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Objective: In this study, we aimed to develop a headspace capillary gas chromatography method to quantify residual methanol, acetone, methylene chloride, diisopropyl ether, ethyl acetate, and n,n-dimethylformamide (DMF), in raw clobetasol propionate. Methods: The headspace gas chromatography method employs a chromatographic column packed with 6% cyanopropylphenyl-94% dimethylpolysiloxane as the stationary phase. The column temperature program initiated at 40 °C, was held for 10 min, then ramped up at 10 °C per minute to 220 °C, and maintained for 1 min. Nitrogen served as the carrier gas at a flow rate of 4.84 ml/min. The injection port temperature was set at 140 °C; the flame ionization detector (FID) operated at 250 °C, and the headspace equilibrium temperature was maintained at 105 °C with a 30 min equilibration time. Results: All six residual solvents exhibited complete separation, displaying strong linearity and achieving high recovery rates. Furthermore, the residual solvent levels in the six samples tested remained comfortably below the permissible limit. Conclusion: Our method is accurate, reliable, rapid, and sensitive, making it well-suited for the detection of organic residual solvents in raw clobetasol propionate. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Food Safety & Quality is the property of Journal of Food Safety & Quality Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Procedures for determination of the residual solvent and volatile impurity content in pharmaceutical products usually rely on dissolution in a solvent, followed by headspace-gas chromatography (HS-GC) analysis. Whereas chromatographic systems can utilize a wide variety of solvents, direct-injection mass spectrometry (DIMS) techniques have fewer solvent options, because elimination of the chromatographic column means that the instrument is more susceptible to saturation. Since water has the lowest impact, it has almost always been the default solvent for DIMS. In this study, selected ion flow tube mass spectrometry (SIFT-MS)—a DIMS technique—was applied to the systematic evaluation of the proportion of solvent that can be utilized (with aqueous diluent) without causing instrument saturation and while maintaining satisfactory analytical performance. The solvents evaluated were N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), methanol, and triacetin. All solvents are compatible with headspace-SIFT-MS analysis at 5% (min) in water, while DMI, DMAC, and DMSO can be used at higher concentrations (50, 100, and 25%, respectively), though suffering substantial diminution of the limit of quantitation for non-polar analytes at higher proportions of non-aqueous solvent. Analytical performance was also evaluated using linearity, repeatability, and recovery measurements. This work demonstrates that organic solvents diluted in water can be utilized with headspace-SIFT-MS and provide an approach for evaluation of additional diluent solvents.

Objective: To establish a headspace gas chromatography method to determine the residual solvents of methanol, acetone, dichloromethane, and toluene in cefepime. Methods: Headspace gas chromatography using a DB-624 capillary column and temperature program was performed to detect four residual solvents in cefepime. The temperature program consisted of an initial temperature of 60 ℃maintained for 4 min, a temperature increased to 120 ℃ at 20 ℃·min−1 maintained for 3 min, and then a temperature increased to 200 ℃ at 40 ℃·min−1 maintained for 3 min. Results: Linear relationships were found between the peak areas and mass concentrations of the four solvents mentioned above within the defined ranges. The limits of detection for methanol, acetone, dichloromethane and toluene were 0.50, 0.15, 0.10 and 0.08 mg·L-1, respectively. The recoveries obtained using the standard addition method ranged from 98.41 % to 100.94 %. Conclusion: This method demonstrated high sensitivity and good reproducibility, and it can be used to effectively control the residual amounts of methanol, acetone, dichloromethane, and toluene, to further improve the quality of cefepime.

The chromatographic conditions were optimized using headspace gas chromatography, and a simple and rapid method was established for the simultaneous determination of five residual solvents in ursodeoxycholic acid raw materials. The corresponding quality standards were revised. The research results demonstrate that by utilizing a capillary column with a stationary phase consisting of 5% phenyl-95% dimethylpolysiloxane (HP-5, 30 m × 0.32 mm, film thickness 1.0 µm) and a flame ionization detector in conjunction with a headspace injection system and a programmed temperature ramping method, satisfactory analytical results can be achieved. The specific operating conditions are as follows: an initial column temperature of 45 °C, followed by a column temperature increase at a rate of 5 °C per minute up to 60 °C, then a further increase at a rate of 10 °C per minute up to 100 °C, and finally a rapid increase at a rate of 40 °C per minute up to 200 °C, where it is held for 10 min. Nitrogen is employed as the carrier gas at a flow rate of 1 mL/min with a split ratio of 14:1. The headspace vial temperature is maintained at 100 °C, with a sample equilibration time of 45 min. The concentration of methanol ranged from 0.06 mg/mL to 0.3 mg/mL, and the concentrations of acetone, tert-butanol, ethyl acetate, and triethylamine showed a good linear relationship with the peak area within the range of 0.1 mg/mL to 0.5 mg/mL (r = 0.999); The quantitation limits for methanol, acetone, tert-butanol, ethyl acetate, and triethylamine were 4.2, 0.9, 1.5, 1, and 0.1 μg/mL, respectively, with detection limits of 1.2, 0.25, 0.025, 0.3, and 0.025 μg/mL, respectively. The recovery rates of each solvent ranged from 92.9% to 106.0%, with RSD% (n = 9) less than 3.8%; the method exhibited good repeatability, with RSD% (n = 6) less than 2.5%. Furthermore, the robustness is good. The established method is simple, accurate, specific, and highly sensitive, and can be used for the simultaneous and rapid determination of five residual solvents in ursodeoxycholic acid raw materials. [ABSTRACT FROM AUTHOR]

