ABSTRACT
OBJECTIVE To establish a method for simultaneous determination of the contents of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material and its formulations. METHODS GC-MS/MS was adopted to determine 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material， Losartan potassium tablet， Losartan potassium capsule and Losartan potassium hydrochlorothiazide tablets， such as N-nitrosodimethylamine （NDMA）， N-nitrosodiethylamine （NDEA）， N-ethyl-N-nitroso-2-propanamine （NEiPA）， N-nitrosodiisopropylamine （NDiPA）， N-nitrosodipropylamine （NDPA） and N-nitrosodibutylamine （NDBA）. The separation was performed on SHIMADZU SH-L-17Sil MS capillary column by temperature- programmed GC， with injector temperature of 250 ℃ ， sample size of 1 μL， carrier gas of helium， and carrier flow rate of 1 mL/min. Electron ionization and multiple reaction monitoring （MRM） data acquisition mode were used， with an ion source temperature of 250 ℃ and solvent delay time of 3.1 min. RESULTS The separation among NDMA， NDEA， NEiPA， NDiPA， NDPA， NDBA and adjacent chromatographic peaks was good， and the separation rate was higher than 3.8； the linear ranges of them were 4.9-486.0， 4.9-488.5， 4.5-451.5， 6.8-683.5， 5.2-525.0 and 5.2-520.0 ng/mL（all r≥0.999 8）. The limits of quantitation were 4.86， 4.88， 4.52， 6.84， 5.25 and 5.20 ng/mL； the limits of detection were 0.97， 0.98， 0.90， 1.37， 1.05 and 1.04 ng/mL. RSDs of repeatability tests were 2.2%-5.6%（n＝6）， those of precision tests were 0.5%-1.4%（n＝6）， and those of stability tests were 1.5%-3.4%（n＝5）， respectively. Average recoveries of low-， medium- and high-concentration solution were 83.4%-103.0% （RSDs were 1.2%-6.3%， n＝3）， respectively. No one among the 6 kinds of N-nitrosamines genotoxic impurities was detected in both losartan potassium raw material and formulations. CONCLUSIONS The method is good in separation effect， highly accurate， sensitive and simple. It can be used in the determination of the 6 kinds of N-nitrosamines genotoxic impurities.
ABSTRACT
Covalent organic nanospheres(CONs)were explored as a fiber coating for solid-phase microextraction of genotoxic impurities(GTIs)from active ingredients(AIs).CONs were synthesized by an easy solution-phase procedure at 25℃.The obtained nanospheres exhibited a high specific surface area,good ther-mostability,high acid and alkali resistance,and favorable crystallinity and porosity.Two types of GTIs,alkyl halides(1-iodooctane,1-chlorobenzene,1-bromododecane,1,2-dichlorobenzene,1-bromooctane,1-chlorohexane,and 1,8-dibromooctane)and sulfonate esters(methyl p-toluenesulfonate and ethyl p-toluenesulfonate),were chosen as target molecules for assessing the performance of the coating.The prepared coating achieved high enhancement factors(5097-9799)for the selected GTIs.The strong affinity between CONs and GTIs was tentatively attributed to T-T and hydrophobicity interactions,large surface area of the CONs,and size-matching of the materials.Combined with gas chromatography-mass spectrometry(GC-MS),the established analytical method detected the GTIs in capecitabine and imatinib mesylate samples over a wide linear range(0.2-200 ng/g)with a low detection limit(0.04-2.0 ng/g),satisfactory recovery(80.03％-109.5％),and high repeatability(6.20％-14.8％)and reproducibility(6.20％-14.1％).Therefore,the CON-coated fibers are promising alternatives for the sensitive detection of GTIs in AI samples.
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Current work discloses the sensitive LC-MS/MS method development for the trace level determination of genotoxicimpurity 2-Methyl-6-nitro aniline in Telmisartan. 2-Methyl-6-nitro aniline was determined by LC-MS/MS methodin selected ion monitoring mode using LiChrospher RP-18 (100 × 4.6 mm) 5.0 µm column. Gradient technique wasapplied for the elution of analytes using acetonitrile (mobile phase A) and 0.01 M ammonium acetate buffer (mobilephase B) in different ratios. The gradient program (T/%B) was set as 0/5, 2.50/15, 5.00/30, 10.00/50, 15.00/95, and20.00/95. Developed method was validated as per International Conference on Harmonization guidelines. The limit ofdetection and limit of quantitation values found for 2-Methyl-6-nitro aniline were 0.05 and 0.1 µg/ml. The developedmethod serves as an upright tool in quality control for quantitation of 2-Methyl-6-nitro aniline impurity at trace levelsin Telmisartan.
