Determination Of Residual Solvents Research Articles

Novel multiple extraction thermal desorption approach prior to gas chromatography for the determination of residual solvents applied to modified cellulose

In this work, multiple extraction thermal desorption (METD), as a sample introduction method for GC, was developed. This technique was used for the determination of residual solvents (RS) in modified cellulose, because it is practically impossible to dissolve or distribute it uniformly in water and common organic solvents. Moreover, METD facilitates the optimization of the desorption time and it is more sensitive to quantify trace level volatiles in insoluble material, compared to direct dynamic desorption (DDD). In addition, METD provides diagnostic information about the sample-sorbent interaction. Three solvents (methanol, ethanol and tert-butanol) were determined in two types of modified cellulose (dialdehyde cellulose (DAC) and DAC-ethylenediamine (DAC-EDA)). It was shown that good linearity over a wide concentration range was achieved. The limits of detection (LOD) and limits of quantification (LOQ) for the different solvents ranged from 0.1 to 0.3 μg and from 0.3 to 0.9 μg per tube, respectively. Accuracy of the METD method was verified by using an alternative method based on the decomposition of the modified celluloses by Trichoderma reesei cellulase, followed by headspace-trap-GC (HS-trap-GC). The results obtained from the two validated methods were found to be similar (relative deviation < 17.0 %). However, the developed METD-GC method is preferable for the analysis of RS in modified cellulose since it does not require sample pretreatment and possesses higher sensitivity.

DETERMINATION OF RESIDUAL SOLVENTS IN PSMA 11 - AN ACTIVE PHARMACEUTICAL SUBSTANCE IN PSMA-11 KIT FOR Ga-68 LABELLING

A selective, sensitive and low sample consumption GC method for determination of residual solvents in PSMA samples was developed. Selectivity with respect to solvents such as ethanol, diethyl ether, 2-propanole, acetonitrile, dichloromethane, used in manufacturing of PSMA-11, was obtained on two different GC systems and columns. In all these cases, good separation and other system suitability parameters were obtained. The values of detection limit (LOD) and limit of quantitation (LOQ) were estimated and verified experimentally for ethanol, diethyl ether, 2-propanol (IPA), acetonitrile (ACN) and dichloromethane. Full validation parameters i.e.: selectivity, limit of detection (LOD), limit of quantitation (LOQ), linearity, precision, accuracy, robustness and system suitability parameters are presented with respect to ACN and IPA. Accuracy and precision were measured on two GC systems. Statistical tests exhibit, that there are no significant differences in accuracy and precision between two GC systems

Platform headspace gas chromatography method for high-throughput determination of residual solvents in pharmaceutical materials

Static headspace capillary gas chromatography (HSGC) has been employed to monitor the level of residual solvents in the pharmaceutical materials. Most of the HSGC methods, however, consume significant amounts of diluents and require considerable amount of sample preparation time. Accordingly, a HSGC method featured with fast turnaround time, and minimal amount of solvent use has been developed for the quantitative analysis of 27 residual solvents frequently used in the development and manufacturing processes of pharmaceutical industry. This HSGC-FID method employs a commercially available fused silica capillary column, a split injection (40:1), and a programmed temperature ramp. It was qualified for specificity, accuracy, repeatability/precision, linearity, LOQ, solution stability, and robustness using two representative sample matrices. The standards, samples and spiked samples were demonstrated to be stable for at least 10 days at room temperature in sealed headspace vials with a recovery of ≥ 93%. The method was also shown to be robust, and its performance was not affected by small changes of carrier gas flow rate, initial oven temperature or the headspace oven temperature. In this new approach, the analytical sample was prepared by dissolving the sample into 1 mL of the diluent and the standard solution was prepared by diluting 1 mL of the custom-made stock into 9 mL of the diluent whereas the traditional approach requires liters of the diluent, making the new approach environmentally friendly, sustainable, economical, agile, error-proofing and thus appropriate for a variety of pharmaceutical applications.

