[Determination of multiple residual solvents in ibandronate sodium using headspace-gas chromatography].

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.

Contamination of herbal medicinal products in low-and-middle-income countries: A systematic review.

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.

Chromatographic method development using multivariate approaches for organic solvents optimized analysis in [18F]fluorocholine.

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).

Acetone as Artifact of Analysis in Terpene Samples by HS-GC/MS.

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.

An assessment of solvent residue contaminants related to cannabis-based products in the South African market.

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.

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

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

Determination of contaminants in artisanal cannabis products used for childhood epilepsy in the Australian community: A sub-analysis of the 'PELICAN' study.

Despite recent approval of pharmaceutical-grade cannabis products for the treatment of childhood epilepsy, some families continue to use artisanal cannabis products as a way to manage seizures in their children. However, such products are typically of unknown composition and quality, and may therefore pose an unpredictable health risk to the child. In the present analysis, 78 samples of cannabis products collected (as part of a previous study) from families of children with epilepsy (average age 8.8 ± 4.6 years) were analyzed for heavy metals (arsenic, cadmium, lead, and mercury), residual solvents (panel of 19 solvents) and pesticides (panel of 57 pesticides). Due to small sample volumes obtained, only a subset of samples was used in each analysis. Results showed that no cannabis sample exceeded the toxicity limits for heavy metals (n = 51 samples tested). Of the 58 cannabis samples tested for residual solvents, 17 (29%) contained concentrations of ethanol or isopropanol above the generally accepted limit of 5000 parts per million. With the volumes consumed, it was thought unlikely that children were consuming hazardous amounts of residual solvents, although this could not be ruled out in every case. Most samples (n = 31 samples tested) yielded inconclusive results for the pesticides, although one sample contained concentrations of bifenthrin that were 4.9 times higher than the acceptable limit. Overall, these results highlight the need for improved access to quality-assured cannabis products and the education of doctors, patients, and artisanal manufacturers around the contaminant exposure risk in unregulated cannabis products.

Quality of Active Pharmaceutical Ingredients Present on Algerian Soil: Control of Impurities of Ciprofloxacin, Metronidazole and Fluconazole.

INTRODUCTION: The medicine quality is defined by its aptitude to meet certain requirements declared by the regulatory authorities. Among these, impurities control which constitutes the major fear of pharmaceutical manufacturers in efficiency and safety terms. Nowadays, in many developing countries, the presence of poor quality drugs is common, for this reason, an increased control should be instituted including impurities which represent a serious public health problem threatening the efficacy and the safety medicines, because of their nocuous repercussions on health. The objective of this study is to verify that impurities in certain APIs: Ciprofloxacin, Metronidazole and Fluconazole actually collected on Algerian soil meet the impurity requirements. MATERIALS AND METHODS: An observational experimental study was carried out from 1st December 2013 to 31st December 2017, on impurities control in the APIs of Ciprofloxacin, Metronidazole and Fluconazole medicines registered in the Algerian Medicines Nomenclature and marketed in Algeria. All samples collected were analyzed to detect, quantify and evaluate impurties for rigorous control of three categories of impurties, such as: Organic related-impurities analysis by High-Pressure Liquid Chromatography with UV Detector (HPLC-UV), Elemental-impurities analysis by Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) and Residual Solvents-impurities analysis by Headspace Gas Chromatography with Flame Ionization Detection (HS-GC-FID). RESULTS AND DISCUSSION: 18 samples collected from 11 laboratories among 27 requested. 22% of non-conformities were detected, including 5.5% Indian origin, 5.5% Spanish origin, 5.5% French origin and 5.5% Chinese origin. These non-conformity cases are due to the high rate of degradation product-impurity for C5 sample, Cobalt-impurity and Nickel-impurity contents exceeding the required limits for C4 and M3 samples respectively, Methanol-impurity and Toluene-impurity contents exceeding the authorized limits for M2 and F3 samples respectively. CONCLUSION: This study concluded that samples non-compliance rate is high because of certain impurities detection exceeding the safety standards. So, we interpellate the health authorities to ensure the APIs impurities control before being put into the manufacturing process in order to prevent the potentially serious health problems that are difficult to control.

Ultra-fast liquid chromatography method coupled with ultraviolet detection to quantify dimethylsulfoxide, dimethylformamide and dimethylacetamide in short half-lives radiopharmaceuticals.

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.

Residual solvent analysis with hyper-fast gas chromatography-mass spectrometry and a liquid carbon dioxide cryofocusing in less than 90 s.

A new hyper-fast gas chromatography method with less than 90 s runtime including the column cool down was developed for the analysis of four gases and 16 residual solvents, combining a CO2 cryofocusing with a flow-field thermal gradient gas chromatograph (FF-TG-GC) and ToF-MS. The extremely low analysis time can be achieved by combining the new FF-TG-GC and a very short Rxi-624 Sil MS separation column with a small inner diameter and small film thickness (2.05 m × 0.1 mm × 1.0 µm). The column is inserted into a low thermal mass, resistively heated stainless steel capillary. This enables fast temperature programs with heating rates up to 3000 °C/min and a column cool down within a few seconds. In addition to temporal temperature gradients, the FF-TG-GC can generate a spatial temperature gradient that leads to an improved peak shape. Further, an external liquid CO2 cryo-trap was designed in order to reduce the injection bandwidths of analytes and to take full advantage of the resolving power of the separation column. No modifications are required to the FF-TG-GC for the use of the cryogenic trap, as the cooled spot is heated by the resistively heated stainless steel capillary during the temperature program. With cryofocusing, analyzed residual solvents are baseline separated. R2 values over 0.99 for calibration curves and low relative standard deviations (mainly < 3%) for repeatability tests were obtained.

