Residual Solvents In Pharmaceuticals Research Articles

Impurity Profiling: A Review

Impurities are any substances, such as starting materials or intermediates, that coexist with the parent drug or arise from side reactions. Interest in impurities present in APIs continues to grow. Nowadays, not only purity profile but also impurity profile is mandated by various regulatory agencies. Impurity profiling is a generic name for a group of analytical working groups such as describing, quantifying and characterizing identified and unidentified impurities present in a new drug substance. Impurity profiling is a novel approach aimed at detecting, identifying, structuring and quantifying organic and inorganic impurities and residual solvents in pharmaceuticals. Various regulatory bodies, such as ICH, USFDA, UKMHRA, and India's CDSCO, focus on impurity profiling and have formulated guidelines for impurity management and restriction. Impurities are classified into different categories based on their origin, type of composition, and biological safety. The presence of these unwanted chemicals or substances may affect the safety and effectiveness of the final medicinal product. This review focuses on the sources of impurities, their classification, and various analytical methods for the identification and quantification of impurities. Terms such as residual solvent, by-product, transformation product, decomposition product, reaction product, and related products are often used to define impurities.

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.

Analytical Method Development and Validation of Glipizide to Determine Residual solvents by head Space-Gas Chromatography

Residual solvents in Pharmaceuticals are termed as organic volatile impurities. These are the chemicals that are used in the manufacture of drug substance or excipients or use in the preparation of final formulation. Most of the available methods use liquid chromatography which could be expensive and time consuming. Hence, an analytical methodology was developed for the quantification of residual solvents in Glipizide using a headspace gas chromatography (HSGC) with the help of flame ionization detector (FID). Methanol, acetone and dimethyl formamide as residual solvents were determined in Glipizide. Analysis was performed by headspace GC/FID method on Auto system- HS40. Nitrogen was used as a carrier gas and the separation of residual solvents was achieved by DB-Wax 0.25mm, 0.3mcm column. The thermostat temperature was 115 °C for 40 minutes for each vial. % RSD for nine injections obtained are in acceptance criteria. The correlation coefficient R2 obtained greater than 0.99. The method parameters were validated includes specificity, limit of detection and quantification, accuracy, linearity, precision, and robustness. According to the International Conference on Harmonization (ICH) guidelines, a new simple, specific, accurate and precise method was developed and validated.

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.

Determination of Residual Solvents in Pharmaceuticals by Static Headspace Gas Chromatography Using Natural Deep Eutectic Solvents as Mediums: A Partition Coefficients Study

A relatively new application of natural deep eutectic solvents (NADESs) as eco-friendly dilution mediums in static headspace gas chromatography (SHS-GC) was further studied. The partition coefficients of twelve organic solvents in NADESs were determined by SHS-GC. Eight NADESs were prepared with choline chloride and carboxylic acids, polyols and urea in different molar ratios. The twelve organic solvents included four haloalkanes, four aprotic solvents, two alcohols, and two alkanes. The partition coefficients (K) of each solvent in different NADESs were determined and discussed. The logK values of alkanes and aprotic solvents in NADESs were low, while the logK of haloalkanes and alcohols was high. That is, alkanes and aprotic solvents in NADESs had better headspace efficiency, indicating that the interaction between the solvents and the NADESs played an important role. The relationship between the logK and the properties of NADESs and organic solvents was further discussed. As an example, the method was applied to determine the residual solvents in paroxetine by SHS-GC with appropriate NADES. This study is beneficial for the selection of suitable NADESs as green mediums for the detection of residual solvents in pharmaceuticals.

Use of ionic liquids as headspace gas chromatography diluents for the analysis of residual solvents in pharmaceuticals

In this study, two ionic liquids (ILs), 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([BMIM][NTf2]) and trihexyltetradecylphosphonium bis[(trifluoromethyl)sulfonyl]imide ([P66614][NTf2]) 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][NTf2] 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 20ppm 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 15min 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][NTf2] 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.

Analysis of residual solvent in thickeners by headspace gas chromatography using a standard addition method

Headspace gas chromatography (HS-GC) is an accepted method for analysis of residual solvents in pharmaceuticals, food additives and food. The amounts of residual solvent present in various food thickeners were analysed by HS-GC standard addition method. Conditions for the HS-GC were optimised, and equilibration time was determined to be 40 min at 60°C for the determination of residual solvent. The results were very similar to those obtained by distillation and gas chromatography (Distillation-GC). We conclude that both methods are equally efficient for the determination of residual solvent in thickeners. In addition capillary column (Aquatic-2 GL Sciences Co.) was used to analyze by headspace or distillation. Corresponding author: Chiye Tatebe, Division of Food Additives, National Institute of Health Sciences, 1-18-1, Kami-yoga, Tokyo 158-8501, Japan

Extraction and preconcentration of residual solvents in pharmaceuticals using dynamic headspace-liquid phase microextraction and their determination by gas chromatography-flame ionization detection.