Residual solvents in pharmaceutical excipients, active pharmaceutical ingredients (APIs), and finished products are usually analyzed using gas chromatography (GC)-based techniques according to a pharmacopeial monograph, such as the United States Pharmacopeia’s (USP) chapter . GC analyses are often slow, which limits sample throughput. Selected ion flow tube mass spectrometry (SIFT-MS) removes the rate-limiting chromatographic separation step, potentially offering faster sample analyses. This approach was demonstrated recently with the publication of an alternative SIFT-MS procedure which was successfully validated against the performance criteria in USP chapter . The present study expands upon the previous work by conducting a head-to-head comparison of GC-flame ionization detection (GC-FID) and SIFT-MS procedures. The results obtained in this cross-platform study demonstrated similar performance for the GC-FID and SIFT-MS procedures for linearity (R2 > 0.94 and 0.97, respectively) and repeatability (

Procedures for determination of the residual solvent and volatile impurity content in pharmaceutical products usually rely on dissolution in a solvent, followed by headspace-gas chromatography (HS-GC) analysis. Whereas chromatographic systems can utilize a wide variety of solvents, direct-injection mass spectrometry (DIMS) techniques have fewer solvent options, because elimination of the chromatographic column means that the instrument is more susceptible to saturation. Since water has the lowest impact, it has almost always been the default solvent for DIMS. In this study, selected ion flow tube mass spectrometry (SIFT-MS)—a DIMS technique—was applied to the systematic evaluation of the proportion of solvent that can be utilized (with aqueous diluent) without causing instrument saturation and while maintaining satisfactory analytical performance. The solvents evaluated were N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), methanol, and triacetin. All solvents are compatible with headspace-SIFT-MS analysis at 5% (min) in water, while DMI, DMAC, and DMSO can be used at higher concentrations (50, 100, and 25%, respectively), though suffering substantial diminution of the limit of quantitation for non-polar analytes at higher proportions of non-aqueous solvent. Analytical performance was also evaluated using linearity, repeatability, and recovery measurements. This work demonstrates that organic solvents diluted in water can be utilized with headspace-SIFT-MS and provide an approach for evaluation of additional diluent solvents. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Shenyang Pharmaceutical University is the property of Shenyang Pharmaceutical University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Residual solvents in pharmaceutical excipients, active pharmaceutical ingredients (APIs), and finished products are usually analyzed using gas chromatography (GC)-based techniques according to a pharmacopeial monograph, such as the United States Pharmacopeia's (USP) chapter <467>. GC analyses are often slow, which limits sample throughput. Selected ion flow tube mass spectrometry (SIFT-MS) removes the rate-limiting chromatographic separation step, potentially offering faster sample analyses. This approach was demonstrated recently with the publication of an alternative SIFT-MS procedure which was successfully validated against the performance criteria in USP chapter <1467>. The present study expands upon the previous work by conducting a head-to-head comparison of GC-flame ionization detection (GC-FID) and SIFT-MS procedures. The results obtained in this cross-platform study demonstrated similar performance for the GC-FID and SIFT-MS procedures for linearity (R2 > 0.94 and 0.97, respectively) and repeatability (<17%RSD and <10%RSD). For accuracy and recovery, acceptance criteria (within 20%) were achieved for most compounds across the two drug products (SIFT-MS suffered fewer failures, possibly due to shorter wait times prior to analysis). Additionally, SIFT-MS analyzed samples over 11-fold faster than GC-FID, increasing daily sample throughput and reducing the time taken to determine the result. This study therefore suggests that residual solvent analysis using SIFT-MS may support workflow improvements for pharmaceutical manufacturers. [ABSTRACT FROM AUTHOR]

