Determination of residual solvents in bulk pharmaceuticals by thermal desorption/gas chromatography/mass spectrometry

Thermal desorption (TD) techniques followed by capillary GC/MS were applied for the analysis of residual solvents in bulk pharmaceuticals. Solvents desorbed from samples by heating were cryofocused at the head of a capillary column prior to GC/MS analysis. This method requires a very small amount of sample and no sample pretreatment. Desorption temperature was set at the point about 20 degrees C higher than the melting point of each sample individually. The relative standard deviations of this method tested by performing six consecutive analyses of 8 different samples were 1.1 to 3.1%, and analytical results of residual solvents were in agreement with those obtained by direct injection of N,N-dimethylformamide solution of the samples into the GC. This novel TD/GC/MS method was demonstrated to be very useful for the identification and quantification of residual solvents in bulk pharmaceuticals.     

Development of a new pyrolyzer for thermal desorption and/or pyrolysis gas chromatography of polymeric materials

A new vertical microfurnace-type pyrolyzer for thermal desorption and/or pyrolysis-gas chromatography has been developed. The pyrolyzer consists of two independent temperature-controlled ovens. Initially, in the desorption process, a sample cup containing the polymeric sample of interest is inserted into an oven at 300°C; the sample is then re-positioned at the upper part of the pyrolyzer where the temperature is maintained at room temperature. The resulting vaporized components such as residual solvents and additives give a desorption chromatogram. The relative peak intensities of desorbed plasticizers in acrylonitrile butadiene-rubber gave a relative standard deviation (RSD) of less than 2%. Subsequently, pyrolysis of the remaining polymer is conducted by dropping the sample cup into the second, pyrolyzing, oven at 55°C; at this stage the pyrogram is recorded. The resulting two chromatograms of desorbed components and pyrolysis products make it easier to characterize the polymer formulation than the complicated pyrogram obtained by an ordinary, single-step pyrolysis.     

Quantitative analysis of phthalates using a pyrolyzer gas chromatography/mass spectrometry method

A pyrolyzer gas chromatography/mass spectrometry (GC/MS) method eliminates toxic solvents that burden our environment and can address the crucial problem of the solvent extraction GC/MS method. The purpose of this study is to establish an efficient quantitative analysis method for 10 phthalates that are regulated by the several governments. A change of concentrations over time for phthalates and internal standards was measured to verify the feasibility of using an auto sampler that facilitates analyzing multiple samples. Both standards maintained constant concentrations over the appropriate time for analysis. A certified reference material under the auspices of the Korea Research Institute of Standards and Science was used to verify the calibration curve obtained by the pyrolyzer GC/MS method, and a deviation was considered similar to the solvent extraction GC/MS method. Then, the limit of detection and limit of quantitation values were confirmed for various consumer products. To verify the reliability of the method, a comparative test with several accredited testing institutes was conducted, and the results were within the standard deviations of the results provided by the institutes. These results indicate that the pyrolyzer GC/MS method can be used in not only screening but also in accurate quantitative analysis.     

Analysis of waterborne paints by gas chromatography-mass spectrometry with a temperature-programmable pyrolyzer

Gas chromatography-mass spectrometry (GC-MS) with a temperature-programmable pyrolyzer was used for the analysis of waterborne paints. Evolved gas analysis (EGA) profiles of the waterborne paints were obtained by this temperature-programmed pyrolysis directly coupled with MS via a deactivated metal capillary tube. The EGA profile suggested the optimal thermal desorption conditions for solvents and additives and the subsequent optimal pyrolysis temperature for the remaining polymeric material. Polymers were identified from pyrograms with the assistance of a new polymer library. The solvents were identified from the electron ionization mass spectra with the corresponding chemical ionization mass spectra. The additive was identified as zinc pyrithione by comparison with authentic standard. Zinc pyrithione cannot be analyzed by GC-MS as it is. However, the thermal decomposition products of zinc pyrithione could be detected. The information on the decomposition temperature and products was useful for the identification of the original compound.     