ABSTRACT
@#An analytical liquid-liquid extraction-gas chromatography–mass spectrometry (LLE-GC-MS) method was established for the determination of genotoxic impurities including methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and isopropyl methanesulfonate (IMS) in methanesulfonic acid. An Agilent HP-1MS capillary column (30 m × 0.32 m, 1 μm) was used for separating the analytes by programmed heating with the inlet temperature of 220 °C. Mass spectrometry was operated in positive ion mode, and selective ion monitors were set at m/z 80 for MMS, m/z 79 for EMS, m/z 123 for IMS and m/z 56 for internal standard butyl methanesulfonate (BMS). Results showed that the baseline separation of MMS, EMS and IMS was achieved, and the blank extraction solution had no interference; good linearity was achieved in the range of 37-1 480 ng/mL for three alkyl methanesulfonates; The mean recoveries of MMS, EMS, IMS were 104.99%, 107.26%,108.85%, respectively, with RSD ≤ 4.54%. The established method has the characteristics of specific, sensitive, accurate, stable and good versatility, and has been used for the detection and control of alkyl methanesulfonate impurities in methanesulfonic acid from a variety of manufacturers.
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@#2,6-dimethylbenzenamine was determined as a genotoxic impurity in lidocaine hydrochloride injection, and 2-chloro-N-(2,6- dimethylphenyl) acetamide was determined as potential genotoxic impurity. An LC-MS/MS method was established to research the profiling of genotoxic impurities in active pharmaceutical ingredients (API), homemade preparation and reference preparation on column Agilent ZORBAX Eclipse Plus C18(4.6 mm250 mm，5 μm). The results show that in the homemade preparation the 2,6-dimethylbenzenamine and the 2-chloro-N-(2,6-dimethylphenyl) acetamide may be degraded under oxidation condition and alkaline condition in addition to the introduction from API preparation process. This study provides guidance for genotoxic risk assessment and prescription process optimization of lidocaine hydrochloride.
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@#The aim of this study was to establish a high performance liquid chromatography-mass spectrometry method for the determination of 5-(4′-(bromomethyl)-［1, 1′-biphenyl］-2-yl)- 1H-tetrazole(BBT1)and 5-(4′-(dibromomethyl)-［1, 1′-biphenyl］-2-yl)-1H-tetrazole(BBT2), which are two genotoxic impurities in olmesartan medoxomil. Chromatographic separation was based on an Agilent Zorbax Eclipse Plus C18(250 mm × 4. 6 mm, 5 μm)column using water(containing 0. 1% formic acid)- acetonitrile as mobile phase in gradient elution mode. Mass spectrometry was operated in positive ion mode. Selective ion monitors were set at m/z 315 for BBT1 and at m/z 395 for BBT2. Good linear correlations were observed in the range of 0. 009 4- 0. 561 0 μg/mL(r=0. 998)with the quantification limit at 9. 35 ng/mL and the detection limit at 3. 12 ng/mL for BBT1, and in the range of 0. 018 2- 0. 547 5 μg/mL(r=0. 999)with the quantification limit at 18. 25 ng/mL and the detection limit at 6. 08 ng/mL for BBT2. Furthermore, the average recoveries of the three spiked concentration level were 96. 5%(n=9, RSD=4. 8%)and 98. 0%(n=9, RSD=5. 1%)for BBT1 and BBT2, respectively. The proposed method is simple, specific and accurate, and quite suitable for the determination of BBT1 and BBT2 in olmesartan medoxomil.
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To develop a sensitive analytical method for the determination of the genotoxic impurity mono ethyl ester of ecabet (Imp-I),an HPLC-MS/MS technique was employed. Imp-I was synthesized according to the previ-ous literatures. MS/MS and NMR were used to confirm the structure of Imp-I. A Thermo C18column was used for chromatographic separations. The mobile phase consisting of A:5 mmol/L ammonium acetate (pH adjusted to 3. 0 with formic acid)and B:acetonitrile,with a gradient program:0 min 50%B,4 min 50%B,12 min 80%B,16 min 80%B,16. 1 min 50%B and 20 min 50%B. The column was maintained at 40 °C throughout the analysis.All measurements were carried out with the mass spectrometer operated under the negative ESI mode. The selective reaction monitor (SRM)transition was used. Good linearity was obtained for Imp-I over the concentration range of 4 150 ng/mL with the coefficient of determination (r)of 0. 999. And the LOQ was 4 ng/mL. A rapid and sensi-tive HPLC-ESI-MS/MS method was developed for quantitative analysis of Imp-I in ecabet sodium APIs. This method can be of used for quality assurance of ecabet sodium in bulk commercial drugs.
