Static Headspace Gas Chromatographic Method Research Articles

A Static Headspace Gas Chromatography Method for Quantitation of Residual Solvents in Nanoformulations.

Various organic solvents are widely used in the manufacturing, processing, and purification of drug substances, drug products, formulations, excipients, etc. These solvents must be removed to the lowest amount permitted, as they do not possess any therapeutic advantages and may cause undesirable toxicities. Therefore, a rapid and sensitive analytical method for the quantitation of residual solvents is needed. The following chapter presents a static headspace gas chromatographic (HSGC) method for determining the concentration of common residual solvents in various nanoformulations. An efficient and sensitive HSGC method has been developed using PerkinElmer's headspace autosampler/gas chromatographic system with a flame ionization detector (FID) and validated according to the International Conference for Harmonization (ICH) guideline Q3C. The method validation indicates that the method is specific, linear, accurate, precise, and sensitive for the analyzed solvents. The method is suitable for the analysis of 13 residual solvents (methanol, ethanol, acetone, diethyl ether, 2-propanol, acetonitrile, 1-propanol, ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, 1-butanol, and pyridine) and utilizes an Elite 624 Crossbond 6% cyanopropylphenyl, 94% dimethylpolysiloxanes column with helium as a carrier gas.

A Full Evaporation Static Headspace Gas Chromatography Method with Nitrogen Phosphorous Detection for Ultrasensitive Analysis of Semi-volatile Nitrosamines in Pharmaceutical Products

The recent detection of potent carcinogenic nitrosamine impurities in several human medicines has triggered product recalls and interrupted the supply of critical medications for hundreds of millions of patients, illuminating the need for increased testing of nitrosamines in pharmaceutical products. However, the development of analytical methods for nitrosamine detection is challenging due to high sensitivity requirements, complex matrices, and the large number and variety of samples requiring testing. Herein, we report an analytical method for the analysis of a common nitrosamine, N-nitrosodimethylamine (NDMA), in pharmaceutical products using full evaporation static headspace gas chromatography with nitrogen phosphorous detection (FE-SHSGC-NPD). This method is sensitive, specific, accurate, and precise and has the potential to serve as a universal method for testing all semi-volatile nitrosamines across different drug products. Through elimination of the detrimental headspace-liquid partition, a quantitation limit of 0.25 ppb is achieved for NDMA, a significant improvement upon traditional LC-MS methods. The extraction of nitrosamines directly from solid sample not only simplifies the sample preparation procedure but also enables the method to be used for different products as is or with minor modifications, as demonstrated by the analysis of NDMA in 10+ pharmaceutical products. The in situ nitrosation that is commonly observed in GC methods for nitrosamine analysis was completely inhibited by the addition of a small volume solvent containing pyrogallol, phosphoric acid, and isopropanol. Employing simple procedures and low-cost instrumentation, this method can be implemented in any analytical laboratory for routine nitrosamine analysis, ensuring patient safety and uninterrupted supply of critical medications.Graphical

Development and Validation of an Automated Gas Chromatography Method for Determination of Dichloromethane in Ampicillin Sodium by Using Capillary Column Technology

Background: The main aim of the study was to develop an automated static headspace gas chromatography (SHS-GC) method for determination of dichloromethane (DCM) in ampicillin sodium by using a capillary column. Methods: SHS-GC also known as gas chromatography-headspace is the technique of choice due to its high sensitivity, excellent separation abilities, low limit of detection and simplicity of the instrumentation used for the technique. The headspace sampling method has more appropriate sensitivity than the direct injection method because it can clearly separate volatile analytes from the sample matrix and effectively concentrate them. Therefore, this method results in less complex sample preparation, decreased instrument contamination, and increased capillary column life. Results: The developed SHS-GC method showed symmetrical peak shape reasonable retention time for DCM. A linear relationship was obtained over the range of 2-240 μg mL-1 with a correlation coefficient (r2) of 0.993. The recovery, system precision and robustness of the method were within the acceptable values. The Limit of Detection (LOD) and Limit of Quantitation (LOQ) were 0.5 μg mL-1 and 2 μg mL-1 respectively. Conclusions: The results obtained in this study demonstrate that SHS-GC method is selective, precise, linear, accurate and robust for determination of dichloromethane in ampicillin sodium and its formulation (injection).

