Headspace-gas Chromatography Analysis of Residual Solvents in Pharmaceuticals

The latent toxicity of organic residual solvents in pharmaceuticals has gradually become recognized. At present, the Pharmacopoeia of each country contains the residual solvent inspection method. The International Conference on Harmonization (ICH) is divided into three categories according to the degree of harm to the human body and environment for the 69 organic solvents commonly used in the production and purification of pharmaceuticals. For pharmaceutical companies, the analysis of residual solvents is an essential part of the production process. Among them, the most commonly used detection method is headspace gas chromatography.

Introduction

Headspace gas chromatography is also known as liquid-gas chromatography. It has the characteristics of faster analysis speed, no need to extract with an organic solvent, easy operation, and little harm to analysts and environment. The principle is that the sample to be tested is placed in a closed container, and the volatile components are volatilized from the sample matrix by heating (Figure 1). Equilibrium is achieved in the gas-liquid (or gas-solid) phase, and the top gas is directly extracted for chromatographic analysis to examine the composition and content of volatile components in the sample. The use of headspace sampling technology eliminates the tedious and tedious sample preparation process, avoids the interference of organic solvents on the analysis, and reduces contamination of the column and inlet.

Fig. 1. Schematic diagram of a pressure balances static headspace system¹.

Application of Headspace-gas Chromatography in the Detection of Residual Solvents

Limits for five organic volatile impurities (benzene, chloroform, dioxane, methylene chloride, and trinitroethylene) are specified in USP41-NF36, which is determined by static head-space analysis. Since the head-space sampler is extremely easy to achieve solvent-free extraction of liquid and solid samples, which can be said to fundamentally eliminate errors and problems that may occur in sample preparation methods, such as adsorption and solvent extraction. Headspace gas chromatography has the following advantages.

Operative convenience

Headspace-gas Chromatography Analysis is the combination of head-space analysis technology and chromatographic analysis. In the analysis of residual solvents, it is often necessary to pretreat the sample prior to measurement, such as separation enrichment. During the analysis process, it is not only impossible to separate the analyte at the μg level from the sample, but also possible to introduce a new error factor by introducing an interference component from the analysis environment. The head-space analysis method does not directly analyze, but analyzes the gas phase in equilibrium with the sample, thereby avoiding the disadvantages of the pretreatment method.

Head-space gas chromatography analysis directly takes a volatile gaseous sample of a liquid sample (or solid sample) and sends it to an air-phase chromatograph for separation and analysis. In many cases, sample preparation can be eliminated, so this method is faster and easier than ordinary chromatographic analysis. Han J et al. had determined the residual isobutylene oxide in medicine by static head-space gas chromatography, the results showed that the head-space GC had less pretreatment time than the direct injection GC. At the same time, the recovery rate (102.4%) is higher.

High sensitivity

When headspace analysis combined with infrared spectrum and the ultraviolet spectrum is used to analyze residual solvents, the total amount of residual solvents can only be determined because of the lack of separation ability, the sensitivity is low, and it is difficult to achieve satisfactory analytical results. Headspace gas chromatography combines the characteristics of good separation performance and high detection sensitivity and can be used to analyze complex mixtures and low-content components, thus expanding the scope of its application. For example, when the residual solvent in musk ketone in artificial musk is determined by headspace gas chromatography, methanol, ethanol, diethyl ether and petroleum ether (60-90 ° C) have a good linear relationship in each concentration range; the detection limits are 1.0, 0.1 and 0.3 μg/ml, respectively.

Prolonging the life of the column

Compared with the direct injection analysis, the gas sample injected by headspace gas chromatography is "clean", and there is no nonvolatile recombined component, which avoids the overload or pollution of the chromatographic column and prolongs the service life of the chromatographic column. In addition, the gasification chamber of headspace gas chromatography is usually operated at a lower temperature, avoiding the decomposition of components.

References

• Nicholas H. Snow. (2002) ‘Head-space analysis in modern gas chromatography.’ Department of Chemistry and Biochemistry, 21(9-10): 608-617.

• Feng-hua Liu, Ye Jiang, (2007) ‘Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography.’ Journal of Chromatography A, 1167(1): 116-119.

• José Luis Pérez Pavón, Miguel del Nogal Sánchez, Carmelo García Pinto, M Esther Fernández Laespada, Bernardo Moreno Cordero, Armando Guerrero Pe?a, (2006) ‘Strategies for qualitative and quantitative analyses with mass spectrometry-based electronic noses.’ TrAC Trends in Analytical Chemistry,25(3): 257-266.

• Raquel Otero, Guillem Carrera, Joan Francesc Dulsat, José Luís Fábregas, Juan Claramunt, (2004) ‘Static headspace gas chromatographic method for quantitative determination of residual solvents in pharmaceutical drug substances according to European Pharmacopoeia requirements.’ Journal of Chromatography A, 1057(1-2): 193-201.

• Han J, Yeung D, Wang F, Semin D, (2008) ‘Determination of residual isobutylene oxide--a genotoxic starting material in a drug substance by static headspace gas chromatography.’ J Chromatogr Sci, 46(7):637-42.

• Liu D, Wang KM, Xiao X, Lun LJ, Zhang S, (2014) ‘Determination of the content of residual solvents in muscone by head-space gas chromatography.’ Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 36(6):606-9.

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