A Novel Analytical Method for the Determination of Residual Solvents in Mesalamine Delayed Release Tablets by GC-HS Method

Background: Residual solvents and organic volatile impurities are monitored using Head Space Gas Chromatography present in pharmaceutical samples. Mesalamine is a 5-aminosalicylic acid 5-ASA based agent which is used to treat adults with ulcerative colitis. &#x0D; Objective: In this study, an attempt was made to analyze the residual organic solvents such as isopropyl alcohol and dichloromethane present in Mesalamine Delayed-Release Tablets by headspace gas chromatography (HS-GC). &#x0D; Method: The carrier gas streamed was nitrogen, the method was developed and optimized by using a DB-624(60 m × 0.53 mm × 3.0 µm) column coupled with a flame ionization detector. A capillary column consisting of 6 % cyanopropylphenyl - 94 % dimethyl polysiloxane was employed as the stationary phase. An injector temperature of 200°C was programmed to prevent degradation. &#x0D; Results: A temperature of 40°C was set as the initial oven temperature for a period of 10 min and set at a rate of 20°C min−1 and monitored at a final temperature of 220°C for 5 min. Chloroform and N, N-dimethylacetamide was selected as the sample solvent. The validation studies were performed with regard to International Council for Harmonization (ICH) Q2 guidelines for the validation of analytical experiments. &#x0D; Conclusion: All the validation parameters complied with the acceptance criteria. Hence, the optimized method developed and validated can be utilized for the concurrent estimation of residual solvents in tablet formulations.

Correction to: High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

Correction to: High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

Development and Validation of Head-Space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual Solvents in Letermovir API synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography / flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: ethyl acetate, MTBE, Toluene and isopropyl acetatein Letermovir API. HS-GC method in a simple and selective manner is delineated for the quantification and determination of Residual Solvents in Letermovir API. The separation of solvents along with drug on Chromatographic chamber was processed on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30 m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 10-50µg/ml for ethyl acetate, MTBE, Toluene and isopropyl acetate (r2&gt;0.999) for the amount of solvent determined through sophisticated methods was in good agreement. The proposed methods were validated. The method of accuracy was assessed by recovery studies at three different levels.The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for ethyl acetate, MTBE, Toluene and isopropyl acetate. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of ethyl acetate, MTBE, Toluene and isopropyl acetate in Letermovir. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity (micrograms/mL) and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

ESTIMATION OF RESIDUAL SOLVENTS IN NETUPITANT API BY HEADSPACE GAS CHROMATOGRAPHY

Objective: Residual solvents are undesirable components present in Active Pharmaceutical Ingredients (API), excipients, or drug products. To meet the specific quality-based requirements, the presence of these solvents in pharmaceutical products should be monitored to ensure their safety. The main objective of this work is to develop a new method for the determination of residual solvents in netupitant API by an HS-GC method with an FID detector. Methods: An automated headspace GC method has been developed and validated for the estimation of the residual solvents-N-methyl pyrrolidine, xylene, toluene, and N, N Dimethylacetamide in netupitant API. The samples were dissolved in dimethyl sulfoxide and the equilibrium headspace gas was formed at 80 ᵒC, which was analyzed using a DB-624 column (30m*0.53 mm, 3.00 µm) with an injector and detector temperature set at 160 ᵒC and 230 ᵒC, respectively. The initial oven temperature was set at 60 ᵒC for 5 min and programmed at a rate of 10 ᵒC/min to the final temperature of 150 ᵒC, with a hold time of 5 min by maintaining the flow rate of 4.0 ml/min with a split ratio of 1:10, and total run time of 20 min. Nitrogen was used as carrier gas. The method developed was validated as per International Conference for Harmonization (ICH) guidelines for repeatability, linearity, range, ruggedness, detection limit, quantification limit, and recovery studies. Results: The linearity range selected was 50-350µg/ml and the correlation coefficient(γ2) values for all the solvents were found to be&gt;0.99; recovery studies values were in a range of 90-110% and %RSD values were also found to be not more than 10 for the solvents. Conclusion: A novel, accurate, sensitive, and simple method was described for estimating residual solvents in Netupitant API by Headspace Gas Chromatography (HS-GC) coupled with a Flame Ionization Detector (FID). Excellent results have been observed for all the validated parameters with good peak resolution and lesser retention times.

Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual solvents in Simeprevir API Synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography/flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir API. A simple and selective HS-GC method is described for the determination &amp; quantification of Residual Solvents in Simeprevir API. Chromatographic separation was achieved on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 40-120% of standard concentrations for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane (r2&gt;0.999) for the amount of solvent estimated by the proposed methods was in good agreement. The proposed methods were validated. The accuracy of the methods was assessed by recovery studies at three different levels. Recovery experiments indicated the absence of interference from commonly encountered diluent and API. The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir. Baseline separation of all five solvents and Simeprevir API is achieved within 20.5 minutes of analysis time. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

A generic gas chromatography method for determination of residual solvents in PET radiopharmaceuticals

A novel gas chromatography (GC) method for quantitation of volatile organic compounds (VOCs) in 18F- and 11C-radiopharmaceuticals listed in the European Pharmacopoeia (Ph. Eur.) was proposed. Optimized chromatographic parameters were used for separation of ethanol, acetone, acetonitrile, tetrahydrofuran (THF), dibromomethane (DBM), 2-dimethylaminoethanol (deanol), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) which could be detected in radioactive drug samples. The calculated peak resolutions (RS) were higher than 2.0 at ethanol concentration of up to 11 m/m%. Reproducible results could be obtained using base deactivated fused silica wool as packing material of inlet liner. Validation parameters showed excellent linearity (r2 ≥0.9998) in the range from 10 to at least 120% of concentration limit of solvents. The accuracy was determined as recovery of concentrations which ranged from 99.3% to 103.8%. Additionally, the relative standard deviation (RSD) of each solvent for inter-day and intra-day precision were in the range of 0.5–4.2% and 0.4–4.4%, respectively. The limit of quantitation (LOQ) for ethanol, acetone, acetonitrile, THF, DBM, deanol, DMF and DMSO was 0.48, 0.42, 0.43, 0.46, 4.35, 0.73, 0.68 and 0.50 mg/L, respectively. The developed procedure was successively applied for quantitation of ethanol, acetone, acetonitrile and deanol in radioactive drug samples of [11C]methionine, [11C]choline, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). The proposed GC method applying flame ionization detection (FID) could be adapted in routine quality control of most frequently used positron emission tomography (PET) radiopharmaceuticals to perform the determination of residual solvents with analysis time of 12 min

Optimization of amorphous solid dispersion techniques to enhance solubility of febuxostat.

Febuxostat is a selective inhibitor of xanthine oxidase and belongs to BCS class II drugs having low solubility and high permeability. Solubility is the most important parameter which directly affects dissolution, absorption and bioavailability of the drugs. There are different techniques by which we can improve solubility and dissolution rate of poorly soluble drug. Amorphous solid dispersion is one of the methods which can improve solubility as well as powder characteristics. The aim of the present study was to formulate and optimize various methods of formulating solid dispersion by using various drug-to-polymer ratios and identifying the batch which gives higher solubility as well as amorphous powder of the drug febuxostat. Different techniques like hot melt method, solvent evaporation method and spray drying techniques were selected for optimization. Attempts were made to improve solubility of febuxostat by employing Kolliphor P 188, Kolliphor P 237, Eudragit RLPO in different drug-to-polymer ratios (1:1, 1:1.5, 1:2) as carrier. The prepared solid dispersion was characterized for the saturation solubility, percentage yield, using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powdered X-ray diffraction studies (PXRD), and residual solvent determination. Solid state characterization indicated that febuxostat was present in the amorphous form after mixing with polymeric carrier. In contrast to the pure form of drug, solid dispersion of the drug showed better solubility and amorphous characteristics which can be attributed to decreased crystallinity due to hydrotrophy. Thus, amorphous solid dispersion approach can be used successfully to enhance solubility, dissolution rate and bioavailability of febuxostat.

Quantitation of Conjugation-related Residual Solvents in Antibody Drug Conjugates using Headspace Gas Chromatography