In this study, a headspace-micro solid phase extraction method combined with dispersive liquid–liquid microextraction was utilized in the extraction of residual solvents from herbal-based medicine samples. A home-made extraction device was used for headspace-micro solid phase extraction by transferring a proper amount of the samples into the device and adsorption of the analytes onto octadecylsilane from the headspace of sample solution. The adsorbed analytes were eluted by dimethylformamide. The eluate was mixed with a few microliters of tetrabutylammonium chloride: p-aminophenol: linalool deep eutectic solvent [1:1:1, mol: mol: mol]. It was used in the microextraction step to preconcentrate the analytes. The enriched analytes were determined by gas chromatography equipped with flame ionization detector. Under optimized conditions, the method validation was done by International Council of Harmonization protocol and the limits of detection and quantification were in the ranges of 0.81–1.2 and 2.8–4.1 ng g−1, respectively. Wide linearity was obtained with a correlation coefficient ≥ 0.994 for the calibration curves. Relative standard deviation values for the repeated analyses in the same day (n = 6) and different days (n = 4) were ≤ 4.9% at a concentration of 5.0 ng g−1 of each analyte. The method was successful in determination of the analytes in herbal medicines at trace levels (ng g−1). [ABSTRACT FROM AUTHOR]

The use of herbal medicinal products (HMPs) has grown significantly across low-and-middle-income countries (LMICs). Consequently, the safety of these products due to contamination is a significant public health concern. This systematic review aimed to determine the prevalence, types, and levels of contaminants in HMPs from LMICs. A search was performed in seven online databases, i.e., Africa journal online (AJOL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Directory of Open Access Journals (DOAJ), Health Inter-Network Access to Research Initiative (HINARI), World Health Organization Global Index Medicus (WHO GIM), Scopus, and PubMed using appropriate search queries and reported as per the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. Ninety-one peer-reviewed articles published from 1982 to 2021 from 28 different countries across four continents were included in the study. Although metals, microbial, mycotoxins, pesticides, and residual solvents were the reported contaminants in the 91 articles, metals (56.0%, 51/91), microbial (27.5%, 25/91), and mycotoxins (18.7%, 17/91) were the most predominant. About 16.4% (1236/7518) of the samples had their contaminant levels above the regulatory limits. Samples tested for microbial contaminants had the highest proportion (46.4%, 482/1039) of contaminants exceeding the regulatory limit, followed by mycotoxins (25.8%, 109/423) and metals (14.3%, 591/4128). The proportion of samples that had their average non-essential metal contaminant levels above the regulatory limit was (57.6%, 377/655), 18.3% (88/480), 10.7% (24/225), and 11.3% (29/257) for Pb, Cd, Hg, and As, respectively. The commonest bacteria species found were Escherichia coli (52.3%, 10/19) and Salmonella species (42.1%, 8/19). This review reported that almost 90% of Candida albicans and more than 80% of moulds exceeded the required regulatory limits. HMP consumption poses profound health implications to consumers and patients. Therefore, designing and/or implementing policies that effectively regulate HMPs to minimize the health hazards related to their consumption while improving the quality of life of persons living in LMICs are urgently needed.

Copyright of Plastics Science & Technology / Suliao Ke-Ji is the property of Plastics Science & Technology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Organic solvents are used for manufacturing herbal medicines and can be detected as residues of such processing in the final products. It is important for the safety of consumers to control these solvent residues. South African cannabis-based product samples were analysed for solvent residue contaminants as classified by the United States Pharmacopeia (USP), chapter 467. The origin of these samples ranged anywhere from crude extract, product development samples, and market ready final products. Samples were submitted to a contract laboratory over a period of 2 years from 2019 to 2021. To date, no data of this kind exist in South Africa specifically relating to cannabis-based medicinal, recreational, or complementary products. A total of 279 samples were analysed in duplicate by full evaporation headspace gas-chromatography mass-spectrometry and the results are reported in an anonymised format. The results showed an alarming 37% sample solvent residue failure rate with respect to adherence to USP 467 specification. It is important to ensure regulation is enforced to control product quality. The South African public need to be educated about the risks associated with cannabis-based products.

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]

