Author(s):
S. V. Pushkin, R. A. Ivanov, S. V. Goriainov
Email(s):
pushkin.sv45@gmail.com
DOI:
10.52711/0974-360X.2026.00636 
Address:
S. V. Pushkin1*, R. A. Ivanov1, S. V. Goriainov2
1Sirius University of Science and Technology, Sochi, Krasnodar Region 354340, Russia, (ORCID 0009-0001-3195-2181).
1Sirius University of Science and Technology, Sochi, Krasnodar Region 354340, Russia, (ORCID 0009-0001-3195-2181) (ORCID 0000-0002-9573-4183).
2Рeoples’ Friendship University of Russia (RUDN University), 117198, Moscow, Russia, (ORCID 0000-0002-7625-9110).
*Corresponding Author
Published In:
Volume - 19,
Issue - 10,
Year - 2026
ABSTRACT:
An analytical method for determining N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), acetic acid (AcOH), and dimethyl sulfoxide (DMSO) as residual solvents in the active pharmaceutical ingredient (API) was developed using direct injection (DI) gas chromatography (GC). The BP20 capillary column used showed good efficiency, including for the asymmetry factor parameter for DIPEA and AcOH peaks. Due to the poor solubility of risdiplam in organic solvents at a concentration of 25-50 mg/ml and osmosis in the liner, acetonitrile was chosen as the solvent - DIPEA, DMF, AcOH, and DMSO transfer to acetonitrile with minimal API solubility when shaken. The extraction of solvents from risdiplam is at least 99.5%. The results of the validation of the method show that it is sensitive, linear, accurate, convergent, and reproducible. Linearity was tested at concentrations of 1.25-150.0 µg/ml with a correlation coefficient of 0.9991-1.0000. The limits of detection (LOD) and quantification (LOQ) were 0.375-1.875 and 1.25-6.25 µg/ml, respectively. Requirements for method validation are approved in the International Council for Harmonization (ICH) of technical requirements for pharmaceuticals for human use "Validation of analytical procedures Q2(R2)". Both a flame ionization detector (FID) for quantification and mass spectrometry (MS) for compound identification were used.
Cite this article:
S. V. Pushkin, R. A. Ivanov, S. V. Goriainov. N,N-Diisopropylethylamine, N,N-dimethylformamide, Acetic Acid and Dimethyl Sulfoxide Direct Injection in the Active Pharmaceutical Ingredient Risdiplam by GC-FID-MS. Research Journal Pharmacy and Technology. 2026;19(10):4573-0 doi: 10.52711/0974-360X.2026.00636
Cite(Electronic):
S. V. Pushkin, R. A. Ivanov, S. V. Goriainov. N,N-Diisopropylethylamine, N,N-dimethylformamide, Acetic Acid and Dimethyl Sulfoxide Direct Injection in the Active Pharmaceutical Ingredient Risdiplam by GC-FID-MS. Research Journal Pharmacy and Technology. 2026;19(10):4573-0 doi: 10.52711/0974-360X.2026.00636 Available on: https://rjptonline.org/AbstractView.aspx?PID=2026-19-10-12
REFERENCES:
1. Stephane Caron. Practical Synthetic Organic Chemistry, USA. 2020.
2. Hajjar F by et al. Quantitative determination content for the Residual Organic Solvents in a combined drug based on Jacob’s Ladder herbs, motherwort herbs and hawthorn fruit by GC-FID. Research Journal of Pharmacy and Technology. 2022; 15: 3669–3673. https://doi.org/10.52711/0974-360X.2022.00615.
3. V Pharmacognosy MG, College P. Gas Chromatographic Ethanol Determination in Bhunimbadi Kwath Introduction: Calibration curve of ethanol. Research Journal of Pharmacy and Technology. 2009; 2: 880–881.
4. Helaliy R by et al. Determination Thymol in Thyme extract and its Pharmaceutical forms by using Gas Chromatography method. Research Journal of Pharmacy and Technology. 2020; 13: 4055–4060. https://doi.org/10.5958/0974-360X.2020.00717.9.
5. Witschi C, Doelker E. Residual solvents in pharmaceutical products: Acceptable limits, influences on physicochemical properties, analytical methods and documented values. Eur. J. Pharm. Biopharm. 1997; 43(3): 215–242.
6. Patil HD by et al. REVIEW ARTICLE A Brief Review on Gas Chromatography. Asian Journal of Pharmaceutical Analysis. 2023; 13(1): 47–52. doi: 10.52711/2231-5675.2023.00008.
7. B’Hymer C. Residual solvent testing: A review of gas-chromatographic and alternative techniques. Pharm Res. 2003; 20(3): 337–344. doi: 10.1023/A:1022693516409.