Background: Antibody Drug Conjugates (ADCs) are complex hybrid molecules comprised of a monoclonal antibody (mAb) connected to a small molecule drug through a linker. The key step in the production of ADCs is bringing together the protein in an aqueous buffer with a hydrophobic small molecule in order to achieve conjugation of the molecules. This step involves dissolving the small molecule portion of the compound in an aqueous miscible organic solvent. These solvents and unconjugated small molecules are ideally cleared by downstream processing in order to achieve the desired product quality. As part of the control system to ensure product quality, the determination of residual solvents in pharmaceuticals is of significant importance in order to protect patient safety and ensure an efficacious drug. Objective: Headspace gas chromatography (HS-GC) is the most widely used tool for quantification of residual solvents for small molecule active pharmaceutical ingredients (APIs) but is not widely used for the analysis of protein-containing samples. In this study, the detection of residual solvents in headspace injections was explored using various conditions in order to detect commonly used conjugation solvents including N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Ethylene Glycol (EG), and Propylene Glycol (PG) in an ADC drug product sample. Methods: Various organic solvents were explored to enhance the response observed with complex protein and residual solvent matrixes. As EG and PG do not partition into the headspace efficiently in the ADC drug product samples that contain large amounts of water, ionic liquids and other ionic compounds were screened with the ADC samples to see if they could improve the partitioning of the key solvents EG and PG. Results: Following headspace and chromatographic optimization, we have developed an approach for the detection and quantification of several conjugation reaction solvents in ADC samples. Conclusion: This new approach is an HS-GC method that simplifies Gas Chromatography (GC) analysis and sample preparation and can be readily implemented in quality control testing for bioconjugated products.

Method Development and Validation for the Determination of Residual Solvents in Racecadotril by Gas Chromatography

Background: The presence of residual solvents in pharmaceuticals can be a potential risk factor to human health because of its toxicity. Gas chromatography is used for its excellent separation abilities and lower limit of detection. Racecadotril, an antidiarrheal drug, is reported having four residual solvents, namely n-Hexane, isopropyl alcohol, toluene, and dimethylformamide. Estimation of the amount of these solvents in active pharmaceutical ingredients to ensure that they are within the permissible limits as per ICH guidelines is necessary. Objective: To develop and validate a new, simple, and sensitive gas chromatographic method for simultaneous determination of n-Hexane, isopropyl alcohol, toluene, and dimethylformamide in racecadotril. Methods: The residual solvents of racecadotril were estimated using a gas chromatographic method by direct injection using FID as a detector. This method employed a 30-meter long DB-FFAP nitroterephthalic-acid-modified polyethene glycol column with 0.53 mm in inner diameter and 1 μm film thickness. The separation was achieved using nitrogen as the carrier gas at a flow rate of 2.8 mL/min using a split ratio of 1:10. Results: The peak shape for all the residual solvents from racecadotril was symmetric with excellent resolution eluting at reasonable retention time. The limit of detection of n-Hexane, isopropyl alcohol, Toluene, and dimethylformamide was found to be 6, 27, 14, and 42 ppm, respectively. The developed method exhibited excellent linearity for each residual solvents in the range studied. Conclusion: The developed gas chromatographic method is simple, specific, precise, accurate, and sensitive. Hence, the method can be successfully used in in the pharmaceutical companies and research laboratories for simultaneous determination of residual solvents in racecadotril active pharmaceutical ingredients.

HEADSPACE GAS CHROMATOGRAPHY FOR THE DETERMINATION OF RESIDUAL SOLVENTS IN METFORMIN HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE

By SK Manirul Haque, Yunusa Umar & 3 more. An accurate analytical method was developed using headspace gas chromatography for the determination of residual solvents in metformin hydrochloride and hydrochlorothiazide.

Determination of residual solvents in paclitaxel by headspace gas chromatography

BackgroundA simple and sensitive gas chromatographic method was developed and validated for the simultaneous determination of methanol, ethanol, acetone, isopropyl alcohol, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, and N,N-diisopropyl ethyl amine in Paclitaxel. A chromatographic separation was done on DB-624 column, 30 m length × 0.53 mm ID, and film thickness 3 μm, using a flame ionization detector (FID) with gradient column oven temperature program. The injection was carried out in split mode, with a split ratio of 5:1. A mixture of N-methyl-2-pyrrolidinone (contains 1% piperazine) and water in the ratio of 80:20 (v/v) was selected as a diluent to obtain good sensitivity along with the recovery.ResultsThe developed gas chromatographic method offers symmetric peak shape, good resolution of more than 2.0 between the solvent peaks, and the relative standard deviation for replicate injections of all the solvents were found to be not more than 15.0% with reasonable retention time for all the solvents. The limit of detection for methanol, ethanol, acetone, isopropyl alcohol, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, and N,N-diisopropyl ethyl amine was found to be 304.69 ppm, 497.98 ppm, 498.99 ppm, 504.49 ppm, 61.81 ppm, 30.07 ppm, 505 ppm, 73.05 ppm, and 2.09 ppm, respectively. Limit of quantitation of methanol, ethanol, acetone, isopropyl alcohol, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, and N,N-diisopropyl ethyl amine was found to be 89.62 ppm, 146.47 ppm, 146.76 ppm, 148.38 ppm, 18.18 ppm, 8.84 ppm, 148.53 ppm, 21.49 ppm, and 0.62 ppm, respectively. Precision was found to be satisfactory. Linear in the range of LOQ to 150% level for all the solvents, and accuracy along with robustness, is performed, and acceptable results were obtained.ConclusionThe proposed method was demonstrated to be simple, sensitive, specific, linear, precise, accurate, and robust, hence can be used to determine the residual organic solvents in Paclitaxel drug substance and drug product.

