authors

P. Bala Krishnaiah
Vignan Institute of Pharmaceutical Technology, Beside VSEZ, Kapujaggarajupeta, Duvvada, Visakhapatnam-530049, India
R. E.M. Prema Chandrika
K.L.E.F, Vaddeswaram, Guntur District-522502, Andhra Pradesh., India

Abstract


Residual solvent testing is an integral part of reference material certification. A gas chromatography / flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: ethyl acetate, MTBE, Toluene and isopropyl acetatein Letermovir API. HS-GC method in a simple and selective manner is delineated for the quantification and determination of Residual Solvents in Letermovir API. The separation of solvents along with drug on Chromatographic chamber was processed on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30 m × 0.32mm × 1.8μm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 10-50μg/ml for ethyl acetate, MTBE, Toluene and isopropyl acetate (r2>0.999) for the amount of solvent determined through sophisticated methods was in good agreement. The proposed methods were validated. The method of accuracy was assessed by recovery studies at three different levels.The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for ethyl acetate, MTBE, Toluene and isopropyl acetate. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of ethyl acetate, MTBE, Toluene and isopropyl acetate in Letermovir. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity (micrograms/mL) and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

Keywords


Letermovir, Head-Space GC, Residual solvents.

References