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Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid

  • Shinkichi Nomura EMAIL logo , Yoshiharu Ito , Shigehiko Takegami and Tatsuya Kitade
Published/Copyright: August 11, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

Alkyl methanesulfonates are genotoxic impurities that should be limited to an intake of not more than 1.5 µg/day, as regulated by the International Council for Harmonization guideline M7. We herein report a trace analysis of methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), and isopropyl methanesulfonate (IPMS) in the delgocitinib drug substance using liquid–liquid extraction, with an ionic liquid as the sample-solving medium, and direct injection gas chromatography detected with a flame-ionization detector. The proposed method takes advantage of the fine solubility of ionic liquids toward the drug substance, the good extraction efficiency of alkyl methanesulfonates in liquid–liquid extraction using the Chem Elut cartridge with low-polar organic solvents, and the ability of alkyl methanesulfonates to concentrate in minimum amounts of organic solvent, resulting in excellent sensitivity and selectivity. Specifically, for the preparation of the sample solution, a mixture of 1-butyl-3-methylimidazolium chloride, water, and acetonitrile was used as the sample-solving media, extracted with diethyl ether, and the eluent was concentrated to 1 mL. The method showed good linearity, accuracy, and precision from 1 to 5 ppm, and the limits of detection of MMS, EMS, and IPMS were 0.1, 0.05, and 0.05 ppm, respectively.

Keywords: alkyl methanesulfonates; ionic liquid; extraction; GC-FID; validation

1 Introduction

Sulfonic acids are often used as salts of drug substances, and sulfonyl halides are frequently employed to introduce the sulfonyl leaving the group during the synthesis of drug substances [1,2]. Alcohols such as methanol, ethanol, or isopropanol are also commonly employed as solvents in the synthesis of drug substances. The reactions between the sulfonates and alcohols may result in the formation of alkyl sulfonates, which are considered as potential genotoxic impurities (PGIs) [3,4,5]. Regarding PGIs, in the pharmaceutical industry, the International Council for Harmonization (ICH) in their ICH M7 guideline has established a threshold of toxicological concern of 1.5 µg/day for durations of more than 10 years [6]. It is not reasonable to consider that the drug product is contaminated by these PGIs if the above chemicals were employed at the primary step of the drug synthesis. However, from a risk-assessment point of view, the development of an analytical method for measuring the residual alkyl sulfonates, and ensuring that their amount in the drug substances and products is less than the recommended maximum value, is still required, according to this guideline [7].

Several analytical approaches have reported on the trace analysis of alkyl sulfonates in drug substances. In the case of alkyl methanesulfonates, which have no UV absorbance, gas chromatography coupled with mass spectrometry (GC-MS) is the most commonly used [8,9]. Due to the high selectivity and sensitivity of MS, liquid chromatography coupled with MS (LC-MS) is also frequently utilized [10,11]. Another approach reported is the derivatization pretreatment prior to GC analysis [12] and solid phase microextraction (SPME) for sample preconcentration [13,14]. However, GC-MS, LC-MS, or SPME techniques are not globally available at pharmaceutical manufacturing sites, and also these techniques require advanced skills for their operation. In this context, there is a need to develop convenient and highly sensitive methods for the analysis of alkyl methanesulfonates using conventionally acquired materials at the general manufacturing sites [15].

In this article, we present a procedure for trace analysis of methyl methanesulfonate, ethyl methanesulfonate, and isopropyl methanesulfonate (MMS, EMS and IPMS, respectively) in a drug substance, using ionic liquid as the sample-solving medium for extraction, followed by identification with a conventional direct injection GC detected with a flame-ionization detector (GC-FID). This method was successfully applied to delgocitinib, a Janus kinase inhibitor, currently in New Drug Application in Japan for the topical treatment of inflammatory skin conditions [16,17,18,19,20]. The method was also validated with respect to specificity, accuracy, precision, linearity, range, limits of detection (LOD), limits of quantitation (LOQ), and system suitability, according to the ICH Q2 guidelines [21].

