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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.
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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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Capillary electrophoresis(CE)is widely used for the impurity profiling of drugs that contain stereo-chemical centers in their structures,analysis of biomolecules,and characterization of bio-pharmaceuticals.Currently,CE is the method of choice for the analysis of foodstuffs and the determination of adulterants.This article discusses the general theory and instrumentation of CE as well as the classification of various CE techniques.It also presents an overview of research on the applications of different CE techniques in the impurity profiling of drugs in the past decade.The review briefly presents a comparison between CE and liquid chromatography methods and highlights the strengths of CE using drug compounds as examples.This review will help scientists,fellow researchers,and students to understand the applications of CE techniques in the impurity profiling of drugs.
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OBJECTIVE@#In this paper, the key points of quality control and safety evaluation of human assisted reproductive medium were summarized to provide reference for the establishment of relevant standards and quality control in the future.@*METHODS@#Through literature research, the key factors of quality control and risk control of human assisted reproductive medium were summarized, and the problems in clinical transformation were discussed.@*RESULTS@#It is very important for the development of human assisted reproduction technology to study the active ingredients and their harmful degradation products and drugs in the culture medium of assisted reproduction.@*CONCLUSIONS@#At present, the biggest challenge is to effectively control the quality of the culture medium for human assisted reproduction, establish corresponding inspection methods and quality standards for the key components, ensure the safety and effectiveness during the product shelf life, and thus improve the success rate of human assisted reproduction technology.
Subject(s)
Humans , Quality Control , Reproduction , Reproductive Techniques, AssistedABSTRACT
@#An analytical method was developed for the determination of five carbohydrate impurities in amino acid drug substances by high performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD). Sugar impurities in the amino acid sample were separated and enriched by cation exchange resin. A Lichropher NH2 column (4.6 mm × 250 mm, 5 μm) was used for chromatographic separation, and a gradient elution was performed using acetonitrile-water as mobile phase. The drift tube temperature was 40 oC, the gain value was 8, and nitrogen (350 kPa) was auxiliary gas. Method validation results showed that the limits of detection for fructose, glucose, sucrose, maltose and lactose were in the range of 20.8-75.0 mg/kg and that the limits of quantitation were in the range of 96.2-238.8 mg/kg. Good linear relationship (r ≥ 0.999) were in the linear range for the five sugars, and the recoveries ranged from 84.9%-107.8%. With easy operation, high sensitivity, good precision and reliable accuracy, the method can be used for analysis of residual sugar impurities in amino acid drug bulk drug.
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Metformin is considered as gold standard anti-diabetic drug and is the preferred initial pharmacologic agent for most of the patients with type 2 diabetes mellitus. Metformin is cheap, widely available and safe, backed by pharmaco-epidemiological evidence of more than 60 years regular use in clinical practice. Due to its durable efficacy, once initiated, metformin will be continued as long as it is tolerated and not contraindicated. It has got additional benefits on cholesterol, liver, cardio vascular system and cancer. Recent evidence and recall of metformin extended release formulation due to detection of excess amount of cancer-causing nitrosamine impurities has created concern among health care providers and patients. Adherence to regulatory guidelines and use of approved technologies in manufacturing and quality control may help in solving the issue.
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SUMMARY This study aimed to develop and validate a stability-indicating liquid chromatography method for the determination of tirofiban hydrochloride and two synthetic impurities (impurity A and impurity C). The method utilizes a RP-18 column (250 mm x 4.6 mm; 5 µm) with the PDA detector for quantitation. A mixture of triethylamine 0.1% (acidified to pH 5.5 with phosphoric acid) and acetonitrile was used as the mobile phase at a flow rate of 1 mL min-1 with gradient elution. The method presented satisfactory linearity, precision, accuracy and robustness, as well as low limits of detection and quantification, which demonstrate sensitivity in the determination of tirofiban and impurities A and C. It was selective for the determination of the drug and impurities analysed, without interference of the degradation products generated under forced conditions, demonstrating the stability-indicating capacity of the proposed method. Tirofiban showed to be practically stable to oxidative (30% H2O2 for 24 h) and thermal (75 °C for 24 h) conditions, but presented degradation to UVA light and acid hydrolysis, obeying the first order kinetics for both. In this way, it can be used as a stability-indicating method in the quality control of the raw material of tirofiban hydrochloride, as well as of the finished product. The obtained results demonstrate the importance of deepening the studies in this area, to guarantee the quality of commercialized pharmaceutical products.
RESUMO Este estudo teve como objetivo desenvolver e validar método indicativo da estabilidade por cromatografía líquida para determinação de cloridrato de tirofibana e duas impurezas de síntese (impureza A e impureza C). O método utilizou coluna de fase reversa RP-18 (250 mm x 4,6 mm; 5 µm) e detector PDA para quantificação. A fase móvel foi composta por uma mistura de trietilamina 0,1% (acidificada com ácido fosfórico para pH 5,5) e acetonitrila, à vazão de 1 mL/min, no modo gradiente. O método apresentou linearidade, precisão, exatidão, robustez, bem como baixos limites de detecção e quantificação, demonstrando sensibilidade na determinação da tirofibana e impurezas A e C. O método apresentou seletividade na determinação do fármaco e das impurezas, sem interferência dos produtos de degradação gerados na degradação forçada da tirofibana, demonstrando sua capacidade indicativa de estabilidade. O fármaco apresentou-se estável a oxidação (H2O2 30% por 24 h) e a degradação térmica (75 °C por 24 h), mas degradou frente à luz UVA e hidrolise ácida, obedecendo cinética de primeira ordem para ambas. Dessa forma, pode ser utilizado como um método indicativo de estabilidade no controle de qualidade da matéria -prima do cloridrato de tirofibana, bem como no produto acabado. Os resultados obtidos demonstram a importância de aprofundar os estudos na área, com intuito de garantir a qualidade dos produtos farmacêuticos comercializados.