Static headspace gas chromatographic determination of hexanal as a marker of lipid oxidation in fat-rich food

Static headspace gas chromatographic method for determination of hexanal as a marker of lipid oxidation was developed. Tetradecane was suggested as a matrix for hexanal release from the sample. Sample equilibration temperature and time, tetradecane volume, injection time were optimized. Benzaldehyde was selected as an internal standard. Under the optimized conditions quality parameters were determined. The calibration curve was linear in the concentration range from 25 µg l–1 to 2 g l–1, the detection limit was 15 µg l–1, RSD was determined by five replication analysis with hexanal concentration 0.1 g l–1 and was 1.2%. The technique was applied for hexanal determination in potato chips and fried potatoes.

Diurnal variations of greenhouse gases emissions from reclamation mariculture ponds

Dissolved concentrations, saturation status, and emission fluxes of greenhouse gases (GHGs) in two reclamation mariculture ponds in the Bohai Gulf, China, were measured using the static headspace gas chromatography method and computed using a two-layer model of diffusive gas exchange. The study was conducted during August 2016 to assess diurnal variations in GHGs emissions. The main influencing factors of GHGs emissions from the ponds under the disturbance of artificial management were identified using Spearman correlation analyses and multiple stepwise regression analyses. Results showed that dissolved GHGs concentrations were stable throughout the day, whereas GHGs emission fluxes showed a clear diurnal variation with larger daytime values. The diurnal variation of N2O emission fluxes was greater than that of CO2 and that of CH4. Results also showed that pH of pond water was negatively correlated with CO2 and N2O emission fluxes and that air temperature was positively correlated with CH4 and N2O emission fluxes. In addition, ammonia (NH4+-N) was positively correlated with CH4 emission fluxes; water temperature and salinity were positively correlated with N2O emission fluxes. The estimated annual emissions from the reclamation aquaculture in Tianjin and the Bohai Rim region were 2.53 × 105 kg C–CO2, 6.94 × 103 kg C–CH4 and 1.11 × 103 kg N–N2O, and 3.42 × 107 kg C–CO2, 9.36 × 105 kg C–CH4 and 1.50 × 105 kg N–N2O respectively, indicating the important contribution of this fishery sector to GHGs emissions.

Analysis of thermolabile residual solvents in a spray dried dispersion using static headspace gas chromatography.

In this study, we discuss the development of a static headspace gas chromatography method for the analysis of residual acetone as well as its enriched impurities including mesityl oxide and diacetone alcohol, in a spray dried dispersion. The major challenges include the instability of mesityl oxide and diacetone alcohol at high temperature and peak tailing of diacetone alcohol. It was found that the headspace oven temperature has to be controlled to 150°C or below to prevent degradation beyond an acceptable level (<1%). The peak tailing of diacetone alcohol was attributed to the "Phase Soaking" effect due to excessive diluent, which may condense and temporarily modify the stationary phase. The peak shape of diacetone alcohol is dependent on the column loading capacity and the peak area of N-methyl pyrrolidone, the solvent that elutes after diacetone alcohol. The headspace oven temperature was set at 140°C, where the highest response ratio of diacetone alcohol/N-methyl pyrrolidone at 1.46 and thus the best sensitivity was obtained. The calculated quantitation limits were 1ppm for acetone, 3ppm for mesityl oxide and 31ppm for diacetone alcohol. The method successfully passed validation criteria for specificity, linearity, accuracy, and precision.

Microbes a Tool for the Remediation of Organotin Pollution Determined by Static Headspace Gas Chromatography-Mass Spectrometry.

Tributyltin (TBT) is one of the most toxic anthropogenic compounds introduced into the marine environment. Despite its global ban in 2008, TBT is still a problem of great concern due to its high affinity for particulate matter, providing a direct and potentially persistent route of entry into benthic sediments. Bioremediation strategies may constitute an alternative approach to conventional physicochemical methods, benefiting from the microorganism’s potential to metabolize anthropogenic compounds. In this work, a simple, precise and accurate static headspace gas chromatography method was developed to investigate the ability of TBT degrading microbes in sedimentary microcosms over a period of 120 days. The proposed method was validated for linearity, repeatability, accuracy, specificity, limit of detection and limit of quantification. The method was subsequently successfully applied for the detection and quantification of TBT and degradation compounds in sediment samples on day 0, 30, 60, 90 and 120 of the experiment employing the principles of green chemistry. On day 120 the concentration of TBT remaining in the microcosms ranged between 91.91 ng/g wet wt for the least effective microbial inoculant to 52.73 ng/g wet wt for the most effective microbial inoculant from a starting concentration of 100 ng/g wet wt.