For trace analysis of MMS, EMS, and IPMS by the conventional analytical device, we anticipated that organic – aqueous bilayer extraction procedures would overcome the matrix effect of MMS, EMS, and IPMS due to the presence of drug substances, by effectively concentrating them in the organic phase, while keeping the drug substances themselves in the aqueous phase. In the organic – aqueous bilayer extraction procedures, we adopted the Chem Elut cartridge, which economically and effectively supported liquid–liquid extraction. Regarding the selection of the sample-solving medium, we previously reported the trace analysis of residual benzene in the delgocitinib drug substance using liquid–liquid extraction and conventional high-performance liquid chromatography (HPLC); and hence, we recommended potassium hydroxide and a hydrochloric acid solution as the sample-solving medium, as most marketed drug substances are soluble in them [22]. However, because MMS, EMS, and IPMS are hydrolyzed under the acidic or basic condition, we focused on ionic liquids that can solubilize complex polar molecules [23,24]. Ionic liquids are typically composed of organic cations and a variety of anions and are commonly defined as salts that melt below 100°C. They are often referred to as “designer solvents” due to the variability of cation and anion selection, which exhibit unique physicochemical properties such as high thermal stability, negligible vapor pressure, no flammability, and tunable water miscibility. Therefore, ionic liquids find application in various research fields, including electronics [25], biorefinery [26], metals [27], synthesis [28], separation [29], and so on; and studies using ionic liquids in analytical chemistry have continued to increase in the last two decades. It is essential for the approach we adopted in this article to solve the drug substance in high concentration and to design the polarity of sample solution, so ionic liquids are considered the most suitable sample-solving medium. We adopted a mixture of high-polar ionic liquids, water, and acetonitrile as the sample-solving medium, and diethyl ether as the organic solvent to meet the pretreatment of liquid–liquid extraction and increase the sensitivity and selectivity of MMS, EMS, and IPMS, thus allowing the application of conventional direct injection GC-FID.

2 Experimental

2.1 Materials and reagents

MMS (research purpose, >96%, expiry date: May 2020), EMS (research purpose, >97%, expiry date: May 2020), special-grade n-hexane (>96.0%, expiry date: May 2020), special-grade diethyl ether (>99.5%, expiry date: May 2020), and HPLC-grade acetonitrile (>99.8%, expiry date: June 2019) were obtained from FUJIFILM Wako Pure Chemical Industries. 1-Butyl-3-methylimidazolium chloride (([BMIM]Cl); research purpose, >98.0%, expiry date: January 2020), 1-butyl-3-methylimidazolium bromide (([BMIM]Br); research purpose, >97.0%, expiry date: January 2020), 1-hexyl-3-methylimidazolium chloride (([HMIM]Cl); research purpose, >97.0%, expiry date: January 2020), 1-methyl-3-octylimidazolium chloride (([OMIM]Cl); research purpose, >97.0%, expiry date: January 2020), 1-butyl-1-methylpyrrolidinium chloride (research purpose, >99.0%, expiry date: January 2020), special-grade sodium sulfate (>99.0%, expiry date: February 2022), and special-grade ethyl acetate (>99.5%, expiry date: May 2020) were obtained from Sigma Aldrich. 1-Butyl-4-methylpyridinium chloride (research purpose, >99.0%, expiry date: January 2020) and 1-ethyl-3-methylimidazolium chloride (([EMIM]Cl); research purpose, >98.0%, expiry date: January 2020) were obtained from the Tokyo Chemical Industry. IPMS (research purpose, >99%, expiry date: January 2020) and HPLC-grade water (expiry date: June 2019) were obtained from ACROS ORGANICS and Nacalai Tesque, respectively. The delgocitinib drug substance used was manufactured by Shiono Finesse, Ltd, Japan, for clinical trials (>99.0%, expiry date: March 2022). As methanesulfonyl chloride was employed during the previous manufacturing process of delgocitinib, the drug substance for clinical use potentially contained methanesulfonates as impurities.

2.2 Instruments

GC analysis was conducted using an Agilent 6890N GC/FID series equipped with an autoinjector of Agilent 7683 series. A DB-624 UI column (0.25 mm × 30 m, 1.4 µm; J&W Scientific) and glass insert (Part number 5183-4711; Agilent Technologies) were used for analysis. Supported by the liquid–liquid extraction cartridge, Chem Elut 3 mL cartridge was obtained from Agilent Technologies. A Mettler Toledo AT261 Semi-Micro Balance was also used for sample preparation.

2.3 Operating conditions for GC

For direct injection GC analysis, the FID and split-less injection were adopted, with an injection volume of 5 µL, injection port temperature of 220°C; detector temperature of 300°C; temperature program set at 50°C for 2 min, raised to 250°C at a rate of 15°C per minute and then maintained at 250°C for 10 min with flow rate of 5.0 mL/min (constant flow); and helium was used as the carrier gas.

