Search

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. [Display omitted] • Multiple headspace extraction approach was applied to thermal desorption. • Optimization of desorption time in a single experiment. • Novel approach was used for determination of residual solvents in modified celluloses. • New methodology gives similar results compared to complex conventional procedure. [ABSTRACT FROM AUTHOR]

Reported here is a simple and rapid static headspace gas chromatography (SHS-GC) method for the determination of trace solvents including ethanol, isopropanol, n -butanol, 1,4-dioxane, tetrahydrofuran, acetonitrile, methanol and acetone which commonly used in drug production process. Natural deep eutectic solvents (NADESs) are firstly used as the matrix medium for this method, which provided high sensitivity for residual solvents detection. With the optimized method, validation experiments were performed and the data showed excellent linearity for all the solvents ( R 2 ≥ 0.999, n  = 7). The limits of detection (LOD) for ethanol, isopropanol, n -butanol, 1,4-dioxane, tetrahydrofuran, acetonitrile, methanol and acetone are 0.09, 0.08, 0.07, 0.11, 0.06, 0.10, 0.12 and 0.08 μg g −1 , respectively. Accuracy was checked by a recovery experiment at three different levels, and the recoveries of the tested solvents were ranged from 94.3% to 105.4%. The relative standard deviation (RSD) of each solvent for intra- and inter-day precision is in the range of 0.85 to 3.65 and 1.51 to 4.53, respectively. The developed approach can be readily used for determination of the residual solvents in six active pharmaceutical ingredients including pramipexole dihydrochloride, rivaroxaban, lisinopril, ramipril, imatinib mesylate and sitagliptin. [ABSTRACT FROM AUTHOR]

In this study, two ionic liquids (ILs), 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([BMIM][NTf 2 ]) and trihexyltetradecylphosphonium bis[(trifluoromethyl)sulfonyl]imide ([P 66614 ][NTf 2 ]) were examined as contemporary diluents for residual solvent analysis using static headspace gas chromatography (SHS-GC) coupled with flame ionization detection (FID). ILs are a class of non-molecular solvents featuring negligible vapor pressure and high thermal stabilities. Owing to these favorable properties, ILs have potential to enable superior sensitivity and reduced interference, compared to conventional organic diluents, at high headspace incubation temperatures. By employing the [BMIM][NTf 2 ] IL as a diluent, a 25-fold improvement in limit of detection (LOD) was observed with respect to traditional HS-GC diluents, such as N-methylpyrrolidone (NMP). The established IL-based method demonstrated LODs ranging from 5.8 parts-per-million (ppm) to 20 ppm of residual solvents in drug substances. The optimization of headspace extraction conditions was performed prior to method validation. An incubation temperature of 140 °C and a 15 min incubation time provided the best sensitivity for the analysis. Under optimized experimental conditions, the mass of residual solvents partitioned in the headspace was higher when using [BMIM][NTf 2 ] than NMP as a diluent. The analytical performance was demonstrated by determining the repeatability, accuracy, and linearity of the method. Linear ranges of up to two orders of magnitude were obtained for class 3 solvents. Excellent analyte recoveries were obtained in the presence of three different active pharmaceutical ingredients. Owing to its robustness, high throughput, and superior sensitivity, the HS-GC IL-based method can be used as an alternative to existing residual solvent methods. [ABSTRACT FROM AUTHOR]

Highlights: [•] Counterfeit tablets and capsules were screened for residual solvents. [•] Detected solvents were quantified. [•] Counterfeit tablets and capsules have significantly higher concentrations of residual solvents than genuine ones. [•] In some toxic amount of residual solvents were detected. [Copyright &y& Elsevier]

Abstract: A fast headspace GC–MS method was developed and validated for the detection and quantification of residual solvents of all three ICH-classes in counterfeit tablets and capsules. The method was validated for 10 solvents, selected based on an initial screening of counterfeit medicinal products. The considered solvents were ethanol, 2-propanol, acetone, ethylacetate, chloroform, carbon tetrachloride, benzene, toluene, dichloromethane and ethylbenzene. The proposed method uses a Phenomenex 624 capillary column (60m×0.32mm; 1.8μm film thickness) (Phenomenex, Torrance, USA) with an oven temperature program from 60°C (held for 5min) to 270°C at 25°C/min. 270°C is held for 10min. The total run time is 23.4min. The obtained method was fully validated by applying the “total error” profile. Calibration lines for all components were linear within the studied ranges. The relative bias and the relative standard deviations for all components were smaller than 5%, the β-expectation tolerance limits did not exceed the acceptance limits of ±10% and the relative expanded uncertainties were acceptable for all of the considered components. A method was obtained for the screening and quantification of residual solvents in counterfeit tablets and capsules, which will allow a fast screening of these products for the presence of residual solvents. [Copyright &y& Elsevier]