The chromatographic conditions were optimized using headspace gas chromatography, and a simple and rapid method was established for the simultaneous determination of five residual solvents in ursodeoxycholic acid raw materials. The corresponding quality standards were revised. The research results demonstrate that by utilizing a capillary column with a stationary phase consisting of 5% phenyl-95% dimethylpolysiloxane (HP-5, 30 m × 0.32 mm, film thickness 1.0 µm) and a flame ionization detector in conjunction with a headspace injection system and a programmed temperature ramping method, satisfactory analytical results can be achieved. The specific operating conditions are as follows: an initial column temperature of 45 °C, followed by a column temperature increase at a rate of 5 °C per minute up to 60 °C, then a further increase at a rate of 10 °C per minute up to 100 °C, and finally a rapid increase at a rate of 40 °C per minute up to 200 °C, where it is held for 10 min. Nitrogen is employed as the carrier gas at a flow rate of 1 mL/min with a split ratio of 14:1. The headspace vial temperature is maintained at 100 °C, with a sample equilibration time of 45 min. The concentration of methanol ranged from 0.06 mg/mL to 0.3 mg/mL, and the concentrations of acetone, tert-butanol, ethyl acetate, and triethylamine showed a good linear relationship with the peak area within the range of 0.1 mg/mL to 0.5 mg/mL (r = 0.999); The quantitation limits for methanol, acetone, tert-butanol, ethyl acetate, and triethylamine were 4.2, 0.9, 1.5, 1, and 0.1 μg/mL, respectively, with detection limits of 1.2, 0.25, 0.025, 0.3, and 0.025 μg/mL, respectively. The recovery rates of each solvent ranged from 92.9% to 106.0%, with RSD% (n = 9) less than 3.8%; the method exhibited good repeatability, with RSD% (n = 6) less than 2.5%. Furthermore, the robustness is good. The established method is simple, accurate, specific, and highly sensitive, and can be used for the simultaneous and rapid determination of five residual solvents in ursodeoxycholic acid raw materials.

Introduction. The standard samples (SS) use is a necessary condition for the medicines' quality control implementation. Their development is an urgent problem for the pharmaceutical industry, especially for new biologically active compounds that can be further used as pharmaceuticals.Aim. This work aim is to establish the 5-butyl-1,2-diphenyl-6-oxo-1,6-dihydro pyrimidone-4-olate sodium quantitative content, for which anti-inflammatory and analgesic activity was previously proven, in a standard sample.Materials and methods. This work aim is to establish the 5-butyl-1,2-diphenyl-6-oxo-1,6-dihydro pyrimidone-4-olate sodium quantitative content, for which anti-inflammatory and analgesic activity was previously proven, in a standard sample. The main method for establishing a substance quantitative content in the SS is the material balance method. The water determination was carried out according to K. Fisher's method (semimicro method). Sulphated ash was determined according to the XIV edition Russian Federation State Pharmacopoeia General Pharmacopoeia Monograph "Sulphated ash". Related impurities and their content were assessed using the HPLC method on a Flexar liquid chromatograph equipped with a diode array detector (Perkin Elmer, USA). The residual solvents' determination was carried out by the headspace method using a gas chromatograph GC-2010Plus Shimadzu with a flame ionization detector. As an additional method for establishing the main component quantitative content, acidimetric titration with the equivalence point potentiometric indication was carried out.Results and discussion. The percentage was determined for the following indicators: water, residual organic solvents, related impurities, sulphated ash. Using the material balance method, it was found that the 5-butyl-1,2-diphenyl-6-oxo-1,6-dihydropyrimidin-4-olate sodium percentage in a standard sample is 96.01 ± 0.50 %. It was found by acidimetric titration that the 5-butyl-1,2-diphenyl-6-oxo 1,6-dihydropyrimidin- 4-olate sodium quantitative content in SS is 95.12 ± 0.02 %. The difference in the certified value can be explained by the fact that during titration, the SS aciform is released, which precipitates in an aqueous medium and contributes to a shift in the equilibrium and pH value. Consequently, the equivalence point is reached somewhat earlier. However, the data are practically comparable, but it is necessary to use the value obtained by the material balance method.Conclusion. A standard sample certification parameters were determined: water content, residual organic solvents, sulphated ash, related impurities. The main component quantitative content was determined using the material balance method and titrimetry (acidimetry with the equivalence point potentiometric indication).

Cannabis-infused product manufacturers often add terpenes to enhance flavor. Meanwhile, labeling requirements for these same products necessitate testing for residual solvent levels. We have found that heating terpene samples containing an oxygen or air atmosphere results in the detection of significantly higher levels of acetone when compared to the same compound in argon atmosphere using temperature regimes common to headspace autosampler routines. This formation was statistically significant (p = 0.05) for most of the predominant terpenes found in cannabis. The largest increase in acetone formation was seen for terpinolene which showed an 885% increase in oxygen atmosphere (4603.6 PPM) when compared to analysis under argon (519.9 PPM). Cannabinoids were shown to reduce this formation and explain why high levels of acetone are not reported in cannabis extracts, even though these can contain up to 40% terpenes. [ABSTRACT FROM AUTHOR]