2.4 Preparation of sample and standard solutions

For sample preparation, 0.5 g of delgocitinib drug substance was accurately weighed and to this about 50 mg of [BMIM]Cl, 2 mL of water, and 1 mL of acetonitrile were added. After dissolving the analyte, the entire solution was applied to the Chem Elut 3 mL cartridge, followed by a waiting period of 5 min. Next, 12 mL of diethyl ether is eluted to the cartridge and 0.2 g of sodium sulfate was added to the elute (diethyl ether) and vigorously stirred. After removing the precipitate, the elute is evaporated with nitrogen gas to achieve a volume of exactly 1 mL, and this solution is used in the GC analysis (Figure 1). In a separate flask, about 0.1 g of MMS, EMS, and IPMS are accurately weighed, and acetonitrile is added to make up the volume to exactly 10 mL. Next, 0.1 mL of this solution was pipetted and acetonitrile was added to make up the volume to exactly 10 mL. Finally, 0.5 mL of this solution was pipetted, and diethyl ether was added to make up the volume to exactly 20 mL and this was used as the standard solution.

Figure 1 Preparation scheme of the sample solution.
Figure 1

Preparation scheme of the sample solution.

2.5 Preparation of solutions for method validation

A mixture of MMS, EMS, and IPMS in diethyl ether was prepared at a concentration of 2.5 µg/mL (equivalent to 5 ppm in the delgocitinib drug substance) to measure the specificity. The samples of MMS, EMS, and IPMS in diethyl ether for linearity were also prepared at 0.25, 0.5, 1, 2.5 and 5 µg/mL (equivalent to 0.5, 1, 2, 5 and 10 ppm in the delgocitinib drug substance), respectively. For accuracy and precision, the sample solutions spiked with MMS, EMS, and IPMS at 0.5, 1 and 2.5 µg/mL were additionally prepared in triplicates. For the LOQ and LOD, sample solutions at concentrations of 0.15 and 0.05 µg/mL of MMS (equivalent to 0.3 and 0.1 ppm in the delgocitinib drug substance), 0.05 and 0.025 µg/mL of EMS (equivalent to 0.1 and 0.05 ppm in the delgocitinib drug substance), and 0.05 and 0.025 µg/mL of IPMS (equivalent to 0.1 and 0.05 ppm in the delgocitinib drug substance) were also prepared.

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 Optimization of solvent extraction and GC method

The selection of an ionic liquid that can completely dissolve the delgocitinib drug substance and show high polarity are keys to analyzing MMS, EMS, and IPMS with the method proposed here. As ionic liquids, we tested [EMIM]Cl, [BMIM]Cl, [BMIM]Br, [HMIM]Cl, [OMIM]Cl, 1-butyl-1-methylpyrrolidinium chloride, and 1-butyl-4-methylpyridinium chloride. Due to high electronegativity, the anion candidates adopted in the ionic liquids were chloride and bromide. In the various marketed ionic liquids, candidates were focused on the cation’s chemical structure and the length of carbon chain; imidazolium salt (1-ethyl-3-methylimidazolium, 1-butyl-3-methylimidazolium, 1-hexyl-3-methylimidazolium, and 1-methyl-3-octylimidazolium), pyridinium salt (1-butyl-4-methylpyridinium), and pyrrolidinium salt (1-butyl-1-methylpyrrolidinium). However, because these ionic liquids are solid at room temperature, small amounts of water and acetonitrile were added to improve the experimental operation. As the organic layer for MMS, EMS, and IPMS extraction, we tested n-hexane, ethyl acetate, and diethyl ether. Although the use of low-polar ionic liquid was considered, the headspace of the GC is not applied to the measurement of MMS, EMS, and IPMS due to the high boiling point, and ionic liquid is not suitable for direct injection GC due to its negligible vapor pressure. Therefore, in this article, we adopted organic solvent for liquid–liquid extraction. In order to find the best combination of ionic liquid and organic solvent, the recovery of spiked MMS, EMS, and IPMS at 0.5 µg/mL (which corresponds to 1 ppm in the delgocitinib drug substance) was compared using the abovementioned media and solvent candidates, according to the preparation method for each sample solution and GC conditions.