A Robust Static Headspace GC-FID Method to Detect and Quantify Formaldehyde Impurity in Pharmaceutical Excipients.

Formaldehyde is a highly reactive impurity that can be found in many pharmaceutical excipients. Trace levels of this impurity may affect drug product stability, safety, efficacy, and performance. A static headspace gas chromatographic method was developed and validated to determine formaldehyde in pharmaceutical excipients after an effective derivatization procedure using acidified ethanol. Diethoxymethane, the derivative of formaldehyde, was then directly analyzed by GC-FID. Despite the simplicity of the developed method, however, it is characterized by its specificity, accuracy, and precision. The limits of detection and quantification of formaldehyde in the samples were of 2.44 and 8.12 µg/g, respectively. This method is characterized by using simple and economic GC-FID technique instead of MS detection, and it is successfully used to analyze formaldehyde in commonly used pharmaceutical excipients.

Headspace gas chromatographic analysis of St John’s Wort (Hypericum perforatum L.) and its medical derivatives

Static headspace gas chromatographic analysis method using flame ionization and mass spectrometric detection was applied for the qualitative and quantitative detection of volatile components in the equilibrium vapor phase of the medicinal St. John's Wort ( Hypericum perforatum L.) plant. The optimal conditions for the gas extraction, producing repeatable and characterizing chromatographic headspace profiles of the St. John's Wort, were established. The retention indices (IiT) for the linear programming of the column temperature with a low-polar stationary phase and the relative areas of the peaks ( A rl,i ) of the St. John's Wort volatile components have been determined. The obtained results were presented in the form of specific headspace-spectra « A rl,i - I i T » of the plants. It has been demonstrated that the headspace spectra of the botanical sample (Samara) and of the three industrial specimens of St. John's Wort obtained from various regions of Russia were close to each other. Major volatile compounds of the Russian St. John's Wort were: ethanal, propanal, dimethylsulfide, 2-methylpropanal, 2-methyl-3-butene-2-ol (marker), 2-methylbuthanal, 2-methyloctane, α-pinene, 3-methylnonane. Current research was the first to suggest using alcohol 2-methyl-3-butene-2-ol ( I i T = 617) as the volatile marker of St. John's Wort. Its relative quantity in the vapor phase of St. John's Wort ( A rl,i ) was equal to 15.53 – 20.75%. It has also been discovered that most of the components of the equilibrium phase of St. John's Wort including the 2-methyl-3-butene-2-ol marker were present in the vapor phase of the St. John's Wort medicines, dry tablet extract of St. John's Wort (Deprim, Slovenia) and oil extract of St. John's Wort (Russia). Keywords : Hypericum perforatum L., medical plant raw material, phytomedicines, volatile organic compounds, gas-liquid chromatography, headspace analysis, chromatographic profile (Russian) DOI: http://dx.doi.org/10.15826/analitika.2018.22.2.002 N.V. Pariichuk 1 , L.A. Onuchak 1 , Iu.A. Arutiunov 1 , V.A. Kurkin 2 , O.E. Pravdivtseva 2 1 Samara National Research University,Moskovskoe sh., 34, Samara, 443086, Russian Federation 2 Samara State Medical University, Chapaevskaia ul., 89, Samara, 443099, Russian Federation

Greenhouse gases emission from the sewage draining rivers

Carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) concentration, saturation and fluxes in rivers (Beitang drainage river, Dagu drainage rive, Duliujianhe river, Yongdingxinhe river and Nanyunhe river) of Tianjin city (Haihe watershed) were investigated during July and October in 2014, and January and April in 2015 by static headspace gas chromatography method and the two-layer model of diffusive gas exchange. The influence of environmental variables on greenhouse gases (GHGs) concentration under the disturbance of anthropogenic activities was discussed by Spearman correlative analysis and multiple stepwise regression analysis. The results showed that the concentration and fluxes of CO2, CH4 and N2O were seasonally variable with >winter>fall>summer, spring>summer>winter>fall and summer>spring>winter>fall for concentrations and spring>summer>fall>winter, spring>summer>winter>fall and summer>spring>fall>winter for fluxes respectively. The GHGs concentration and saturation were higher in comprehensively polluted river sites and lower in lightly polluted river sites. The three GHGs emission fluxes in two sewage draining rivers of Tianjin were clearly higher than those of other rivers (natural rivers) and the spatial variation of CH4 was more obvious than the others. CO2 and N2O air-water interface emission fluxes of the sewage draining rivers in four seasons were about 1.20–2.41 times and 1.13–3.12 times of those in the natural rivers. The CH4 emission fluxes of the sewage draining rivers were 3.09 times in fall to 10.87 times in spring of those in the natural rivers in different season. The wind speed, water temperature and air temperature were related to GHGs concentrations. Nitrate and nitrite (NO3−+NO2−−N) and ammonia (NH4+−N) were positively correlated with CO2 concentration and CH4 concentration; and dissolved oxygen (DO) concentration was negatively correlated with CH4 concentration and N2O concentration. The effect of human activities on carbon and nitrogen cycling in river is great.