Thermoanalytical characterization of polymers: A comparative study between thermogravimetry and evolved gas analysis using a temperature-programmable pyrolyzer

Evolved gas analysis (EGA) was carried out on 15 synthetic polymer samples using a temperature programmable pyrolyzer as a heating unit which was on-line coupled with a MS detector. A deactivated stainless steel tube and a vent free adapter were used to couple the pyrolyzer with the MS detector, and they were placed in a GC oven at 300°C to avoid condensation of evolved gases with high boiling point. Thermograms of polystyrene measured by this system (Py-EGA-MS) showed shifts of the peak temperature to the higher temperature region as the sample mass increased. It was found that the S/N ratios of EGA thermograms were 420-fold superior to those of differential thermogravimetry (DTG) thermograms for the same sample mass of 0.20 mg. Since a good linear relationship was obtained between peak temperatures obtained by Py-EGA-MS and DTG, it can be concluded that Py-EGA-MS can be used to obtain reliable data on thermal properties of samples with high sensitivity and using less sample.     

The use of thermal desorption GC/MS to study weight loss in thermogravimetric analysis of di-acid salts

Thermal desorption gas chromatograph mass spectrometry (TD GC/MS) was used to study weight loss in thermogravimetric analysis (TGA). The technique of thermal desorption utilizes the same temperature heating rate as the TGA to thermally desorb volatiles from solid sample matrices. Volatiles were cryo-trapped at −60 °C. After thermal desorption is complete, the trapped volatiles are separated by a GC capillary column and identified by mass spectrometry. In this study, the TD GC/MS was applied in pharmaceutical development to understand the chemical reactions attributed to the weight loss in the thermal decomposition of two dicarboxylic acid salts of a drug substance. These two salts exhibited different thermal stabilities. The thermally induced chemical reactions obtained from these two salts included dehydration and decarboxylation. Thermal degradation compounds were identified and reaction pathways for decomposition were proposed. The stability of the salts is dependent on the identity of the dicarboxylic acids from which they were generated. The information obtained from TD GC/MS helps better understand the weight loss process in thermogravimetric analysis.     

Analysis of residual solvents in pharmaceuticals with purge-and-membrane mass spectrometry

A method using purge-and-membrane mass spectrometry (PAM-MS) was developed for the analysis of residual solvents in pharmaceutical products. The method combines dynamic headspace and membrane inlet mass spectrometry. The limits of detection for the compounds studied, benzene, toluene, chloroform, 2-pentene and 2-methyl- and 3-methylpentane, were 0.05-0.1 mg/kg. In quantitative analysis the method showed good linearity (r(2) > 0.998) and acceptable within-day (RSD = 7.9-18%) and between-day (RSD = 6.8-10%) repeatability. The PAM-MS method combined with the custom-made Solver program was compared with a method using purge-and-trap gas chromatography/mass spectrometry (P&T-GC/MS) for identification of residual solvents from authentic samples. The results showed that PAM-MS/Solver provides reliable identification of the main volatile organic compounds (VOCs) in the pharmaceuticals, but VOCs with low concentrations (below 0.5 mg/kg) were better identified by P&T-GC/MS. Other advantages of the PAM-MS method were short analysis times and non-requirement for pre-treatment of samples.     

On-probe pyrolysis desorption electrospray ionization (DESI) mass spectrometry for the analysis of non-volatile pyrolysis products

An on-probe pyrolyzer has been constructed and interfaced with desorption electrospray ionization (DESI) mass spectrometry (MS) for the rapid analysis of non-volatile pyrolysis products. The detection and analysis of non-volatile pyrolysis products of peptides, proteins and the synthetic polymer poly(ethylene glycol) were demonstrated with this instrument. The on-probe pyrolyzer can be operated off-line or on-line with the DESI source and was interfaced with a tandem MS (MS/MS) instrument, which allowed for structure characterization of the non-volatile pyrolytic products. Advantages of this system are its simplicity and speed of analysis since the pyrolysis is performed in situ on the DESI source probe and hence, it avoids extraction steps and/or the use of matrices (e.g., as in MALDI–MS analyses).     