In order to improve the efficiency of extraction, the Chem Elut cartridge, which economically and effectively supported liquid–liquid extraction, was adopted, and smaller amounts of organic solvent were used to achieve higher sensitivity to MMS, EMS, and IPMS; therefore, the amount of sample-solving medium and the cartridge size of Chem Elut adopted were small, and elution is concentrated to 1 mL and injected to GC-FID. The recovery rates of MMS, EMS, and IPMS in sample solutions were considered successful between 70.0 and 130.0% and were calculated by using spiked MMS, EMS, and IPMS at 0.5 µg/mL in the sample solution. The results of screening for ionic liquids and organic solvents are summarized in Tables 1 and 2. The typical chromatogram of spiked MMS, EMS, and IPMS in the sample solution is shown in Figure 2.

Table 1

Summary for the screening ionic liquids and organic solvents focused on the carbon chain length of ionic liquids

Recovery (%) of spiked MMS, EMS, and IPMS at 0.5 µg/mL into the sample solution (equivalent to 1 ppm in the delgocitinib drug substance)
Ionic liquidsOrganic solventsa
Diethyl etherEthyl acetate
1-Ethyl-3-methylimidazolium chloride ([EMIM]Cl)MMS: 96.5%MMS: 14.3%
EMS: 127.0% EMS: 37.6%
IPMS: 93.7%IPMS: 22.7%
1-Butyl-3-methylimidazolium chloride ([BMIM]Cl)MMS: 115.6%MMS: not detected
EMS: 103.9%EMS: 53.8%
IPMS: 104.6%IPMS: 78.2%
1-Hexyl-3-methylimidazolium chloride ([HMIM]Cl)MMS: not detectedMMS: not detected
EMS: 45.7%EMS: not detected
IPMS: 44.0%IPMS: not detected
1-Methyl-3-octylimidazolium chloride ([OMIM]Cl)MMS: not detectedMMS: not detected
EMS: not detectedEMS: not detected
IPMS: not detectedIPMS: not detected
  1. a

    n-Hexane was not listed in the table because MMS, EMS, and IPMS were not recovered in every condition.

Table 2

Summary for the screening ionic liquids and organic solvents focused on the cation’s structure and the anion’s electronegativity

Recovery (%) of spiked MMS, EMS, and IPMS at 0.5 µg/mL into the sample solution (equivalent to 1 ppm in the delgocitinib drug substance)
Ionic liquidsOrganic solventsa
Diethyl etherEthyl acetate
1-Butyl-3-methylimidazolium chloride ([BMIM]Cl)MMS: 115.6%MMS: not detected
EMS: 103.9%EMS: 53.8%
IPMS: 104.6%IPMS: 78.2%
1-Butyl-3-methylimidazolium bromide ([BMIM]Br)MMS: 33.7%MMS: not detected
EMS: 30.3%EMS: 49.8%
IPMS: 28.8%IPMS: 45.7%
1-Butyl-4-methylpyridinium chlorideMMS: 24.8%MMS: not detected
EMS: 32.8%EMS: 28.1%
IPMS: 24.1%IPMS: 36.7%
1-Butyl-1-methylpyrrolidinium chlorideMMS: 85.0%MMS: not detected
EMS: 82.1%EMS: 44.4%
IPMS: 81.2%IPMS: 50.8%
  1. a

    n-Hexane was not listed in the table because MMS, EMS, and IPMS were not recovered in every condition.

Figure 2 GC chromatograms for MMS, EMS, and IPMS spiked sample solutions and standard solution equivalent to 1 ppm in the delgocitinib drug substance.
Figure 2

GC chromatograms for MMS, EMS, and IPMS spiked sample solutions and standard solution equivalent to 1 ppm in the delgocitinib drug substance.

With respect to the selection of organic solvents, the results showed that diethyl ether was a better organic solvent in terms of the recovery rate, compared to the other solvents. In the case of ethyl acetate, it was speculated to result in lower recovery rates due to the matrix effect resulting in the precipitation of delgocitinib drug substance during elution concentration. Also, it was indicated that n-hexane being a non-polar solvent was not suitable for the extraction of alkyl methanesulfonate.