Application of the SHS-GC-FID method and HPLC-DAD method in the prediction of the shelf-life of gluten-free cookies

The aim of this study was to compare the sensitivity of two analytical methods for the prediction of the shelf-life of unpacked and packed gluten-free rice?buckwheat cookies kept at ambient (23?1?C) and elevated (40?1?C) temperature during storage, namely the static headspace gas chromatographic method with flame ionisation detection (SHS-GC-FID) for volatile saturated aldehydes (propanal (C3), pentanal (C5), hexanal (C6), heptanal (C7) and octanal (C8)) and the HPLC method for malondialdehyde (MDA) determination. Both methods resulted in obtaining the same end-points of cookie shelf-life, i.e., 3 and 5 months for unpacked and packed cookies kept at elevated temperature, respectively, and 11 and 14 months for unpacked and packed cookies kept at ambient temperature, respectively. Two computational approaches, i.e., the second order polynomial (SOP) and artificial neural network (ANN) models, were used accordingly. The calculations of the contents of aldehydes and MDA could be predicted with an overall coefficient of determination of 0.722 using the ANN model compared to 0.312?0.773 for SOP models. According to sensitivity analysis, it might be suggested that the relevant parameter for the prediction of the end-point of cookie shelf-life is the MDA rather than the C3, C5, C6, C7 and C8 content.

Formation of Acrolein in the Autoxidation of Triacylglycerols with Different Fatty Acid Compositions

AbstractFish, echium, linseed, and soybean oil triacyglycerols (TAGs) were oxidized at 50 or 60 °C to determine the effect of the polyunsaturated fatty acid composition on the volatile product formation. The analysis of the oxygen consumption and total volatile formation demonstrated that the soybean oil TAG had the highest oxidative stability followed by linseed, echium, and fish oil TAGs. Our results were in agreement with the expected average number of bis‐allylic positions of each TAG. Higher quantities of acrolein (2‐propenal) and propanal were detected using the static headspace gas chromatography method at the early stages of oxidation of echium and fish oil TAGs; however, a considerable amount of propanal and only a small amount of acrolein were found in the oxidized linseed oil TAG. The peak area ratios of acrolein to propanal were 0.115, 0.569, and 2.554 after the 8‐h oxidation of linseed, echium, and fish oil TAG, respectively, suggesting the preferential formation of acrolein, especially during the fish oil TAG oxidation. The acrolein quickly increased during the first stage of oxidation, but thereafter it either did not change or slightly decreased during the fish oil oxidation. Because fish oil induces flavor deterioration from the very early stage of the oxidation, the acrolein formation observed in the present study may be important for fish oil deterioration.

Static headspace gas chromatographic method for the determination of residual solvents in cephalosporins

The pharmaceutical industry is facing a daunting challenge in the control of impurities.

Development and Validation of Static HS-GC Method for the Determination and Quantification of Residual Solvents of Bromhexine Hydrochloride (BHX)

The determination of residual solvents in drug substances is the mandatory requirement by various health authorities in the world. There are no analytical methods available in the literature that can simultaneously separate and quantitate residual solvents in bromhexine hydrochloride (BHX) active pharmaceutical ingredient (API). This paper describes the development and validation of a simple, efficient, accurate, and robust static headspace gas chromatography method for the determination of residual solvents, namely methanol, ethanol, ethyl acetate, monochlorobenzene, and benzene, in BHXAPI. This new method has been demonstrated to be accurate, linear, precise, reproducible, specific, and robust for its intended purpose. The method gives very good sensitivities viz. detection limits for benzene is 0.4 ppm, ethyl acetate 2 ppm and for others solvents 5 ppm and precision (below 9.0 % RSD) for all solvents. The results of this evaluation strongly indicate that this method can be readily used to determine residual solvents in BHX.