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.

A novel simple and precise method for the determination of azide impurity in sartans using headspace gas chromatography with two dissimilar capillary columns and two flame ionization detectors (HS-GC-FID/FID).

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.

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

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

SPME fiber coated by arrayed ZNRs for sampling and concentration of polar residual solvents for further analysis using GC FID.

In this work, fused silica coated by arrayed ZNRs were successfully applied as a sorbent for analysis of polar residual solvents in pantoprazole feedstocks. ZnO nanoparticles were produced and deposited on a fused silica surface applying the dip coating technique and hydrothermal growth to synthesize the arrayed nanorods. The ZNRs array fiber coating was characterized by SEM, EDS, XRD, and TGA. The manufactured SPME fiber was coupled to a glass syringe of 10 µL and applied for the sampling of acetone, n-butanol, dichloromethane, ethyl acetate and methanol for further analysis using GC FID. Optimum operating conditions were determined for the incubation temperature (70 °C), incubation time (15 min), extraction time (120 s), and desorption time (0.6 min). Employing the optimum conditions, the proposed method resulted in a good linearity (> 0.997) and precision (< 7.1%) for the evaluated analytes. Recovery tests were also performed on three levels (below, equal to and above the ICH specification limit for residual solvents in pharmaceutical products). Recoveries ranging from 96% to 107% were obtained. Comparison between the reference method and developed method shows errors smaller than 4%.

UV-Vis spectroscopic quantification of residual acetone during the development of nanoparticulate drug delivery systems.

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.

Determination of residual solvents in isobutylboronic acid: Masking derivatization improves stability of GC column.

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.

A high thermally stable oligomer-based supramolecular solvent for universal headspace Gas Chromatography: Proof-of-principle determination of residual solvents in drugs.

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.

Simultaneous Determination of 9 Kinds of Organic Solvents Residues in Total Flavonoids Extracts from Abelmoschus manihot by Headspace GC / 中国药房

OBJECTIVE： To establish a method for simultaneous determination of 9 kinds of organic solvents residues in total flavonoids extracts from Abelmoschus manihot. METHODS： Headspace GC was adopted to determine the contents of 9 kinds of organic solvents residues in total flavonoids extracts from A. manihot， such as benzene， acrylonitrile， methyl methacrylate， toluene， 1，2-dichloroethane， xylene， chlorobenzene， styrene and divinylbenzene. The determination was performed on Agilent DB-WAX capillary column （30 m×0.25 mm， 0.25 μm） through temperature-programmed route. The inlet temperature and FID detector temperature were set at 250 ℃. The carrier gas was nitrogen with the flow rate of 1.2 mL/min. The split ratio was 10 ∶ 1. The containers of headspace injector were in equilibrium at 90 ℃ for 45 min and the sample size was 1 mL. RESULTS： The separation degree among the peaks of 9 components was greater than 1.5， and the blank solvent （10％ N-methyl pyrrolidone aqueous solution） had no interference. The linear ranges of them were 0.16-1.21， 0.80-6.03， 1.61-12.09，1.62-12.12， 0.16-1.21， 1.60-12.01， 0.81-6.11， 1.60-12.03， 0.80-6.03 μg/mL， respectively （r≥0.999 4）. The limits of quantitation were 0.162 08， 0.201 08， 0.080 6， 0.080 768， 0.161 92， 0.400 36， 0.040 712， 0.026 736， 0.013 395 μg/mL； the limits of detection were 0.040 52， 0.040 216， 0.026 87， 0.026 9，0.040 48， 0.080 072， 0.013 57， 0.008 912， 0.004 465 μg/mL， respectively. RSDs of precision （n＝5） and reproducibility （n＝6） tests were all lower than 5％. Average recoveries were 99.41％-111.27％（RSD＜9％， n＝9）. Above 9 residual solvents were not detected in 3 batches of total flavonoids extracts from A. manihot. CONCLUSIONS： Established method is simple， accurate and reliable， and can be applied for simultaneous detection of 9 kinds of organic solvents residues in total flavonoids extracts from A. manihot.

A Cryogenic Process for Antisolvent-Free High-Performance Perovskite Solar Cells.

A cryogenic process is introduced to control the crystallization of perovskite layers, eliminating the need for the use of environmentally harmful antisolvents. This process enables decoupling of the nucleation and the crystallization phases by inhibiting chemical reactions in as-cast precursor films rapidly cooled down by immersion in liquid nitrogen. The cooling is followed by blow-drying with nitrogen gas, which induces uniform precipitation of precursors due to the supersaturation of precursors in the residual solvents at very low temperature, while at the same time enhancing the evaporation of the residual solvents and preventing the ordered precursors/perovskite from redissolving into the residual solvents. Using the proposed techniques, the crystallization process can be initiated after the formation of a uniform precursor seed layer. The process is generally applicable to improve the performance of solar cells using perovskite films with different compositions, as demonstrated on three different types of mixed halide perovskites. A champion power conversion efficiency (PCE) of 21.4% with open-circuit voltage (VOC ) = 1.14 V, short-circuit current density ( JSC ) = 23.5 mA cm-2 , and fill factor (FF) = 0.80 is achieved using the proposed cryogenic process.

Natural deep eutectic solvents as eco-friendly and sustainable dilution medium for the determination of residual organic solvents in pharmaceuticals with static headspace-gas chromatography.

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 (R2 ≥ 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.