In drug discovery environment, determination of residual solvents is indispensable and requires rapid analysis covering a maximum number of commonly used solvents especially with small quantity of sample and short run times. As of now, the reported methods require a large amount of sample (~ 50 to 200 mg) and long run times, which is not feasible in the drug discovery environment. Hence, in the present work, we have reported a high-throughput and sensitive GC-FID method by using less amount of sample (5 mg) within 9 min of total run time on DB-624 column with helium as carrier gas. This method is capable of resolving 40 residual solvents and particularly separated nine critical pairs which were not resolved well in earlier reports. As a part of method development, we have evaluated and optimized the relevant chromatographic parameters to improve the separation efficiency and sensitivity. The data acquisition rate of the FID detector was evaluated at different scan rates and significant improvement in the peak response of the analytes was found at 5 Hz by 100-fold. This developed method was validated as per ICH Q2 (R1) and is more advantageous in the drug discovery environment, as it provides high sensitivity and low turnaround time (TAT). [ABSTRACT FROM AUTHOR]

Residual solvents are not desirable substances they are monitored using gas chromatography with head space based on good manufacturing practices. Measuring residual solvents is mandatory for the release testing of all active pharmaceutical ingredients was investigated. The head space gas chromatography method described in this investigation utilized a 30m x 0.530mm x3.0µ, DB-624 Capillary Column. The injector temperature was set at 200°C. To prevent degradation. The initial oven temperature was set at 90°C for 5 min and programmed at a rate of 40°C a final temperature of 220°C for 5 min. Nitrogen was used as carrier gas. The simple solvent selected was benzyl alcohol. The method was validated to be specific, linear, precise, sensitive, rugged, and showed excellent recovery. [ABSTRACT FROM AUTHOR]

Background: In spite of the importance and wide use of toltrazuril as an antiprotozoal drug, the literature is a lack of relevant analytical methods to control its quality. The development and validation of an accurate, selective, and precise HPLC method for the assay of toltrazuril in the presence of its impurities and degradation products. Also, the development and validation of an accurate, selective, and precise GC-head space method for the quantitative determination of residual solvents used during the manufacturing of toltrazuril. Methods: In the HPLC method separation between toltrazuril and its impurities was successfully achieved using LiChrospher RP-18 (4.6 mm, 250 mm, 5 ╊m) column, using a mixture of acetonitrile and water (60:40) (V: V) as a mobile phase at a flow rate of 1.4 ml/min. The detection wavelength was set to be 244 nm. In the GC method separation was achieved using ZB-624 (0.53mm*30m*3.0um) column, N2 as a carrier gas flowing at a rate of 3 ml/min. The column temperature was gradually raised from 40 °C to 180 °C while the injector and detector temperatures were maintained at 180 °C and 250 °C respectively. Results: The developed methods were validated according to ICH guidelines in terms of specificity, linearity, accuracy, precision, and system suitability. Both methods were found to be linear with a correlation coefficient ranging from 0.9996 to 0.9997. Mean recoveries of toltrazuril and its residual solvents at three different levels were found to be ranging between 92.5 and 104.1 %. Conclusion: The developed methods could be used during quality control and stability testing of toltrazuril either alone or in the formulation.

The use of herbal medicinal products for complementary and alternative medicine is well established in Ghana. The potential public health risks associated with the use of these products due to the presence of residual solvents have not yet been investigated and/or reported. In this pilot study, 7 liquid dosage forms of herbal medicinal products obtained from pharmacies and licensed chemical seller shops within the Accra metropolis in Ghana were investigated for the presence of 28 residual solvents using a combination of two orthogonal headspace gas chromatography with flame ionization detector methods from a compendial approach in the general chapter Residual Solvents in the United States Pharmacopeia without modification. One herbal medicinal product was contaminated with 498.33 ppm of chloroform, resulting in daily exposure of 41.82 mg/day, which is above the permissible daily exposure level of 0.6 mg/day. The detection of chloroform in herbal medicinal products suggests further investigation into the profile of residual solvent contaminants in herbal medicinal products as a matter of public health concern and the potential need for more stringent regulation of herbal medicinal products marketed in Ghana.

Radiolabelling with short half‐lives radionuclides (e.g., fluorine‐18 and carbon‐11) must be as efficient and as fast as possible. Nucleophilic radiofluorinations and radiomethylations are conducted in polar aprotic solvents, such as dimethylsulfoxyde (DMSO), N,N‐dimethylformamide (DMF) and N,N‐dimethylacetamide (DMA), at high temperature. Those solvents are classified as toxic according to the ICH guidelines and must be evaluated in drug such as radiopharmaceuticals. Headspace gas chromatography is the standard method for the quantification of residual solvents but is not optimized for a rapid quantification of low vapor pressure solvents such as DMSO, DMF and DMA in radiopharmaceuticals. Direct injection gas chromatography is an interesting option without incubation step but the analysis run‐time remains beyond 10 min long. In consequence, we developed a very simple ultra‐high performance liquid chromatography method coupled with UV detection. Following the EMA requirements, we successfully validated a 3‐min run‐time analysis for quantification of three solvents in short half‐lives radiopharmaceuticals. We currently use this method for the quality control of radiopharmaceuticals produced in our PET center. [ABSTRACT FROM AUTHOR]