The present study describes a microextraction and determination method for analyzing residual solvents in pharmaceutical products using dynamic headspace-liquid phase microextraction technique followed by gas chromatography-flame ionization detection. In this method dimethyl sulfoxide (μL level) placed into a GC liner-shaped extraction vessel is used as a collection/extraction solvent. Then the liner is exposed to the headspace of a vial containing the sample solution. The effect of different parameters influencing the microextraction procedure including collection/extraction solvent type and its volume, ionic strength, extraction time, extraction temperature and concentration of NaOH solution used in dissolving the studied pharmaceuticals are investigated and optimized. Under the optimum extraction conditions, the method showed wide linear ranges between 0.5 and 5000 mg L-1 . The other analytical parameters were obtained in the following ranges: enrichment factors 240-327, extraction recoveries 72-98% and limits of detection 0.1-0.8 mg L-1 in solution and 0.6-3.2 μg g-1 in solid. Relative standard deviations for the extraction of 100 mg L-1 of each analyte were obtained in the ranges of 4-7 and 5-8% for intra-day (n = 6) and inter-day (n = 4) respectively. Finally the target analytes were determined in different samples such as erythromycin, azithromycin, cefalexin, amoxicillin and co-amoxiclav by the proposed method.

Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals

An efficient generic static headspace gas chromatography (HSGC) method was developed, optimized and validated for the routine determination of several residual solvents (RS) in drug substance, using a strategy with two sets of calibration. Dimethylsulfoxide (DMSO) was selected as the sample diluent and internal standards were used to minimize signal variations due to the preparative step. A gas chromatograph from Agilent Model 6890 equipped with flame ionization detector (FID) and a DB-624 (30m×0.53mm i.d., 3.00µm film thickness) column was used. The inlet split ratio was 5:1. The influencing factors in the chromatographic separation of the analytes were determined through a fractional factorial experimental design. Significant variables: the initial temperature (IT), the final temperature (FT) of the oven and the carrier gas flow rate (F) were optimized using a central composite design. Response transformation and desirability function were applied to find out the optimal combination of the chromatographic variables to achieve an adequate resolution of the analytes and short analysis time. These conditions were 30°C for IT, 158°C for FT and 1.90mL/min for F. The method was proven to be accurate, linear in a wide range and very sensitive for the analyzed solvents through a comprehensive validation according to the ICH guidelines.

Rapid Monitoring and Determination of Class 1 Residual Solvents in Pharmaceuticals Using Dispersive Liquid-Liquid Microextraction and Gas Chromatography-Mass Spectrometry.

A simple and rapid dispersive liquid-liquid microextraction (DLLME) method coupled with gas chromatography-mass spectrometry (GC-MS) for monitoring and determination of class 1 residual solvents, benzene (Bz), carbon tetrachloride (CT), 1,2-dichloroethane (1,2-DCE), 1,1-dichloroethene (1,1-DCE), 1,1,1-trichloroethane (1,1,1-TCE), in pharmaceuticals was developed and evaluated. The parameters affecting the extraction efficiency of analytes such as type and volume of extraction solvent, type and volume of dispersive solvent and ionic strength were investigated and optimized. 1-Octanol and methanol proved to be the most suitable extraction and dispersive solvents, respectively. The method showed linearity for 1,1-DCE, 1,1,1-TCE, CT, Bz and 1,2-DCE in the ranges of 0.001-80, 0.005-80, 0.002-80, 0.0001-40 and 0.001-80 µg/mL, respectively. The relative recoveries were in the range of 84-92, 87-98, 83-94, 89-98 and 87-96% for 1,1-DCE, 1,1,1-TCE, CT, Bz and 1,2-DCE, respectively. The obtained results showed that the proposed method can be used to monitor and determine class 1 residual solvents in pharmaceuticals.

Dispersive liquid-liquid microextraction combined with gas chromatography for extraction and determination of class 1 residual solvents in pharmaceuticals

The present study reports a new method for analyzing class 1 residual solvents (RSs), 1,1-dichloroethene (1,1-DCE), 1,2-dichloroethane (1,2-DCE), 1,1,1-trichloroethane (1,1,1-TCE), carbon tetrachloride (CT), and benzene (Bz), in pharmaceutical products using dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography-flame ionization detection (GC-FID). Unlike common DLLME methods, solvents of high boiling point were selected as dispersive and extraction solvents in order to prevent their chromatographic peaks from overlapping with those of analytes that have short retention times. Therefore N,N-dimethyl formamide (DMF) and 1,2-dibromoethane (1,2-DBE) were chosen as dispersive and extraction solvents, respectively. Analytical parameters of the proposed method were determined and good linearities and broad linear ranges (LRs) were obtained. Taking 500 mg samples, limit of detections for the tested pharmaceuticals were obtained as 0.11, 0.03, 0.05, 0.05, and 0.006 μg g(-1) for CT, 1,1-DCE, 1,2-DCE, 1,1,1-TCE, and Bz, respectively, which are considerably much lower than their permissible limits in pharmaceuticals.

