Development and Validation of a Procedure for the Quantitative Determination of Residual Organic Solvents in Allergen Preparations by GC

Introduction. One of the requirements for the quality of pharmaceuticals, including allergens, is the determination of residual organic solvents in them. In the production of allergen preparations, in a number of cases in the technological process, organic solvents of the third toxicity class are used, diethyl ether and acetone, which are solvents of low toxicity and their maximum content is allowed up to 0.5 % (5000 ppm). Since diethyl ether or acetone, and in some cases both solvents can be used simultaneously in the production process of allergen preparations for degreasing and cleaning, it is therefore advisable to develop and use a unified technique to determine them.

Aim. The aim of the study was to develop and validate a method for the quantitative determination of residual organic solvents in allergen preparations.

Materials and methods. The studies were carried out by gas-liquid chromatography with a flame ionization detector with injection of the test samples using an autosampler on a Zebron ZB-624 capillary quartz column (G43, 6 % cyanopropylphenyl / 94 % dimethylpoly siloxane).

Results and discussion. The conditions for the chromatographic separation of acetone and diethyl ether on a capillary quartz column were selected. The parameters of the suitability of the chromatographic system have been determined. The developed method was validated according to the following characteristics: specificity, linearity, limit of quantitative determination, correctness and precision at the level of repeatability and intra-laboratory precision. The content of acetone and diethyl ether in 26 preparations of allergens was determined. The results of the quantitative determination of diethyl ether and acetone in allergen preparations, in the technological process of which OOP are used, are in the range of 0.0053–0.0524 % for diethyl ether and 0.0029–0.0994 % for acetone. Thus, the content of diethyl ether and acetone in all tested allergen preparations was below the established norm (less than 0.5 %).

Conclusion. An analytical method has been developed for determining the quantitative content of diethyl ether and acetone in allergen preparations using the GLC method; the method has been validated according to characteristics that meet the requirements of General Pharmacopoeia Monograph 1.1.0012.15 "Validation of analytical methods". The analysis of allergen preparations was carried out in accordance with the methodology. In all preparations, the content of diethyl ether and acetone was no more than 0.5 %.

1. Olefir Yu. V., Sakanyan E. I., Shishova L. I., Senchenko S. P. Pharmacopoeial requirements to the quality of medicinal products. Pharmaceutical Chemistry Journal. 2018;(52)11:48–54. DOI: 10.30906/0023-1134-2018-52-11-48-54. (In Russ.)

2. Taube A. A., Gilyok M. T., Sakanyan E. I. Methodological approaches to improving the quality of raw medicinal plant materials of the pollen morphology group. Pharmaceutical Chemistry Journal. 2021;(55)12:56–60. DOI: 10.30906/0023-1134-2021-55-12-56-60. (In Russ.)

3. Nevskaya L. V., Lavrenchik E. I., Zhdanova M. Yu., Fadeykina O. V., Kapitanova V. K. International practice of allergen products standardization. BIOpreparaty. Profilaktika, diagnostika, lechenie. 2017;17(4):222–229. (In Russ.)

4. Olefir Y. V., Sakanyan E. I., Shemeryankina T. B., Senchenko S. P., Zaitsev S. A., Barmin A. V. Standardization of drug substances according to the purity section. Pharmaceutical Chemistry Journal. 2018;(52)8:56–60. (In Russ.)

5. Teryoshkina O. I., Guskova T. A., Ramenskaya G. V., Samylina I. A. Pharmacopoeial approaches to rationing residual organic solvents in medicines. Pharmacy. 2017;(66)1:9–13. (In Russ.)

6. Dudenkova M. E., Grushevskaya L. N., Sergeeva M. S. Development and validation of methods for identification and quantitative determination of residual organic solvents in the substance of the dipeptide mimetic of nerve growth factor GK-2. Pharmaceutical Chemistry Journal. 2020;(54)2:49–53. DOI: 10.30906/0023-1134-2020-54-2-49-53. (In Russ.)

7. Petukhov A. E., Petrykina E. A., Tereshkina O. I., Ramenskaya G. V., Antipova O. M., Turashev A. D., Zav’yalova E. G., Golovin A. V., Pavlova G. V., Kopylov A. M. Standardization of thrombaptanib drug substance for residual organic solvents. Pharmaceutical Chemistry Journal. 2018;(52)4:53–58. DOI: 10.30906/0023-1134-2018-52-4-53-58. (In Russ.)

8. Lastovka A. V., Yakovleva E. Yu., Kollegov V. F., Fadeeva V. P., Salahutdinov N. F. Chromatographic determination of residual organic solvents in (2r,4r,4ar,7r,8ar)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2h-chromen-4-ol which exhibits high analgesic activity. Zavodskaya Laboratoriya. Diagnostika Materialov. 2018;84(9):13–20. (In Russ.)

9. Kompantseva E. V., Lutsenko D. N., Larsky M. V. Determination of residual organic solvents in a new cardioprotective compound by gas chromatography. Problems of Biological, Medical and Pharmaceutical Chemistry. 2021;(24)10:52–58. (In Russ.)

10. Butina E. V., Zaitsev S. A., Basevich A. V. Development and validation of method of quantitative determination of residual organic solvents in innovative active pharmaceutical ingredient with GC-FID. Drug development & registration. 2016;(4):124–128. (In Russ.)

11. Holbert K. A., Wigdergauz M. S. Introduction to Gas Chromatography. Moscow: Khimiya; 1990; 344 p. (In Russ.)