With respect to the selection of ionic liquids, the results showed that [BMIM]Cl, [EMIM]Cl, and 1-butyl-1-methylpyrrolidinium chloride were better ionic liquids in terms of recovery rate, compared to the other ionic liquids. In the selection of an anion, chloride showed a better recovery rate than bromide; and in terms of cation selection, the cations with shorter carbon chains demonstrated better recovery rates. Chloride has higher electronegativity compared to bromide, and shorter carbon chains have lower affinity for organic solvents. Therefore, it was speculated that the extracting efficiency are correlated with difference in the polarity between ionic liquids and selected organic solvent. Although some ionic liquids showed good recovery rates, considering the commercial availability and the price, [BMIM]Cl was adopted as the ionic liquid of choice.

Following the design of the alkyl methanesulfonate extraction method, a simple conventional GC-FID condition is found in Section 2. The split-less injection and ultra-inert column were adopted in order to raise sensitivity. These conditions were successful in detecting 0.10 ppm of MMS, and 0.05 ppm of EMS, and 0.05 ppm of IPMS in the delgocitinib drug substance at a sample intake of 0.5 g with adequate sensitivity.

3.2 Method validation

3.2.1 Specificity

The GC conditions used in this study resulted in a clear separation of MMS, EMS, and IPMS peaks from those of the blank, respectively. The GC chromatograms of a blank (diethyl ether) solution and a standard solution containing 0.5 µg/mL of MMS, EMS, and IPMS (which corresponds to 1 ppm in the delgocitinib drug substance) are shown in Figure 2. No peaks were observed at the retention time of MMS, EMS, and IPMS in the blank solution chromatogram, whereas the chromatogram of the mixed solution showed clear peak separation for MMS, EMS, and IPMS.

3.2.2 Accuracy

The accuracy of the method proposed in this article was determined by the recovery rate of MMS, EMS, and IPMS using sample solutions spiked with MMS, EMS, and IPMS at concentrations of 0.5, 1, and 2.5 µg/mL (equivalent to 1, 2, and 5 ppm in the delgocitinib drug substance). Recovery rates were evaluated in triplicate and obtained by comparing the calculated values with the theoretical value. The average recovery for MMS, EMS, and IPMS at concentrations ranging from 1 to 5 ppm was between 78.9 and 116.2% for MMS, 74.7 and 109.9% for EMS and 82.7 and 123.8% for IPMS (acceptance criteria: 70.0–130.0%; Table 3).

Table 3

Recovery of MMS, EMS, and IPMS at 0.5, 1, and 2.5 µg/mL (equivalent to 1, 2, and 5 ppm in the delgocitinib drug substance) obtained in triplicate

ReplicateRecovery (%)
0.5 µg/mL1 µg/mL2.5 µg/mL
MMSEMSIPMSMMSEMSIPMSMMSEMSIPMS
199.675.0112.198.690.4111.099.089.582.7
282.874.790.286.282.8114.3116.2100.1116.5
378.978.8123.895.6109.9120.4103.691.2100.7
Average (%)87.176.2108.793.594.4115.2106.393.6100.0
RSD (%)12.63.015.76.914.84.18.46.116.9
95% lower limit59.870.566.377.459.7103.484.279.558.0
95% upper limit114.481.9151.1109.6129.1127.0128.4107.7142.0
Acceptance criteriaRecovery (%): 70.0–130.0
RSD (%): Not more than 20

3.2.3 Precision

The precision of the method proposed in this article was determined by the relative standard deviation (RSD) of the recovery test described in Section 3.2.2, in which MMS, EMS, and IPMS were evaluated in triplicate at concentrations of 0.5, 1, and 2.5 µg/mL (equivalent to 1, 2, and 5 ppm in the delgocitinib drug substance). As shown in Table 3, the RSD of MMS, EMS, and IPMS recovery was found to be between 6.9 and 12.6% for MMS, 3.0 and 14.8% for EMS, and 4.1 and 16.9% for IPMS (acceptance criteria: not more than 20%).

3.2.4 LOD and LOQ

The LOD and LOQ were assessed using a signal to noise ratio. Solutions containing 0.05 and 0.15 µg/mL of MMS (which correspond to 0.1 and 0.3 ppm in the delgocitinib drug substance, respectively), 0.025 and 0.05 µg/mL of EMS and IPMS (which correspond to 0.05 and 0.1 ppm in the delgocitinib drug substance, respectively) were assessed. The signal to noise ratio of the 0.05 and 0.15 µg/mL concentrations for MMS was 4.7 and 13.3, the 0.025 and 0.05 µg/mL concentrations for EMS were 4.7 and 10.6, and the 0.025 and 0.05 µg/mL concentrations for IPMS were 7.5 and 16.4, respectively. The data indicated that the LOD (acceptance criteria: signal to noise ratio > 2) for MMS, EMS, and IPMS was approximately 0.05 µg/mL (0.1 ppm), 0.025 µg/mL (0.05 ppm), and 0.025 µg/mL (0.05 ppm), respectively; and the LOQ (acceptance criteria: signal to noise ratio > 10) for MMS, EMS, and IPMS was approximately 0.15 µg/mL (0.3 ppm), 0.05 µg/mL (0.1 ppm), and 0.05 µg/mL (0.1 ppm), respectively.