Determination of volatile residual solvents in pharmaceutical products by static and dynamic headspace liquid-phase microextraction combined with gas chromatography-flame ionization detection

Headspace single-drop microextraction (HS-SDME) and dynamic headspace liquid-phase microextraction (DHS-LPME) combined with GC-FID were used to determine thirteen residual solvents in pharmaceuticals. Different extraction conditions such as microdrop volume, ionic strength of the sample, extraction time, stirring rate, extraction temperature, solvent volume, sampling volume and number of extraction cycles were studied. n-Octanol was used as the extracting solvent for both methods. Under the optimal conditions, the limits of detection for the analytes obtained by DHS-LPME and HS-SDME ranged from 1.9 to 44 μg L−1 and 0.3 to 21 μg L−1, respectively. Enrichment factors ranged 9–212 and 15–379 for DHS-LPME and HS-SDME, respectively. The relative standard deviations (RSDs, n = 5) for both methods are lower than 9.1%. The applicability of the selected method (HS-SDME) in real sample analysis was investigated.

Ecotoxicological risk of Residual Solvents in Pharmaceuticals on Daphnia Magna

Ecotoxicity of residual solvents of pharmaceuticals on daphnia magna was studied by acute test. The results showed the order of toxicity of residual solvents of terramycin, thiamine hydrochloride and thiamine mononitrate was benzene > carbon tetrachloride > 1, 2-dichloroethane > 1, 1-dichloroethylene > 1, 1, 1-trichloroethane, dichloromethane > tetrahydrofuran > toluene > methanol> ethyl acetate = acetic acid = ethanol, Nmethylpyrrolidon > N, N-dimethylacetamide > methanol > aether, respectively. The ecotoxicity of methanol in combined system was more severe than that of in single system. The LC50 s of methanol were 72.21, 91.94 and 3.357×10 4mg/L in thiamine hydrochloride, thiamine mononitrate and in single system, respectively. It was likely that the toxic effect of residual solvents increased in the presence of potential competitors. The study provided baseline information which was necessary to assess the potential hazard of some residual solvents released into water ecosystems.

Current situation and the trend in impurity control of chemical drugs

The safety of the drug therapy is closely related to the quality of drugs. The impurity profiling which means that analytical activities with the aim of detecting, identifying or elucidating the structure and quantitatively determining organic and inorganic impurities as well as residual solvents in pharmaceuticals, has become the most important activity in assuring the high quality of drugs, and the concept of impurity profiling control in specifications has currently been acceptable all over the world. After discussing the technique used in impurity profiling control with emphasis on impurity determination, impurity identification as well as impurity qualification, the trends of this field in China has been outlined.

Considerations regarding a permitted daily exposure calculation for ethyl methanesulfonate

Specification of human exposure limits to compounds with toxicities based on modes of action that allow considerations of a threshold and the safe estimation of a no-observed-effect level (NOEL) is normally based on acceptable daily intake (ADI) or permitted daily exposure (PDE) calculations using appropriate safety factors to account for differences between species, populations, length of observation and severity of lesions. In view of the reliable experimental evidence for a thresholded dose response of the genotoxicity of ethyl methanesulfonate (EMS) as reported in this special issue of Toxicology Letters such an acceptable daily intake proposal is made using the approach for setting permitted daily exposure limits outlined in appendix 3 of the ICH Q3C consensus guideline on residual solvents in pharmaceuticals (ICH, 2005). Up to now the specification of EMS exposure limits was based on the generic threshold of toxicological concern (TTC)-derived limit of 1.5 μg/person/day as advocated by the CHMP [CHMP, 2006. Guideline on the limits of genotoxic impurities. www.emea.europa.eu/pdfs/human/swp/519902en.pdf (June 28, 2006) with Q&A www.emea.europa.eu/pdfs/human/swp/43199407en.pdf (June 25, 2008)] or on as low as technically achievable criteria. Such limits have been based on conservative linear dose-effect extrapolations corresponding to an excess cancer risk of 1 in 100,000. We now present an EMS-specific PDE based on the reliable demonstration of a NOEL for induction of mutations in vivo of 25 mg/kg/day. Using the most conservative safety factors described in ICH Q3C we derive a PDE of ∼100 μg/person/day using product safety factors still amounting to 12,000.

Application of the solvation parameter model in method development for analysis of residual solvents in pharmaceuticals

The solvation parameter model was applied in the development of a method for the analysis of residual solvents in pharmaceuticals. The interactions between organic solvents and six different stationary phases were studied using gas chromatography. The retention times of the organic solvents on these columns could be predicted under isothermal or temperature-programmed conditions using the established solvation parameter models. The predicted retention times helped in column selection and in optimizing chromatographic conditions during method development, and will form the basis for the development of a computer-aided method.

Evaluation of the European Pharmacopoeia method for control of residual solvents in some antibiotics

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.