Method development and validation for the determination of residual solvents in quinabut API by using gas chromatography. Message 2

Aim. The aim of study was to develop and validate a simple, precise and accurate method using gas chromatography for analysis of residual solvents – acetone and 2-propanol – in quinabut API. Materials and methods. All experiments were performed on a gas chromatographic system equipped with FID detector (Shimadzu GC System) using the DB-624 (30 m × 0.32 mm ID, 3.0 μm film sickness) column as stationary phase. Nitrogen was used as carrier gas with flow rate 7.5 mL/ min. Split ratio was 1:5, injector temperature was 140 °C, detector temperature was 250 °C, oven temperature was programmed from 40 °C (2 min) to 50 °C at 1 °C/min and then increased at a rate of 15 °C/min up to 215 °C; and maintained for 2 min. All solutions were prepared using water as diluent. Results. This proposed method is assessed for separation of residual solvent from quinabut with quantification. The obtained results are compared with the corresponding specified limits of ICH standard guidelines. The method validation was done by evaluating specificity, limit of detection (LOD) and limit of quantitation (LOQ), linearity, accuracy, repeatability, ruggedness, system suitability and method precision of residual solvents as indicated in the ICH harmonized tripartite guideline. The separation between acetone and 2-propanol peaks is 2.07. Hence method was found to be specific. The linear relationship evaluated across range of 15 to 180% for acetone and 2-propanol of ICH specified limit of residual solvents. The graphs of theoretical concentration versus obtained concentration are linear and the regression coefficients ‘R’ for residual solvents were more than 0.9968. The values of LOD and LOQ were much less than the lower limit of the concentration range and cannot affect the accuracy of the test. The technique was characterized by high intra-laboratory accuracy at concentrations close to the nominal acetone and 2-propanol concentration. All solutions were stable in water for at least 1 hour when stored at room temperature. Conclusion. A simple, specific, accurate, precise and rugged gas chromatography method was developed and validated for the quantification of residual solvents present in quinabut API through an understanding of the synthetic process, nature of solvents and nature of stationary phases of columns. The residual solvents acetone and 2-propanol were determined.

Development and Validation of a Headspace Gas Chromatographic (HS-GC) Method for Determination of Residual Solvents in Nitazoxanide API

Controlling residual solvents in the drug substances or active pharmaceutical ingredients (API) is mandatory to the specified limits as per the International Conference on Harmonisation (ICH) Q3C guidelines. Residual solvents in pharmaceuticals are mostly determined by Gas Chromatography with Headspace. A simple and sensitive headspace gas chromatographic (HS-GC) method has been developed for the determination of Acetone, Dichloromethane and Cyclohexane in Nitazoxanide API. The separation of analytes was achieved with DB – 624 (30 m length, 0.53 mm inner diameter and 3.0 μm in film thickness) capillary column. Dimethyl formamide was used as a diluent. Nitrogen was used as carrier gas with 3.0 mL/minutes and Flame ionisation detector (FID) for detecting analytes. The oven temperature was set at 60°C for 5 minutes at initial and programmed at a rate of 20°C per minute to a final temperature of 240°C for 2 minutes. Run time was 16 minutes, and total GC cycle time was 25 minutes. The spilt ratio used as 1:20 to get optimum peak response. The developed method was validated as per the ICH guidelines for specificity, accuracy, precision, linearity, range, the limit of detection, the limit of quantification and robustness. The results of validation were indicated no interference, good recoveries, precise, linear, rugged and robust method, suitable for the determination of residual solvents in Nitazoxanide API for research and routine quality control laboratory.