Cannabis-infused product manufacturers often add terpenes to enhance flavor. Meanwhile, labeling requirements for these same products necessitate testing for residual solvent levels. We have found that heating terpene samples containing an oxygen or air atmosphere results in the detection of significantly higher levels of acetone when compared to the same compound in argon atmosphere using temperature regimes common to headspace autosampler routines. This formation was statistically significant (p = 0.05) for most of the predominant terpenes found in cannabis. The largest increase in acetone formation was seen for terpinolene which showed an 885% increase in oxygen atmosphere (4603.6 PPM) when compared to analysis under argon (519.9 PPM). Cannabinoids were shown to reduce this formation and explain why high levels of acetone are not reported in cannabis extracts, even though these can contain up to 40% terpenes.

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. [ABSTRACT FROM AUTHOR]

Ibandronate sodium, a third-generation diphosphate drug used worldwide to treat osteoporosis, has the advantages of convenient use, low toxicity, and significant therapeutic effects. However, the residual organic solvents in the synthesis process of sodium ibandronate not only have a negative impact on the efficacy of the drug, but also lead to a decrease in drug stability. Moreover, if the residual amounts of these solvents exceed safety standards, they may pose serious threats to human health. This study successfully established a convenient and efficient method based on headspace-gas chromatography (HS-GC) for the simultaneous determination of five residual solvents (methanol, acetone, benzene, toluene, 1-pentanol) in the raw materials of ibandronate sodium. The results indicated that satisfactory analytical performance can be achieved by using DB-624 capillary column (30 m×0.32 mm×1.8 μm) and a flame ionization detector in conjunction with headspace autosampling and a temperature program. The specific operating conditions included an initial temperature of 40 ℃, with a hold of 2 min, followed by a temperature ramp first to 200 ℃ at a rate of 5 ℃/min and then to 240 ℃ at a rate of 20 ℃/min, with a hold of 5 min. Nitrogen with a flow rate of 1 mL/min and split ratio of 14∶1 was used as the carrier gas. The headspace vial temperature was maintained at 80 ℃, and the sample equilibration time was 20 min. Under the established analytical conditions, good linear relationships were obtained between the mass concentrations of methanol (72-216 μg/mL), acetone (120-360 μg/mL), benzene (0.048-0.144 μg/mL), toluene (21.36-64.08 μg/mL), and 1-pentanol (120-360 μg/mL) and their corresponding peak areas, with correlation coefficients ( r ) greater than 0.990. The limits of detection for these solvents were 2.88, 0.011, 0.90, 0.24, and 0.024 ng/mL, respectively, with limits of quantification of 11.5, 0.043, 3.6, 0.96, and 0.096 ng/mL, respectively. Furthermore, the recoveries of these solvents ranged from 86.3% to 101.9%, with relative standard deviations (RSDs, n =3) of less than 2.49%. The proposed method is simple, accurate, reliable, and suitable for the rapid and simultaneous determination of five residual solvents in the raw materials of ibandronate sodium. This study has important practical significance in improving drug safety and ensuring public health.

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. [ABSTRACT FROM AUTHOR]

In this study, a drying method using ethanol pretreatment was developed that can effectively remove residual solvent from crystalline vancomycin. Microwave-assisted drying with ethanol pretreatment was sufficient to remove residual acetone and ethanol concentrations below the ICH limits (5,000 ppm for acetone and 5,000 ppm for ethanol). At all the microwave power (100, 200, 300 W), a large amount of the residual acetone was initially removed during the drying, and the drying efficiency increased when increasing the microwave power. In addition, the drying kinetics and thermodynamics were examined. The experimental data were fitted to the Newton, Page, Modified Page, Henderson and Pabis, and Geometric models. Comparison of results revealed that the Page model was the most appropriate. The activation energy of microwave-assisted drying was found to be 10.8792 kJ/mol. The Standard Gibbs free energy change was determined to be negative, while the standard enthalpy change and entropy change were positive. These results revealed the endothermic, irreversible and spontaneous nature of drying. [ABSTRACT FROM AUTHOR]