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Objective To establish a LC-MS analytical method for determination of N,N-dimethylaniline which is genotoxic impurity in quetiapine fumarate.Methods The method was achieved by an Waters ACQUITY UPLC CSHTM PhenylHexyl(2.1 mm× 100 mm,1.7 μm) utilizing a mobile phase of buffer-methanol(900∶ 100) (A)-acetonitrile(B) with gradient elution at the flow rate of 0.4 mL·min-1.The temperature of column was set at 50 ℃;The DIONEX Ultimate 3000 HPLC-AB Science 4000 QTrap Tripling Four bar LC-MS to detect N,N-Dimethylaniline (ESI source,in MRM positive mode).Results Standard curve was linear in the range of 0.4-8.0 ng(r =0.999 3);The limit of detection was 0.2 ng;The limit of quantification of N,N-dimethylaniline was 0.4 ng,respectively.The average recovery of N,N-dimethylaniline was 103.3 ％;RSD was 4.3％ (n =9),respectively.Conclusion The method is convenient and sensitive for the determination of N,N-dimethylaniline in quetiapine fumarate.
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Objective To establish a method to determine genotoxic impurities in saxagliptin bulk drug. Methods The gas chromatography(GC) was carried out with INNOWAX capillary column. The inlet temperature was 120°C. The injection volume was 5 µl and separation ratio was 1:10. The column temperature was programmed: the initial temperature was 70°C, maintained for 1 min, raised to 190°C with a rate of 16 °C/min, and then maintained for another 5 min. The detector was flame ionization detector(FID), with temperature of 250°C. The carrying gas was N2 with the flow rate of 1 ml/min. Methanol was used as solvent for saxagliptin. Results Methyl mesylate, ethyl mesylate and isopropyl mesylate could be separated completely with good linear relationship between 2.44- 36.6, 2.38-35.7 and 2.46-36.9 µg/ml, respectively. The average recovery was 96.94%, 95.96% and 105.47%(n=9), respectively. Conclusion This method is simple, reproducible and accurate enough for the determination of genotoxic impurities in saxagliptin bulk drug.
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@#Genotoxic or potentially genotoxic impurities seriously threaten people′s health, therefore, it is necessary to identify and quantify these impurities in pharmaceutical materials even at trace levels. Due to the special requirements on the sensitivity, selectivity, analyte stability and matrix effect, development of analytical methods is a challenge for the determination of genotoxic impurities. This paper reviews the recent advances in analytical methods for trace levels of commonly encountered genotoxic or potentially genotoxic impurities, including alkyl halides, alkyl sulfonates, hydrazines, epoxides and acyl halides, which would be helpful to control these impurities.
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Objective To establish a method to determine genotoxic impurities in saxagliptin bulk drug. Methods The gas chromatography(GC)was carried out with INNOWAX capillary column. The inlet temperature was 120℃. The injection volume was 5μl and separation ratio was 1∶10. The column temperature was programmed:the initial temperature was 70℃,maintained for 1 min, raised to 190℃with a rate of 16℃/min,and then maintained for another 5 min. The detector was flame ionization detector(FID),with temperature of 250℃. The carrying gas was N2 with the flow rate of 1 ml/min. Methanol was used as solvent for saxagliptin. Results Methyl mesylate,ethyl mesylate and isopropyl mesylate could be separated completely with good linear relationship between 2.44-36.6,2.38-35.7 and 2.46-36.9μg/ml,respectively. The average recovery was 96.94%,95.96%and 105.47%(n=9),respectively. Conclusion This method is simple,reproducible and accurate enough for the determination of genotoxic impurities in saxagliptin bulk drug.
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@#Pharmaceutical impurities affect the quality of drugs, and their research is essential in drug development, production and sale. Recently, there have been tremendous advancements in instrumental techniques that allow rapid development of technologies and analytical methods in the research of pharmaceutical impurities. This review discusses the origins and analytical methods of pharmaceutical impurities including genotoxic impurities, and mainly describes the analytical techniques and strategies to assess the genotoxicity of impurities, providing technical references for the study of pharmaceutical impurities.