Static Headspace Gas Chromatographic Method for Aldehyde Determination in Crackers

The aim of this work was to develop and validate static headspace gas chromatography with flame ionization detection method for determination of five aldehydes selected as markers for lipid oxidation, present in freshly baked and stored crackers with high fat content. Chromatographic conditions defined in this method allow the separation of propanal, pentanal, hexanal, heptanal and octanal within 15 min. Relative standard deviations (RSD) of the retention times for repeatability and intermediate precision for all compounds were less than 1.75 and 0.22 %, respectively. For the obtained peak areas, RSD for repeatability and intermediate precision were less than 3.86 and 4.32 %, respectively. Recovery was within the range of 60–99 %. Each analyte showed an excellent linear behaviour over the set concentration range, with correlation coefficient (R2) values above 0.99. Limits of quantification for propanal, pentanal, hexanal, heptanal and octanal were 0.10, 0.05, 0.08, 0.02 and 0.02 μg, respectively. The proposed method accomplishes the requirements for the method selectivity, precision, sensitivity, accuracy and linearity needed for determination of aldehydes in bakery products. Quantification of aldehydes was achieved for both freshly baked and stored crackers over a long period of time.

Analysis of Residual Solvents in Annatto Extracts Using a Static Headspace Gas Chromatography Method

An analytical method for the quantification of residual solvents in annatto extracts, natural food colorants, was established using a static headspace gas chromatography (HSGC) coupled with a flame ionization detector (FID). As a sample diluent in a headspace sampling, dimethylformamide (DMF) was selected owing to its high capacity for dissolving both bixin-based and norbixin-based annatto extracts. The quantification of residual solvents was performed using the external standard method. The linearity of the calibration curves was assured with relative coefficients (R2) that were greater than 0.999. The recoveries of all standard solvents spiked in the annatto extracts were in the range from 95.1% to 107.1% to verify the accuracy and the relative standard deviation (RSD%) values (n = 3) were in the range from 0.57% to 3.31%. The quantification limits (QL) were sufficiently lower than the limits specified by Joint FAO/WHO Expert Committee on Food Additives (JECFA). With the established HSGC method, six residual solvents (methanol, ethanol, 2-propanol, acetone, ethyl acetate, and hexane) in 23 commercial annatto-extract products that consist of seven bixin-based and 16 norbixin-based products were quantified. The levels of residual ethyl acetate and hexane in all products were lower than the specified limits of JECFA. However, three samples of bixin-based products showed higher levels of residual 2-propanol (approximately 313.9 - 427.7 ppm) than the specified limit. Other bixin products also showed higher concentrations of residual methanol (approximately 166.6 - 394.7 ppm) and residual acetone (approximately 75.2 - 179.8 ppm) than the limits of JECFA. In the case of norbixin-based products, nine samples showed higher levels of residual acetone (approximately 42.6 - 139.5 ppm) than the limits of JECFA. This is the first survey of residual solvents in annatto extracts using the validated HSGC method.

Improving quantitative gas chromatography–electron ionization mass spectrometry results using a modified ion source: Demonstration for a pharmaceutical application

Gas chromatography–mass spectrometry is a well established analytical technique. However, mass spectrometers with electron ionization sources may suffer from signal drifts, hereby negatively influencing quantitative performance. To demonstrate this phenomenon for a real application, a static headspace-gas chromatography method in combination with electron ionization-quadrupole mass spectrometry was optimized for the determination of residual dichloromethane in coronary stent coatings. Validating the method, the quantitative performance of an original stainless steel ion source was compared to that of a modified ion source. Ion source modification included the application of a gold coating on the repeller and exit plate. Several validation aspects such as limit of detection, limit of quantification, linearity and precision were evaluated using both ion sources. It was found that, as expected, the stainless steel ion source suffered from signal drift. As a consequence, non-linearity and high RSD values for repeated analyses were obtained. An additional experiment was performed to check whether an internal standard compound would lead to better results. It was found that the signal drift patterns of the analyte and internal standard were different, consequently leading to high RSD values for the response factor. With the modified ion source however, a more stable signal was observed resulting in acceptable linearity and precision. Moreover, it was also found that sensitivity improved compared to the stainless steel ion source. Finally, the optimized method with the modified ion source was applied to determine residual dichloromethane in the coating of coronary stents. The solvent was detected but found to be below the limit of quantification.