Simultaneous quantitation of water and residual solvents in pharmaceuticals by rapid headspace gas chromatography with thermal conductivity detection (GC-TCD)

In the pharmaceutical industry, an array of analytical testing is performed to demonstrate the safety and efficacy of drug substance and drug products. Among the most critical attributes of release testing are quantitation of residual solvents from the manufacturing process, which pose toxicity concerns, and determination of water content, which can impact potency and shelf life. Residual solvent determination in pharmaceuticals is most commonly performed using headspace capillary gas chromatography (GC) with flame ionization detection (FID), a robust technique that incorporates a mode of detection noteworthy for its sensitivity and wide dynamic range. However, FID responds exclusively to combustible organic species, and does not produce any signal for common gases such as carbon dioxide, ammonia, and notably water. While thermal conductivity detection (TCD) is an alternate, universal mode of detection that has a known response to all GC-appropriate compounds, including water, its use among pharmaceutical companies is uncommon due to the ubiquity of the more sensitive FID and the availability of other techniques for water quantitation such as Karl Fischer titrations (KF). In this work, the use of headspace GC-TCD was successfully demonstrated for the development of a 7.5-minute method for simultaneous quantitation of water, over 25 common residual solvents, and other volatile impurities in small molecule pharmaceutical samples. By carefully controlling sample preparation to minimize the impact of residual water from the diluent, the results for residual solvents and water obtained by this technique were found to be comparable to those of GC-FID and KF, respectively. Headspace GC-TCD improves the throughput of drug testing by greatly reducing the need for KF testing and associated expensive reagents, and helps to conserve samples that are often limited in early stages of development. The technique has desired sensitivity, precision, accuracy and linear dynamic range suitable for pharmaceutical analysis.

Headspace gas chromatographic analysis of residual solvents in pharmaceuticals: comparison of two matrix media

Dimethylformamide (DMF) and a deep eutectic solvent choline chloride-ethylene glycol (ChCl-Eg) were investigated as potential matrix media for static headspace gas chromatographic (SHS-GC) determination of residual solvents in pharmaceuticals. Sample equilibration temperature, equilibration time and injection time were optimized. In the case of DMF 140°C equilibration temperature was applied. For ChCl-Eg equilibration temperature could not exceed 80°C as ChCl-Eg started to degrade at elevated temperatures. The higher equilibration temperature of DMF solutions favoured a transition of the analytes to the headspace and consequently resulted in lower detection limits of the analytes. Thus DMF has been considered a more suitable matrix medium than ChCl-Eg and was applied for the SHS-GC determination of residual solvents in pharmaceuticals.

Development and validation of a thermal desorber gas chromatography method for determination of residual solvents in drug loaded albumin

The conventional approach for residual solvent (RS) analysis is headspace-gas chromatography (HS-GC). This starts from a homogenous sample solution and is based on the equilibrium of the analyte between the sample and the gas phase. Unfortunately, aqueous solutions of albumin form irreversible hydrophobic aggregates when heated above 50 °C. Consequently, the use of HS-GC for RS analysis in albumin becomes problematic due to the presence of an additional solid phase in the HS vial.In this work, a method using a thermal desorber (TD) combined with GC was developed for the determination of RS in drug loaded albumin. Samples were immobilized between two double layers of quartz filter (QF) in a polytetrafluoroethylene (PTFE) insert which was placed in an empty desorption tube prior to TD-GC analysis. The liquid standard mix consisted of ethanol (EtOH), acetone (Ace), dichloromethane (DCM) and chloroform (Chl) dissolved in toluene. Offline liquid calibration (OLC) was applied by introducing 2 μL of the standard mix under counter flow of an inert gas into the TD tube containing a mixed bed of mesoporous silica (MPSi) immobilized between two double layers of QF. The OLC results were verified using the inline liquid calibration (ILC) approach based on a heated GC injector installed on the TD. The validation results revealed that the proposed method has good recovery (> 98 %). R2-values (> 0.998) indicated good linearity over a wide range. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.01 and 0.04 μg on tube, respectively. Repeatability of the method was reported as RSD-values and they were lower than 3 %. A method based on the complete enzymatic digestion of albumin combined with conventional HS-GC was developed to verify the completeness of release of the RS from the albumin. Both the TD-GC and HS-GC methods were applied for the determination of EtOH and DCM in two different albumin samples loaded with experimental drugs. Statistical comparison indicated that there was no significant difference (p > 0.05) between the two methods. However, the HS-GC method following enzymatic degradation is much more expensive and time consuming.