Novel Method for Quantification of Residual Solvent by Head-Space Gas Chromatography for Phenylephrine Hydrochloride USP
Abstract
The manufacturing process of phenylephrine hydrochloride drug substance contains the use of different solvents in synthesis. USP monograph doesn’t provide method for the residual solvents of Active Pharmaceutical Ingredients (API) as the usage of solvents in manufacturing process depends on route of synthesis. Thus, a novel method has been developed and validated as per ICH guidelines for the quantification of solvents in APIs. The method has been developed for the quantification of ethanol, methanol and isopropanol residual solvents present in phenylephrine hydrochloride USP by Head-Space Gas Chromatography (HS-GC) using Agilent GC-7890B with HS-7697A and Restek MXT-502.2 (diphenyl / dimethyl polysiloxane) 105m x 0.53mm x 3.0µm column. The method has been validated according to ICH Q2R2 guidelines with validation parameters including Specificity, Linearity, Limit of Detection (LOD)/ Limit of Quantification (LOQ), Precision (System precision, Method precision, LOQ Precision), Accuracy. The system precision obtained the %RSD of 2.5, 2.7 and 2.7 and the LOQ was established as 23.5 ppm. 39.0 ppm and 16.4 ppm respectively for ethanol, methanol and isopropanol. The LOD of 7.7 ppm, 12.8 ppm and 5.4 ppm for ethanol, methanol and isopropanol indicated the sensitivity of the method for the detection of analytes. The linearity range of 1% to 100% level of specification revealed the correlation coefficient of 0.9987, 0.9978, 0.9991 respectively for ethanol, methanol and isopropanol solvents.
Keywords:
Head-Space Gas Chromatography, Residual Solvent, Phenylephrine hydrochloride, Validation, ICHDOI
https://doi.org/10.25004/IJPSDR.2025.170208References
Richards E, Lopez MJ, Maani CV. Phenylephrine [Internet]. U.S. National Library of Medicine; 2023 [cited 2025 Mar 7]. Available from:
PubChem: National Center for Biotechnology Information. Phenylephrine Hydrochloride [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004 [cited 2025 Jan 23]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Phenylephrine-Hydrochloride
United State Pharmacopoeia and National Formulary (USP-NF). Phenylephrine Hydrochloride. Rockville, MD: United States Pharmacopeial Convention; 2024. [cited 2025 Jan 29]. Available from: https://online.uspnf.com/uspnf/document/1_GUID-3A30DAC5-A752-4351-A62B-4FCB7490364C_2_en-US
Guidance for Industry Residual Solvents in Drug Products Marketed in the United States [Internet]. Silver Spring, MD: U.S Department of Health and Human Services Food and Drug Administration; 2009 Nov. [cited 2025 Jan 29]. Available from: https://www.fda.gov/media/70928/download
United State Pharmacopoeia and National Formulary (USP-NF). USP General Chapter <467> Residual Solvent. Rockville, MD: United States Pharmacopeial Convention; 2024. [cited 2025 Jan 29]. Available from: https://online.uspnf.com/uspnf/document/1_GUID-2DBF4188-861C-4B0E-B7DF-E3BEE82B0D9E_8_en-US
Tian J, Rustum A. Development and validation of a fast static headspace GC method for determination of residual solvents in permethrin. J Pharm Biomed Anal. 2016;128:408-415. https://doi.org/10.1016/j.jpba.2016.06.020
Puranik SB, Pawar VR, Lalitha N, Pai PN, Rao GK. Residual solvent analysis in hydrochloride salts of active pharmaceutical ingredients. Pak J Pharm Sci. 2009;22(4):410-4. PMID: 19783521.
Klick S, Sköld A. Validation of a generic analytical procedure for determination of residual solvents in drug substances. J Pharm Biomed Anal. 2004;36(2):401-9. https://doi.org/10.1016/j.jpba.2004.06.014.
Tankiewicz M, Namieśnik J, Sawicki W. Analytical procedures for quality control of pharmaceuticals in terms of residual solvents content: Challenges and recent developments, TrAC Trends in Analytical Chemistry. 2016;80:328-44, ISSN 0165-9936, https://doi.org/10.1016/j.trac.2015.09.008.
Li J, Shao S, Solorzano M, Allmaier GJ, Kurtulik PT. Determination of the residual ethanol in hydroalcoholic sealed hard gelatin capsules by static headspace gas chromatography with immiscible binary solvents, Journal of Chromatography A. 2009;1216(15):3328-36, ISSN 0021-9673. https://www.sciencedirect.com/science/article/pii/S0021967309002556
Sojitra, C, Tehare, A, Dholakia C, Padmaja S, Agarwal S, Singh KK. Development and validation of residual solvent determination by headspace gas chromatography in Imatinib Mesylate API. SN Appl. Sci. 2019;1:233. https://doi.org/10.1007/s42452-019-0233-x
Sivasaikiran B, Chowdary YN, Sreelakshmi V, Shrivastava SK, Pugazhendhy S, Development and Validation of a Headspace Gas Chromatographic Method for determination of Residual solvents in Bosentan Monohydrate. International Journal of Pharm Tech Research. 2014;6(2):421-7.
Pasha S. I, Liyaqat S, Khan M. M. A, Farhan M. A, Koneru A. Analytical Method for the Development and Validation of Residual Solvents in Tigecycline by Gas Chromatography Using Headspace Sampling Technology. Biotech Res Asia 2024;21(3). Available from: https://bit.ly/4euEldb.
Vallakeerthi N, Ravinder Nath A, Moorthy RS, Reddy PM. HS-GC-FID Method Development and Validation for Quantification of Residual Solvents in Fvipiravir. Journal of Pharmaceutical Negative Results. [Internet]. 2022 Dec. 31 [cited 2025 Feb. 17];:3675-8. Available from: https://www.pnrjournal.com/index.php/home/article/view/9459
International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use Guideline. Validation of Analytical Procedures Q2(R2). Geneva, Switzerland: International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use; 2023 Nov. [cited 2025 Jan 29]. Available from: https://www.ich.org/page/quality-guidelines
Cheng C, Liu S, Mueller BJ, Yan Z. A generic static headspace gas chromatography method for determination of residual solvents in drug substance, Journal of Chromatography A. 2010;1217(41):6413-6421. ISSN 0021-9673. Available from: https://doi.org/10.1016/j.chroma.2010.08.016.
Louati K, Sayadi M, Safta F. Development and Validation of a Separation and Quantification Method for Residual Solvents in Active Substances by Headspace Gas Chromatography. ASRJETS-Journal [Internet]. 2018 Mar. 14 [cited 2025 Feb. 17];41(1):57-75. Available from: https://asrjetsjournal.org/index.php/American_Scientific_Journal/article/view/3892
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