Abstract: Residual solvents are volatile organic compounds which can be present in pharmaceutical substances. A generic static headspace-gas chromatography analysis method for the identification and control of residual solvents is described in the European Pharmacopoeia. Although this method is proved to be suitable for the majority of samples and residual solvents, the method may lack sensitivity for high boiling point residual solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and benzyl alcohol. In this study, liquid paraffin was investigated as new dilution medium for the analysis of these residual solvents. The headspace-gas chromatography method was developed and optimized taking the official Pharmacopoeia method as a starting point. The optimized method was validated according to ICH criteria. It was found that the detection limits were below 1μg/vial for each compound, indicating a drastically increased sensitivity compared to the Pharmacopoeia method, which failed to detect the compounds at their respective limit concentrations. Linearity was evaluated based on the R 2 values, which were above 0.997 for all compounds, and inspection of residual plots. Instrument and method precision were examined by calculating the relative standard deviations (RSD) of repeated analyses within the linearity and accuracy experiments, respectively. It was found that all RSD values were below 10%. Accuracy was checked by a recovery experiment at three different levels. Mean recovery values were all in the range 95–105%. Finally, the optimized method was applied to residual DMSO analysis in four different Kollicoat® sample batches. [Copyright &y& Elsevier]

• A single GC method was proposed for analysis of volatile compounds in PET tracers. • Quantitation of solvents could be performed at ethanol concentration of up to 11 m/m%. • Base deactivated silica wool is recommended for packaging material of inlet liner. • The validation was performed according to Q2(R2)/Q14 ICH guideline. • Solvents were determined in [11C]methionine, [11C]choline, [18F]FDG and [18F]FET. [Display omitted] 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 (R S) 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 [ABSTRACT FROM AUTHOR]

Abstract: Residual solvents (RS) are volatile organic chemicals that are used or produced during the manufacturing process of drug substances or excipients. The European Pharmacopoeia (Ph. Eur.) limits the amount of RS in pharmaceuticals, considering the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines for RS. According to the Ph. Eur. general method, water insoluble samples may be analyzed using DMF as dilution solvent at high equilibration temperatures such as 105°C. This could be problematic in the case of antibiotics, many of which are water insoluble and temperature sensitive. Moreover, antibiotics are complex in nature and beside RS, one can expect several other volatile impurity peaks in the chromatogram. In this study, the Ph. Eur. method for RS analysis was evaluated for selected groups of antibiotics. An alternative dilution medium was proposed (DMSO–water), which offers optimum sensitivity while working at lower equilibration temperatures such as 80°C. The optimized method was investigated for precision, accuracy, linearity and detection limits. [Copyright &y& Elsevier]

Abstract: The purge-and-trap (P&T) gas extraction method combined with gas chromatography was studied for its suitability for quantitative residual solvents determination in a water-soluble active pharmaceutical ingredient (API). Some analytical method performance characteristics were investigated, namely, the repeatability, the accuracy and the detection limit of determination. The results show that the P&T technique is – as expected – more sensitive than the static headspace, thus it can be used for the determination of residual solvents pertaining to the ICH Class 1 group. It was found that it could be an alternative sample preparation method besides the static headspace (HS) method. [Copyright &y& Elsevier]

Abstract: D-002 is a new natural product consisting of a mixture of aliphatic fatty alcohols, which shows antioxidant and anti-ulcer effects in experimental models. A new validated methodology for determining simultaneously residual n-hexane and acetone in D-002 using the headspace gas chromatography (HS/GC) is described. The very poor solubility of D-002 in most solvents did necessary sample preparations in solid state. Limit test conditions allowed a detection of residual n-hexane and acetone more sensitively than that recommended for such purposes in the general method of the European Pharmacopoeia. Validation assays, applied to both D-002 residual solvents, proved: suitable sensitivity; very high linearity (correlation coefficients ≥0.999, R.S.D. of slopes ≤0.8% and R.S.D. of response factors ≤5% and no biases) and accuracy (average recoveries between 94.7 and 100.1%); and precision was ≤2.1%. The method was found suitable for quality control and stability studies of this new product. [Copyright &y& Elsevier]

A generic analytical procedure for determination of residual solvents in drug substances is described and validated. The procedure is based on methods described in the European and United States parmacopeias, but is faster than the compendial procedures. It is applicable both during drug development and for quality control in commercial manufacture. The method is accurate, linear and shows a satisfactory level of precision. The solvents included in the validation comprise the five class 1 solvents, 17 out of 27 class 2 solvents, 17 out of 27 class 3 solvents and three unclassified solvents according to ICH guideline Q3C. The solvents can be detected and quantified at levels at or below the ppm limits given in the guideline. In most cases the quantification limit is in the lower ppm range. A strategy is proposed to choose between water or N,N-dimethyl formamide as a diluent. The need for re-validation of the method, mandatory for quantitative procedures according to the European Pharmacopeia, is minimised when using the generic procedure. [Copyright &y& Elsevier]