3.2.5 Linearity and range

Linearity testing (data summarized in Table 4) was conducted over a range from 0.25 to 5 µg/mL (equivalent of 0.5–10 ppm in the delgocitinib drug substance) of MMS, EMS, and IPMS. Figure 3 shows the linear plot of the peak response versus the concentration of MMS, EMS, and IPMS. For MMS, EMS, and IPMS, the coefficient of correlation (r) was 1.00 (acceptance criteria: no less than 0.99), the Y-intercept was close to zero, and no biased trends were observed in the residual plots. Analyzing the results for accuracy, precision, and linearity, the method proposed in this article shows sensitiveness to MMS, EMS, and IPMS concentrations ranging between 0.5 and 2.5 µg/mL (equivalent of 1–5 ppm in the delgocitinib drug substance).

Table 4

Linear regression data of MMS, EMS, and IPMS from 0.25 to 5 µg/mL (corresponding to 0.5–10 ppm in the delgocitinib drug substance)

Concentration (µg/mL)Peak responserSlopeY-intercept95% lower limit95% upper limit
MMS0.250.9209510.9993.58−0.00965−0.6470.628
0.51.86033
13.73529
2.58.48502
518.09925
EMS0.252.099340.9998.550.0750−1.511.66
0.54.42802
19.33186
2.520.41108
543.22175
IPMS0.253.039980.99912.30.177−2.322.68
0.56.38903
113.6064
2.529.20741
562.07457
Figure 3 Linear plot for MMS, EMS, and IPMS from 0.25 to 5 µg/mL (corresponding to 0.5–10 ppm in the delgocitinib drug substance).
Figure 3

Linear plot for MMS, EMS, and IPMS from 0.25 to 5 µg/mL (corresponding to 0.5–10 ppm in the delgocitinib drug substance).

3.2.6 System suitability

When the procedure was carried out using the standard solution under the GC operating conditions, the symmetry factor of the MMS, EMS, and IPMS peaks was 1.5, 1.2, and 1.1, respectively, and peak resolution among the MMS, EMS, and IPMS peaks was 20.2 (MMS-EMS) and 7.5 (EMS-IPMS). After repeating the test six times, the RSD of the peak areas of MMS, EMS, and IPMS was 1.3%, 1.2%, and 1.3%, respectively.

4 Conclusions

A trace analysis method for MMS, EMS, and IPMS in pharmaceutical drug substances, using GC-FID and liquid–liquid extraction with ionic liquid, was successfully developed. The method was proven to be applicable to the trace analysis of MMS, EMS, and IPMS in the delgocitinib drug substance, in line with the requirements of ICH M7 guideline, and reported that in every lot of delgocitinib manufactured for clinical use so far, MMS, EMS and IPMS were not detected.

The method presented here showed the almost equivalent relative sensitivity of MMS, EMS, and IPMS compared to the other analytical method presented in Section 1 [8,9,10,11,12,13,14] and possess the uniqueness to be able to conduct the quantitative analysis of them using the conventional direct injection GC-FID. This method is expected to be particularly useful for the analysis of MMS, EMS, and IPMS in drug substances, since many drug substances are soluble in ionic liquids. Although [BMIM]Cl and diethyl ether were selected as the ionic liquid and the organic solvent, respectively, we also demonstrated that other combinations of ionic liquids and organic solvents could be used for this method, thus making this approach applicable to other analytes. Since the pharmaceutical industry is currently required by ICH M7 guideline to evaluate various PGIs, we speculate that this approach could also be applicable for the trace analysis of other PGIs.