The methods for controlling organic volatile impurities, including residual solvents and reagents, in the travoprost active pharmaceutical ingredient, has been reported. Monitoring the chemical purity of the starting material ñ TV-38A ((R)-(-)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluoromethylphenoxy)propan-1-ol) ñ is critical, as it may directly affect the impurity profile and the quality of the final product. The proposed methods have been developed using gas chromatography as well as gas chromatography with headspace injection and they have been validated according to the requirements of the ICH (International Conference of Harmonization) Q2R1 validation guidelines and the Q3C guideline for residual solvents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Methods for nanoparticles preparation often employ organic solvents in order to solubilize the non-polar constituents of the final nanostructures. In the research process, nanoparticles are assayed as aqueous suspensions in several cases, so that an excessive residual concentration of the organic solvent needs to be avoided since may lead to undesired secondary effects during biological tests. Despite the importance, residual solvent concentration is rarely determined, making necessary the development of quantification methods suitable for this purpose. Acetone is frequently used in drug delivery systems preparation, being capable to exert significant toxicities both, in vitro and in vivo. Thus, a simple and inexpensive UV–Vis spectrophotometric method is proposed to directly determine acetone from nanoparticles suspensions employing its reaction with vanillin. Central composite designs were employed to correct and optimize the quantification method, which was then validated according to international guidelines. The optimized method resulted accurate, precise, and linear in the range of 10–50 µg/mL, with an R2 of 0.998 and limits of detection and quantification of 2.6 and 7.8 µg/mL, respectively. The effect of several surfactants employed during nanoparticles preparation was not detrimental to the method. The proposed procedure can be successfully applied to directly quantify acetone from nanoparticles suspensions. [ABSTRACT FROM AUTHOR]

Masking derivatization was introduced for the determination of residual solvents in samples containing a volatile reactive matrix component(s). Isobutylboronic acid, used in the last step of Bortezomib synthesis, represents a compound passing to the gas phase and deteriorating a chromatographic column during a headspace analysis. The masking derivatization with 1,8‐diaminonaphthalene allowed a simple and straightforward conversion of isobutylboronic acid to a stable nonvolatile derivative and thus prevented gas chromatography column deterioration. The method was successfully validated according to the guidelines of International Committee for Harmonization (Q3C (R6) Guideline for Residual Solvents) and international pharmacopoeias (Ph. Eur., USP) and approved by Teva Czech Industries for routine application. [ABSTRACT FROM AUTHOR]

Abstract Supramolecular solvent (SUPRAS) extraction is gaining attraction as a sample treatment technique because of its great performance in terms of effectiveness, versatility, sample clean-up, quickness, cost and sustainability. However, the nature of SUPRASs, being formed by amphiphile molecules, results in poor compatibility with Gas Chromatography (GC). Here, we show the hitherto unexplored development of a SUPRAS with high thermal stability (HTS) suitable for subsequent direct analysis by Headspace (HS)-GC. This novel HTS-SUPRAS, based on poly-undecylenic acid -an oligomeric surfactant-, tetraglyme -a polar aprotic solvent with excellent chemical and thermal stability- and water, was fully characterized in terms of composition and physical properties such as thermal stability. Subsequently, the HTS-SUPRAS developed was further successfully applied, as a proof-of-principle, to the extraction and determination of residual solvents in pharmaceutical drugs, including several solvents (class 2C) whose analysis by HS-GC has been shown to be highly complex. Analytical performance was demonstrated as mandated by the International Council for Harmonisation of technical requirements for pharmaceuticals for human use (ICH). Furthermore, excellent recoveries (70–120%) and high precisions (<20%, expressed as relative standard deviations) were obtained for the analysis of several different drug formulations spiked with the analyzed 37 residual solvents at their respective maximum residue levels. Graphical abstract Image 1 Highlights • A supramolecular solvent with high thermal stability is described for the first time. • This new solvent is based on poly-undecylenic acid, an oligomeric surfactant. • It opens a new avenue for sample treatment prior to Headspace - Gas Chromatography. • A validated determination of 37 residual solvents in 10 different drugs was achieved. [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]

Availability of herbal food supplements and belief in their efficacy and safety contributed to their increased use, causing exposure to ethanol and residues of extraction solvents. Liquid herbal food supplements (103) were purchased from pharmacies (Novi Sad, Serbia) during 2021, and analysed for presence of ethanol and selected residual solvents using HSS-GC-MS method. Ethanol was not quantified in only one of 18 products for infants or toddlers less than two years old. WHO proposed requirement for ethanol content in products intended for children less than 6 years old (<0.5%) was not met by 26 samples, in products for children 6–12 years (<5%) by four samples and in products for children over 12 years (<10%) by two samples. Calculated blood alcohol concentrations exceeded the relevant toxicological levels for 37 samples following a single dose, and for 31 samples in case of accidental poisoning (entire package). Methanol was quantified in 38 samples, in one of them above the limit of 0.05%, (Ph. Eur. 9), causing exceedance of permitted daily exposure. Other residual solvents were quantified rarely and in low concentrations. Study findings confirmed a need for raising awareness of professionals and public and establishment of strict guidelines for ethanol content and labelling. [Display omitted] • Risk assessment of ethanol and residual solvents in 103 herbal food supplements. • 26/58 samples exceeded WHO limit for ethanol in products for children under 6 years. • Single dose of 37 samples caused blood alcohol concentration (BAC) above EMA limit. • Ingestion of the entire package of 31 samples caused BAC tox above EMA limit. • One out of 38 samples containing methanol was found to pose a risk concern. [ABSTRACT FROM AUTHOR]