8. Snow NH, Slack GC. Head-space analysis in modern gas chromatography. TrAC - Trends Anal Chem. 2002; 21(9-10): 608–617. doi: 10.1016/S0165-9936(02)00802-6.
9. Tankiewicz M by et al. Analytical procedures for quality control of pharmaceuticals in terms of residual solvents content: Challenges and recent developments. TrAC - Trends Anal Chem. 2016; 80: 328–344. doi: 10.1016/j.trac.2015.09.008.
10. Bhupatiraju RV, Rao BS. Gas Chromatography-Head Space-Flame Ionization Sensor based assessment of four residuary solvents in rivaroxaban bulk medication. Research Journal of Pharmacy and Technology. 2022; 15: 5158–5163. https://doi.org/10.52711/0974-360X.2022.00868.
11. Patrudu TB, Suneel Kumar. 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. doi: 10.5958/2349-2988.2018.00014.1.
12. Christian Reichardt. Solvents and Solvent Effects in Organic Chemistry, Germany. 2003.
13. Soria AC by et al. Volatile sampling by headspace techniques. TrAC - Trends Anal Chem. 2015; 71: 85–99. doi: 10.1016/j.trac.2015.04.015.
14. B RK, Soundarya J. Method Development and Validation for the estimation of Class-2 Residual Solvents in Valacyclovir by HS-GC. Research Journal of Pharmacy and Technology. 2022 Dec; 15: 5388–5392. doi: 10.52711/0974-360X.2022.00908.
15. Rao SS, Vijayalakshmi A. Analytical Method Development and Validation of Glipizide to Determine Residual solvents by head Space-Gas Chromatography. Research Journal of Pharmacy and Technology. 2021 May; 14: 2440–2444. doi: 10.52711/0974-360X.2021.00429.
16. Babu JR by et al. Residual Solvents in Bendamustine Hydrochloride By Headspace Chromatography. Asian Journal of Pharmaceutical Analysis. 2018; 8(1): 7–12. doi: 10.5958/2231-5675.2018.00002.9.
17. Cheng C by et al. A generic static headspace gas chromatography method for determination of residual solvents in drug substance. J Chromatogr A. 2010; 1217(41): 6413–6421. doi: 10.1016/j.chroma.2010.08.016.
18. Ian M. Smallwood. Handbook of organic solvent properties, London. 1996.
19. Camarasu C by et al. Recent progress in the determination of volatile impurities in pharmaceuticals. TrAC - Trends Anal Chem. 2006; 25(8): 768–777. doi: 10.1016/j.trac.2006.05.013.
20. Grodowska K, Parczewski A. Analytical methods for residual solvents determination in pharmaceutical products. Acta Pol Pharm - Drug Res. 2010; 67(1): 13–26.
21. International Council for Harmonisation (ICH) of technical requirements for pharmaceuticals for human use (2024), impurities: guideline for residual solvents Q3C(R9). https://www.ich.org/page/quality-guidelines. Accessed date: 24 January 2024.
22. European Pharmacopoeia 11.0, https://www.edqm.eu/en/european-pharmacopoeia-ph.-eur.-11th-edition, (2023).
23. European Chemicals Agency, Ethyldiisopropylamine, Toxicological information. https://echa.europa.eu/de/registration-dossier/-/registered-dossier/13609/7/9/2.
24. Ismail A, Alahmad Y. Determination of ethanol and n-hexane residues in bulk rosuvastatin and atorvastatin and their dosage forms using HS-GC-MS developed method. Research Journal of Pharmacy and Technology. 2018; 11: 4829–4836. https://doi.org/10.5958/0974-360X.2018.00878.8.
25. Telavane SA by et al. Method of Validation for Residual Solvents in Bisoprolol Fumarate by GC Technique. Asian Journal of Pharmaceutical Research. 2021; 11: 147–155. https://doi.org/10.52711/2231-5691.2021.00028.
26. Alahmad S, Almardini MA. Validated HS-GC-FID Method for Determination of Residual Ethanol in Solid Dosage Form. Research Journal of Pharmacy and Technology. 2014;7:184–187.
27. International Council for Harmonisation (ICH) of technical requirements for pharmaceuticals for human use (2023), Validation of analytical procedures Q2(R2). https://www.ich.org/page/quality-guidelines. Accessed date: 1 November 2023.
28. Shou M, Qiu H. Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1,1,3,3-tetramethylguanidine residues in an active pharmaceutical ingredient. J Pharm Anal. 2021; 11(2): 251–256. doi: 10.1016/j.jpha.2020.06.007.
29. Zhang H by et al. Development and validation of a GC-FID method for quantitative analysis of oleic acid and related fatty acids. J Pharm Anal. 2015; 5(4): 223–230. doi: 10.1016/j.jpha.2015.01.005.