On-probe pyrolysis desorption electrospray ionization (DESI) mass spectrometry for the analysis of non-volatile pyrolysis products

An on-probe pyrolyzer has been constructed and interfaced with desorption electrospray ionization (DESI) mass spectrometry (MS) for the rapid analysis of non-volatile pyrolysis products. The detection and analysis of non-volatile pyrolysis products of peptides, proteins and the synthetic polymer poly(ethylene glycol) were demonstrated with this instrument. The on-probe pyrolyzer can be operated off-line or on-line with the DESI source and was interfaced with a tandem MS (MS/MS) instrument, which allowed for structure characterization of the non-volatile pyrolytic products. Advantages of this system are its simplicity and speed of analysis since the pyrolysis is performed in situ on the DESI source probe and hence, it avoids extraction steps and/or the use of matrices (e.g., as in MALDI–MS analyses).     

Solid-phase extraction element based on epoxy polymer monolith for determination of polar organic compounds in aqueous media

A solid-phase extraction element based on epoxy polymer monolith was fabricated for sorptive enrichment of polar compounds from liquid and gaseous samples. After ultrasonication of the element in an aqueous solution for a given period of time, the thermal desorption (TD) using a pyrolyzer with gas chromatography/mass spectrometry (GC/MS), in which TD temperature was programmed from 50 to 250 °C for the analytes absorbed in the element, was used to evaluate the element for basic extraction performance using the aqueous standard mixtures consisting of compounds having varied polarities such as hexanol, isoamyl acetate, linalool, furfural and decanoic acid, in concentrations ranging from 10 μg/L to 1 mg/L. Excellent linear relationships were observed for all compounds in the standard mixture, except decanoic acid. In the extraction of beverages such as red wine, the extraction element showed stronger adsorption characteristics for polar compounds such as alcohols and acids than a non-polar polydimethylsiloxane-based element. This feature is derived from the main polymer structure along with hydroxyl and amino groups present in the epoxy-based monolith polymer matrix.     

Application of an automatic thermal desorption–gas chromatography–mass spectrometry system for the analysis of polycyclic aromatic hydrocarbons in airborne particulate matter

The application of the thermal desorption (TD) method coupled with gas chromatography–mass spectrometry (GC–MS) to the analysis of aerosol organics has been the focus of many studies in recent years. This technique overcomes the main drawbacks of the solvent extraction approach such as the use of large amounts of toxic organic solvents and long and laborious extraction processes. In this work, the application of an automatic TD–GC–MS instrument for the determination of particle-bound polycyclic aromatic hydrocarbons (PAHs) is evaluated. This device offers the advantage of allowing the analysis of either gaseous or particulate organics without any modification. Once the thermal desorption conditions for PAH extraction were optimised, the method was verified on NIST standard reference material (SRM) 1649a urban dust, showing good linearity, reproducibility and accuracy for all target PAHs. The method has been applied to PM10 and PM2.5 samples collected on quartz fibre filters with low volume samplers, demonstrating its capability to quantify PAHs when only a small amount of sample is available.     

Purge and trap/thermal desorption device for the determination of dimethylselenide and dimethyldiselenide

A method is described for the determination of dimethylselenide and dimethyldiselenide using a purge-and-trap/thermal desorption device (PT/TD) coupled to a capillary column gas chromatograph with a six-way Valco valve. The system is constructed in such a way that it allows also on-column injections of the volatile compounds in organic solvents for external calibration purposes without the need to disassemble the PT/TD. The influence of the purge flow, purge time and volume of sample, on the purge efficiency of the PT system is studied. Desorption time and temperature are optimised for the TD mode of operation. Atomic absorption spectrometry (AAS) and flame photometric detection (FPD) have been used for the final determination of the volatile compounds. The figures of merit achieved with both detectors are reported.     