Determination of Residual Solvents in Eprosartan Mesylate by Static Headspace Gas Chromatographic Method Optimized by Response Surface Methodology

A static headspace gas chromatographic (sHS-GC) method for quantitative determination of residual organic solvents in eprosartan mesylate drug substance is developed. SE-30 capillary column (30 m x 0.25 mm i.d., 0.5 μm film thickness) and FID detector are adopted. Response surface methodology (RSM) has been successfully applied to obtain the optimum headspace conditions: the equilibrium temperature is set at 80 °C, equilibrium time at 40 min and the ionic strength (K2CO3) at 4.0 mol/L. Injection is carried out in split mode, with a split ratio of 15. A 0.1 mol/L NaOH solution is proposed as the sample solvent to obtain good sensitivity and recovery. The method of internal standard is used for quantitative analysis of three solvents utilized in the synthesis of eprosartan mesylate: methanol, dichloromethane and pyridine. Validation is performed within the requirements of ICH validation guidelines Q2A and Q2B. System suitability requirements described in the Chinese Pharmacopoeia are checked. Limits of detection and quantitation, precision, linearity and accuracy are determined, and acceptable results are obtained. The proposed method is demonstrated to be simple, accurate and sensitive, and can be used to determine the residual organic solvents in eprosartan mesylate drug substance. Keywords: Eprosartan mesylate, Gas chromatography, Internal standard, Response surface methodology, Residual solvents, Static Headspace, static headspace gas chromatographic (sHS-GC), FID detector, Response surface methodology (RSM), ICH validation guidelines Q2A and Q2B, Limits of detection, Limits of quantitation, Box, –, Behnken Design Matrix

A general static-headspace gas chromatographic method for determination of residual benzene in oral liquid pharmaceutical products

Sodium benzoate is used in oral liquid pharmaceutical products for its anti-microbial properties. The benzoate salts present in liquid pharmaceutical products can potentially generate residual levels of free benzene during manufacturing of the drug product and or during the shelf-life of the product under its storage conditions. To ensure the safety and quality of the pharmaceutical products (containing benzoate in the formulation), a selective and sensitive analytical method is required to monitor residual benzene in oral liquid pharmaceutical products. In this paper, we report the development and validation of a general static-headspace gas chromatographic (SH-GC) method to determine residual benzene in oral liquid pharmaceutical products. The liquid pharmaceutical drug product sample is dissolved in dimethylsulfoxide (DMSO) in a GC headspace vial. A DB-624 capillary column (30 m × 0.32 mm I.D. and 1.8 μm film thickness) was used under isothermal conditions with a flame ionization detection (FID). The benzene peak was well separated from all other volatile compounds that are present in the formulation of a number of liquid drug products. This method was successfully validated using a representative oral liquid pharmaceutical drug product. The limit of detection of the method for benzene is 0.5 ppm which met the 2 ppm limit of current ICH guideline for residual benzene in pharmaceutical products.

A generic static headspace gas chromatography method for determination of residual solvents in drug substance

In order to increase productivity of drug analysis in the pharmaceutical industry, an efficient and sensitive generic static headspace gas chromatography (HSGC) method was successfully developed and validated for the determination of 44 classes 2 and 3 solvents of International Conference of Harmonization (ICH) guideline Q3C, as residual solvents in drug substance. In order to increase the method sensitivity and efficiency in sample equilibration, dimethylsulfoxide (DMSO) was selected as the sample diluent based on its high capacity of dissolving drug substance, stability and high boiling point. The HS sample equilibration temperature and equilibration time are assessed in ranges of 125–150 °C and 8–15 min, respectively. The results indicate that the residual solvents in 200 mg of drug substance can be equilibrated efficiently in HS sampler at 140 °C for 10 min. The GC parameters, e.g. sample split ratio, carrier flow rate and oven temperature gradient are manipulated to enhance the method sensitivity and separation efficiency. The two-stage gradient GC run from 35 to 240 °C, using an Agilent DB-624 capillary column (30 m long, 0.32 mm I.D., 1.8 μm film thickness), is suitable to determine 44 ICH classes 2 and 3 solvents in 30 min. The method validation results indicate that the method is accurate, precise, linear and sensitive for solvents assessed. The recoveries of most of these solvents from four drug substances are greater than 80% within the method determination ranges. However, this method is not suitable for the 10 remaining ICH classes 2 and 3 solvents, because they are too polar (e.g. formic acid and acidic acid), or have boiling points higher than 150 °C, (e.g. anisol and cumene). In comparison with the previous published methods, this method has a much shorter sample equilibration time, a better separation for many solvents, a higher sensitivity and a broader concentration range.