Abbreviations

ICH

International Council for Harmonization

MMS

methyl methanesulfonate

EMS

ethyl methanesulfonate

IPMS

isopropyl methanesulfonate

PGIs

potential genotoxic impurities

[EMIM]Cl

1-ethyl-3-methylimidazolium chloride

[BMIM]Cl

1-butyl-3-methylimidazolium chloride

[BMIM]Br

1-butyl-3-methylimidazolium bromide

[HMIM]Cl

1-hexyl-3-methylimidazolium chloride

[OMIM]Cl

1-methyl-3-octylimidazolium chloride

Acknowledgments

Our greatest appreciation to Hideto Uehara and Shoji Onogi who provided considerable feedback and valuable comments. We would also like to thank our colleagues who encouraged us with invaluable comments.

  1. Conflict of interest: The authors declare that there is no conflict of interest with respect to this article.

References

[1] Abu TMS. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59:603–16. 10.1016/j.addr.2007.05.010.Search in Google Scholar PubMed

[2] Norman OVS. The reactions of alifatic acid chlorides. Chem Rev. 1953;52(2):237–416. 10.1021/cr60162a001.Search in Google Scholar

[3] David PE, Lipczynski AM, Teasdale A. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). J Pharm Biomed Anal. 2008;48(3):497–507. 10.1016/j.jpba.2008.06.009.Search in Google Scholar PubMed

[4] Susanne G, Wilfried F, Thomas A, Hans-Joerg M, Willi S, Lutz M. Structure-activity considerations and in vivo approaches to assess the genotoxicity of 19 methane-, benzene- and toluenesulfonic acid esters. Mutat Res. 2005;581:23–34. 10.1016/j.mrgentox.2004.10.004.Search in Google Scholar PubMed

[5] Lutz M, Elmar G, Thierry L, Thomas P. Ethyl methanesulfonate toxicity in Viracept – A comprehensive human risk assessment based on threshold data for genotoxicity. Toxicol Lett. 2009;190:317–29. 10.1016/j.toxlet.2009.04.003.Search in Google Scholar PubMed

[6] International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic M7 (R1) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. 2017.Search in Google Scholar

[7] Alexander A, James SH, Andreas C, Hans-Peter S, Sharon R, Angela W, et al. Do carboxylic/sulfonic acid halides really present a mutagenic and carcinogenic risk as impurities in final drug products? Org Process Res Dev. 2015;19:1495–506. 10.1021/acs.oprd.5b00106.Search in Google Scholar

[8] Karine J, Delaney, ED, Teasdale A, Steve E, Karen TW, Lipczynski A, et al. Development and validation of an automated static headspace gas chromatography-mass spectrometry (SHS-GC-MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid. J Pharm Biomed Anal. 2008;48:1339–44. 10.1016/j.jpba.2008.09.028.Search in Google Scholar PubMed

[9] Ramakrishna K, Raman NVVSS, Narayana KMV, Prasad AVSS, Subhaschander RK. Development and validation of GC-MS method for the determination of methyl methanesulfonate and ethyl methanesulfonate in imatinib mesylate. J Pharm Biomed Anal. 2007;46:780–3. 10.1016/j.jpba.2007.11.013.Search in Google Scholar PubMed

[10] Jianguo A, Mingjiang S, Lin B, Ted C, David QL, Alireza K. A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances. J Pharm Biomed Anal. 2008;48:1006–10. 10.1016/j.jpba.2008.06.019.Search in Google Scholar PubMed

[11] Tian G, Yuanyuan S, Li Z, Feng F, Feng Z, Wenyuan L. Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry: comparison of different ionization modes. J Chromatogr A. 2014;1355:73–9. 10.1016/j.chroma.2014.05.079.Search in Google Scholar PubMed

[12] Roberto A, Robert WR, Karen TW, Andrew ML, Roman S, Pat S. A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry. J Pharm Biomed Anal. 2007;45:472–9. 10.1016/j.jpba.2007.07.017.Search in Google Scholar PubMed

[13] Iveliss C, Stephen MR. Determination of methyl and ethyl esters of methanesulfonic, benzenesulfonic and p-toluenesulfonic acids in active pharmaceutical ingredients by solid-phase microextraction (SPME) coupled to GC/SIM-MS. J Pharm Biomed Anal. 2005;39:477–85. 10.1016/j.jpba.2005.04.0373.Search in Google Scholar