Rapid determination of decabromodiphenyl ether in polystyrene by thermal desorption-GC/MS.

A rapid determination of decabromodiphenyl ether (DeBDE) in polystyrene (PS) by thermal desorption (TD)-GC/MS was studied. The TD-GC/MS method using a pyrolysis-GC/MS system allowed the quick quantification of DeBDE in a waste TV back plate composing of a PS flame-retarded with polybrominated diphenyl ethers on the basis of the resulting chromatogram with a ca. 4% relative standard deviation without using any tedious sample pretreatment, such as solvent extraction.     

顶空气相色谱法测定氟尼辛葡甲胺原料药中有机溶剂残留量

建立了氟尼辛葡甲胺原料药中乙酸乙酯、甲醇、异丙醇、乙醇和乙腈有机溶剂残留量的顶空气相色谱分析方法。以HP-FFAP色谱柱(30 m×0.32 mm×1.0 μm)为分离柱,火焰离子化检测器检测,外标法定量,并考察了顶空平衡温度、平衡时间等对残留有机溶剂测定的影响。实验结果表明,在顶空平衡温度为90 ℃、平衡时间为30 min条件下获得较好的定量结果。乙酸乙酯、甲醇、异丙醇、乙醇和乙腈的线性范围分别为0.40～7.93 mg/L (r=0.9998)、7.32～146.48 mg/L (r=0.9996)、4.53～90.61 mg/L (r=0.9999)、3.62～72.32 mg/L (r=0.9998)和2.31～46.24 mg/L (r=0.9996);平均回收率范围为95.96%～100.31%,精密度(以相对标准偏差计,n=6)为1.97%～3.28%;检出限分别为0.08、0.9、0.2、0.4和0.3 mg/L。利用该方法对实际样品氟尼辛葡甲胺原料药中有机溶剂残留量进行了检测。结果表明,该样品中含有异丙醇和乙醇,其含量分别为177.44 μg/g与69.32 μg/g。本方法快速、灵敏、准确,适用于氟尼辛葡甲胺原料药中残留溶剂的检测。     

Thermal desorption gas chromatography–mass spectrometry as an enhanced method for the quantification of polycyclic aromatic hydrocarbons from ambient air particulate matter

Polycyclic aromatic hydrocarbons (PAHs) from ambient air particulate matter (PM) were analysed by a two-step thermal desorption (TD) injection system integrated to a gas chromatograph–mass spectrometer (GC/MS). The operational variables of the TD method were optimised and the analytical expanded uncertainties were calculated to vary from 8% to 16% over the operative concentration range (40–4000 pg). The performance of the TD method was validated by the analysis of a standard reference material and by comparison of PAH concentrations in PM samples to those obtained by a conventional liquid extraction (LE) method. The TD method reported lower uncertainties than the LE method for the analysis of similar concentrations in air. The TD method also showed advantages for shorter sampling times in comparison to 24 h for source apportionment applications and for reducing losses of more reactive compounds such as benzo[a]pyrene.     

顶空气相色谱法测定盐酸司他斯汀中6种残留溶剂

建立了顶空气相色谱法(HS-GC)测定盐酸司他斯汀中乙醚、丙酮、异丙醇、四氢呋喃、甲苯与二甲苯6种有机溶剂残留量的方法。样品用二甲基亚砜溶解,在110℃加热20 min,使气液平衡,采用氢火焰离子化检测器(FID),以DB-1701(60 m×0.320 mm,1.00μm)为分析柱,程序升温测定。在优化的气相色谱条件下,6种残留溶剂均能有效分离,在考察浓度范围内,线性关系良好(R²=0.9998~1.0000),平均回收率96.5%~98.9%(n=9)。方法适用于盐酸司他斯汀中残留溶剂的日常检测。     