A simple, inexpensive and rapid analytical approach for the determination of organic volatile impurities in pharmaceutical drug substances is developed, where sample preparation step was conducted using solid phase microextraction (SPME), followed by a fast GC separation. With an extraction time between 3 and 5 min and separation of 13 solvents in less than 3 min employing fast temperature programming using resistively heated column, organic volatile impurities can be analyzed within a total analysis time of 6–9 min. Various SPME phases were evaluated towards sensitivity and selectivity for the extraction of 13 commonly found solvents in drug substances dissolved in dimethyl sulfoxide and water. A 2-cm Carboxen/polydimethyl siloxane/divinylbenzene (Carboxen/PDMS/DVB) phase and a 65-μm DVB/PDMS phase showed better sensitivity towards these solvents when extracted from organic and aqueous matrix in comparison with the sensitivity obtained with direct injection approach. Extraction parameters such as extraction time, extraction stir rate, etc. are discussed. %RSD of peak area of replicate extraction was between 2 and 10% when 100 μm PDMS was used for extracting solvents from aqueous matrix. When DVB/PDMS fiber was evaluated for precision, %RSD of peak area from replicate extractions of solvents from organic matrix was between 2 and 8%. One-hundred micrometer PDMS showed excellent linearity from 10 to 500 μg/ml for analytes extracted from water solutions. On the other hand, DVB/PDMS phase showed better linearity than Carboxen/PDMS/DVB fiber when it was used to extract analytes in the concentration range of 10–5000 μg/ml from organic matrix. [Copyright &y& Elsevier]

A rapid static headspace-gas chromatographic (SHS-GC) method was developed and validated for the quantitation of residual solvents in pharmaceutical gel extrusion module (GEM) tablet formulations. A static headspace sampling technique was utilized to overcome the difficulties imposed by direct injection methods. A Rtx-1701 megabore capillary column was selected to achieve optimal resolution among organic volatile chemicals used commonly in the manufacturing of GEM tablets, residual solvents in the active ingredient and excipients, and other formulation matrix artifacts. A 50-mM pH 3.0 sodium phosphate buffer was used as a sample diluent to minimize matrix effects. The instrumental parameters of the SHS-GC method were optimized for sensitivity and precision. Quantitation was performed by external standard analysis. The SHS-GC method was validated according to regulatory requirements and produced acceptable results with respect to specificity, linearity, range, detection and quantitation limits, precision, and accuracy. [Copyright &y& Elsevier]

Over 25 common pharmaceutical industry solvents, air, ammonia and water are well resolved within 7.5 min. • Water and over 25 residual solvents are baseline resolved by GC within 7.5 min. • Simultaneous analysis of residual solvents and water using GC with TCD. • Water & residual solvent analysis in by GC-TCD comparable to KF and GC-FID results. • Water absorbed by hygroscopic GC diluents is reproducible and hence does not impact GC quantitation. • Lactose monohydrate an alternative solid standard for water quantitation. 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. [ABSTRACT FROM AUTHOR]

• Novel HS-GC-FID/FID method for determination of azide is evaluated. • The method has been applied to the quality control of Sartans. • Validation parameters are in accordance to ICH and Pharmacopeia guidelines. • All samples contained traces of residual solvents. Determination of azide as an impurity in medicinal products was performed for the following sartans with tetrazole functional group (synthesized with the use of azide ion): candesartan, losartan, irbesartan, olmesartan medoxomil, and valsartan. This was achieved using headspace gas chromatography using a dual column/dual flame ionization detector (HS-GC-FID/FID). The method was linear in range, from 5.0–30.0 μg/g, with a coefficient of determination of >0.998 (R2). The limit of quantification was 5.0 μg/g and the detection limit was 1.9 μg/g. The sample preparation procedure is fast and simple. The validation procedure was performed in accordance with International Conference on Harmonization (ICH) and Pharmacopeia guidelines. Moreover, besides the content of azide ions, trace quantities of residual solvents (methanol, ethanol, acetone, isopropanol) were found in the majority of sartan tablets. [ABSTRACT FROM AUTHOR]

• Residual solvent determination in albumin is not possible using conventional approach. • Alternative use of thermal desorber solved the problem. • Performance of different calibration techniques was evaluated. • Confirmation of results by HS-GC following enzymatic digestion. 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. [ABSTRACT FROM AUTHOR]