[14] Mingxian L, Congcong G, Lan L, Jie Z, Jing L, Feng Z. Determination of trace methanesulfonates in drug matrix using derivatization and headspace single drop microextraction followed byhigh-performance liquid chromatography with ultraviolet detection. J Chromatogr A. 2019;1591:131–7. 10.1016/j.chroma.2019.01.038.Search in Google Scholar PubMed

[15] Tien DH, Peter MY, Nik PC, Jin W, Jared LA, Qiqing Z. Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection. J Chromatogr A. 2014;1361:217–28. 10.1016/j.chroma.2014.07.099.Search in Google Scholar PubMed

[16] Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, et al. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015;64(1):41–51. 10.1007/s00011-014-0782-9.Search in Google Scholar PubMed PubMed Central

[17] Tanimoto A, Shinozaki Y, Yamamoto Y, Katsuda Y, Taniai-Riya E, Toyoda K, et al. A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. Exp Dermatol. 2018;27(1):22–9. 10.1111/exd.13370.Search in Google Scholar PubMed

[18] Amano W, Nakajima S, Kunugi H, Numata Y, Kitoh A, Egawa G, et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol. 2015;136(3):667–77. 10.1016/j.jaci.2015.03.051.Search in Google Scholar PubMed

[19] Amano W, Nakajima S, Yamamoto Y, Tanimoto A, Matsushita M, Miyachi Y, et al. JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation. J Dermatol Sci. 2016;84(3):258–65. 10.1016/j.jdermsci.2016.09.007.Search in Google Scholar PubMed

[20] Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2017;178(2):424–32. org/10.1111/bjd.16014.Search in Google Scholar

[21] International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q2A and Q2B (R6). Guideline on validation of analytical procedures. 2005.Search in Google Scholar

[22] Nomura S, Ito Y, Takegami S, Kitade T. Development and validation of an assay method for benzene in the delgocitinib drug substance using conventional HPLC. Chem Pap. 2019;73:673–81. 10.1007/s11696-018-0608-2.Search in Google Scholar

[23] Jonathan GH, Heather DW, Richard PS, Ann EV, Robin DR. Room temperature ionic liquids as novel media for ‘clean’ liquid–liquid extraction. Chem Commun. 1998;16:1765–66. 10.1039/A803999B.Search in Google Scholar

[24] Neil W. Solubilization of polymers by ionic liquids. J Mater Chem. 2006;16:4281–93. 10.1039/B610143G.Search in Google Scholar

[25] Changsheng D, Toshiyuki N, Rika H. A high-capacity TiO2/C negative electrode for sodium secondary batteries with an ionic liquid electrolyte. J Mater Chem A. 2015;3:20767–71. 10.1039/C5TA04256A.Search in Google Scholar

[26] Anthe G, Agnieszka B, Kim T, Shahrul MS, Nizan SZ, Daniel KM, et al. Design of low-cost ionic liquids for lignocellulosic biomass pretreatment. Green Chem. 2015;17:1728–34. 10.1039/C4GC01208A.Search in Google Scholar

[27] Daphne D, Arne, VB, Wim D, Koen B. Metal extraction with a short-chain imidazolium nitrate ionic liquid. Chem Commun. 2017;53:5271–4. 10.1039/C7CC01685A.Search in Google Scholar PubMed

[28] Peter W, Thomas W. Ionic Liquids in Synthesis, 2nd edn. Weinheim: Wiley-VCH; 2008. 10.1002/9783527621194.Search in Google Scholar

[29] Paul S, Jesse K, Daniel AF, Carl K, Daniel LD, Richard N. Gas separations using non-hexafluorophosphate [PF6]-anion supported ionic liquid membranes. J Membr Sci. 2004;238(1–2):57–63. 10.1016/j.memsci.2004.02.033.Search in Google Scholar

Received: 2020-04-26
Revised: 2020-06-10
Accepted: 2020-06-18
Published Online: 2020-08-11

© 2020 Shinkichi Nomura et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
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  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
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https://doi.org/10.1515/chem-2020-0093
Keywords for this article
alkyl methanesulfonates; ionic liquid; extraction; GC-FID; validation
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
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  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
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  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
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  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
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  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
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  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
  71. Citrullus colocynthis (L.) Schrad: Chemical characterization, scavenging and cytotoxic activities
  72. Development and validation of a high performance liquid chromatography/diode array detection method for estrogen determination: Application to residual analysis in meat products
  73. PCSK9 concentrations in different stages of subclinical atherosclerosis and their relationship with inflammation
  74. Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid
  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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