A simple and sensitive gas chromatographic method has been developed and validated for simultaneous determination of heptane, acetone, tetrahydrofuran, ethyl acetate, methanol, 2-propanol, dichloromethane, toluene and pyridine in docetaxel. The separation was achieved on 60 m long DB-WAXETR Polyethylene glycol column, 0.250 mm in inner diameter and 0.25 μm in film thickness. The developed gas chromatographic method offers symmetric peak shape, good resolution and reasonable retention time for all the solvents. The limit of detection of methanol, acetone, iso-propanol, ethyl acetate, toluene, dichloromethane, tetrahydrofuran, pyridine and heptane was found to be 0.027, 0.50, 0.12, 0.070, 0.070, 0.180, 0.040, 0.170 and 0.040, respectively. The linear regression equations obtained were heptane, A = −0.62 + 1.55 × 10−4; acetone = −1.49 + 7.07 × 10−5; tetrahydrofuran, A = −1.01 + 5.05 × 10−5; ethyl acetate, A = −2.87 + 1.08 × 10−4; methanol, A = 1.33 + 7.73 × 10−5; isopropanol = −2.07 + 1.60 × 10−4; dichloromethane, A = −3.93 + 3.06 × 10−4; toluene = −0.62 + 1.78 × 10−5; pyridine, A = −4.87 + 3.28 × 10−4.

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]

In this work, thermal desorption-gas chromatography-flame ionization detection (TD-GC-FID) was adapted to enable the determination of residual solvents (RS) in mesoporous silica (MPSi). MPSi is often utilized in various pharmaceutical formulations or drug delivery systems and the accurate determination of RS is an important part of pharmaceutical quality control. Seven commonly used solvents (methanol, ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran and hexafluoroisopropanol) were evaluated in combination with 3 types of MPSi having pore sizes of 2–3, 15 and 25 nm. Validation results showed general recovery values > 98% and good linearity over the concentration ranges studied. The limits of detection (LOD) and limits of quantification (LOQ) for the different solvents ranged from 0.03 to 0.08 μg and from 0.1 to 0.2 μg per tube, respectively. Verification of the accuracy of the TD method was investigated by using an alternative method based on complete dissolution of MPSi in hydrofluoric acid (HF) followed by full evaporation headspace-GC (HS-GC). The results obtained from both procedures were not statistically different (p > 0.05) when applied to actual experimental drug samples consisting of itraconazole loaded on MPSi. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A simple and sensitive headspace gas chromatographic method has been developed and validated for simultaneous determination of isopropyl alcohol and methylene chloride in zopiclone tablets. The separation was achieved on 75 m long DB-624 fused silica column, 0.53 mm inner diameter and 3 ì film thickness using nitrogen as a carrier gas at 6 ml/min flow and FID as a detector. The developed gas chromatographic method offers symmetric peak shape, good resolution and reasonable retention time for all the solvents. The limit of detection of isopropyl alcohol and methylene chloride was found to be 250 ìg/tablet and 90 ìg/tablet, respectively. [ABSTRACT FROM AUTHOR]

A fast and simple method using Gas Chromatography combined with Flame Ionization Detection (GC-FID) was developed for the determination of ethanol, acetonitrile, dibromomethane, dimethylaminoethanol, and dimethyl sulfoxide in [18F]fluorocholine. The combination of fractional factorial design, Doehlert design, and Desirability function was used to evaluate the operational parameters and to establish the best working condition. The validation results revealed that the proposed method has good recovery (85.1–104.1%) and repeatability (RSD ≤8.1%). Correlation coefficients (R ≥ 0.983) indicated good linearity over a wide range. The limit of detection (≤2.5 ppm) and the limit of quantification (≤7.5 ppm) were satisfactory. The proposed method is based on minimum manual operation, sample preparation free, direct injection technique, and short chromatographic separation time. This method is useful for routine analysis of organic solvents in [18F]fluorocholine, feasible for the modernization of specific monograph, and was therefore successfully implemented to assess samples manufactured by Nuclear Technology Development Center (CDTN). [Display omitted] • Simple and reliable determination of organic impurities in radiopharmaceutical. • Chemometric approaches were applied for simultaneous optimization of responses. • No sample preparation is needed before GC-FID analysis. • By using direct injection we could overcome the limitations of headspace. • Method is suitable for the [18F]fluorocholine specific monograph actualization. [ABSTRACT FROM AUTHOR]