Multiresidue analytical method using dispersive solid-phase extraction and gas chromatography/ion trap mass spectrometry to determine pharmaceuticals in whole blood

A convenient analytical method for the simultaneous determination of more than 40 pharmaceuticals belonging to various therapeutic categories in whole blood has been developed. Exemplarily, the method was fully validated for eight different pharmaceuticals. The procedure entails addition of acetonitrile, magnesium sulfate and sodium chloride to a small amount of blood, then the mixture is shaken intensively and centrifuged for phase separation. An aliquot of the organic layer is cleaned up by dispersive solid-phase extraction employing bulk sorbents as well as magnesium sulfate for the removal of residual water. This method was based on the QuEChERS approach developed for pesticide residue analysis in food. Gas chromatography/ion trap mass spectrometry (GC/MS) with electron (EI) and chemical (CI) ionisation was then used for qualitative and quantitative determination of the pharmaceuticals. The dispersive SPE with PSA (sorbent functionalized with primary and secondary amines) was found more suitable than aminopropyl and a styrene-divinylbenzene sorbent for sample clean-up before drug level determination in whole blood and plasma, as it was found that most of endogenous matrix components were removed and the analytes were isolated from spiked samples with recoveries above 80%. Variation coefficients of the repeatability typically smaller than 10% have been achieved for a wide range of the investigated substances. The used analytical conditions allowed to separate successively a variety of drugs and poisons with the typical limit of detection at <20 ng mL(-1) levels using 1 microL injection of equivalent blood sample in whole blood. The method is simple, rapid, cheap and very effective for therapeutic drug monitoring and forensic chemistry.     

Direct analysis of oligomeric tackifying resins in rubber compounds by automatic thermal desorption gas chromatography/mass spectrometry

Two analytical methods, automatic thermal desorption gas chromatography/mass spectrometry (ATD-GC/MS) and pyrolysis gas chromatography/mass spectrometry (Py-GC/MS), were applied as direct methods for the analysis of oligomeric tackifying resins in a vulcanized rubber. The ATD-GC/MS method, based on discontinuous volatile extraction, was found to be an effective means for direct analysis of the oligomeric tackifying resins contained in a vulcanized rubber. The oligomeric tackifying resins, such as t-octylphenolformaldehyde (TOPF) resin, rosin-modified terpene resin, and cashew resin, could be directly analyzed in vulcanized rubber by ATD-GC/MS. Much simpler total ion chromatograms were obtained by ATD-GC/MS than by flash pyrolysis with a Curie-point pyrolyzer, permitting much easier interpretation. Ions at m/z 206, 135, and 107 were fingerprints in the characteristic mass spectra obtained by ATD-GC/MS for TOPF resin in the vulcanized rubber. 1H-Indene, styrene, and isolongifolene were observed as their characteristic mass spectra in the pyrolyzate of the rosin-modified terpene resin. From the cashew resin, phenol, 3-methylphenol, and 4-(1,1,3, 3-tetramethylbutyl)phenol were obtained as the characteristic pyrolyzates by discontinuous thermal extraction via ATD-GC/MS. Copyright 1999 John Wiley & Sons, Ltd.     

Evaluation of the Thermal Desorption-GC/MS Method for the Determination of Decabromodiphenyl Ether (DeBDE) in Order of a Few Hundred ppm Contained in a Certified Standard Polystyrene Sample

Thermal desorption (TD)-GC/MS, recently developed for the determination of DeBDE in a polystyrene (PS) sample to an order of a few %, was evaluated in detail by using a certified standard PS sample containing 317 ppm of DeBDE. Not only the accuracy and precision of the results, but also the linearity of the working calibration curve were discussed in terms of the catalytic decomposition of DeBDE induced by the degrading macro-radical of the matrix polymer.     

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.