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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.
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The liquid chromatography mass spectrometry (LC-MS) compatible, stability-indicating, specific, linear, accurate, sensitive with less run-time related impurities reversed phase high-performance liquid chromatography (RP-HPLC) related impurities method has been developed for olmesartan medoxomil (OLM), chlorthalidone (CHLR), and cilnidipine (CIL) drug combinations, and the method has been validated according to ICH and US-FDA guidelines. The chromatographic separation was performed by using Hypersil-BDS Thermo-Scientific, C18 (12.5 cm, 4.6 mm, 5 microns particle size) column. Mobile phase-A was prepared by mixing 3.85 gm ammonium acetate in HPLC water and adjust pH 5.0 by using diluted acetic acid. Acetonitrile was taken as mobile phase-B. Initial mobile phase ratio (55:45 v/v) was adjusted for mobile phase-A: mobile phase-B followed by gradient program. Other chromatographic conditions such as column temperature 25 degrees, flow rate 1.0 mL/minutes with the detection wavelength at 260 nm. The retention time for CHLR impurity A, olmesartan (OL), OLM impurity A, were found about 2.7, 3.3, and 7.2 minutes respectively, with a total run time of 18.0 minutes. The linearity calibration plot was performed and found linear relationship over the concentration range of 1.25 limit of quantitation (LoQ)–18.75 μg/mL, 3.6 LoQ–60.0 μg/mL, 3.6 LoQ– 60.0 μg/mL respectively for CHLR impurity A, OL and OLM impurity A respectively. The limit of detection (LoD) and LoQ were found 0.4 ppm (μg/mL) and 1.2 ppm (μg/mL), 1.2 ppm (μg/mL) and 3.5 ppm (μg/mL), 1.1 ppm (μg/mL) and 3.3 ppm (μg/mL) for CHLR impurity A, OL and OLM impurity A respectively. The accuracy was determined by recovery studies and was found between 90.0–110.0%. The developed analytical method has been validated for LoD-LoQ, specificity, linearity, accuracy, precision, robustness, and ruggedness, which were well within the acceptance limit as per ICH guidelines. All the degradation products generated by stress conditions were found to be well separated from one another (all drug components and impurities). The developed method with shorter runtime was successfully implemented for routine quality control and stability analysis to check the quality of OLM, CHLR, and CIL drug combinations.
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Resumo Amiodarone hydrochloride is one of the most important drugs used to treat arrhythmias. The USP monograph for amiodarone hydrochloride describes an HPLC method for the quantification of seven impurities, however, this method shows problems that result in unresolved peaks. Moreover, there is no monograph for tablets in this compendium. Thus, a stability indicating HPLC method was developed for the determination of amiodarone, its known impurities and degradation products in tablets. A detailed forced degradation study was performed submitting amiodarone API, tablets and placebo to different stress conditions: acid and alkaline hydrolysis, oxidation, metal ions, heat, humidity, and light. Amiodarone hydrochloride API was susceptible to degradation in all stress conditions. The tablets also showed degradation in all environments, except in acidic condition. The analytes separation and quantification were achieved on an Agilent Zorbax Eclipse XDB-C18 column (100 x 3.0 mm, 3.5 µm). The mobile phase was composed of 50 mM acetate buffer pH 5.5 (A) and a mixture of methanol-acetonitrile (3:4, v/v) (B) in gradient elution. The method was validated in the range of 350-650 µg/mL for assay and 10-24 µg/mL for impurities determination. Therefore, this method can be used both for stability studies and routine quality control analyses.
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@#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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@#For a long time, oral exfoliative cytology (OEC) has been implemented as an effective preliminary diagnostic tool for pathological lesions and various methods for fixation of the cytology specimens have been studied. The present study was undertaken to compare the efficacy between the wet and spray type of fixation methods for Papanicolaou (PAP) stained oral cytosmears. The study comprised of 45 healthy subjects in the age group of 20-25 yrs. For each subject, two smears were collected from the buccal mucosa and subjected to wet and spray fixation methods respectively. Both the smears were stained using a commercial Rapid Pap Kit. Smears were observed microscopically and evaluated for cytomorphological features involving uniformity of staining, cellular morphology, nuclear morphology, cellular staining, nuclear staining and presence of impurities. Comparisons were made between the two methods of fixation and statistically analysed using McNemar non-parametric test. Cells were evenly distributed in wet-fixed smears (n=38, 95%) compared to spray fixed smears (n=19, 47.5%). Wet-fixed smears showed lesser impurities (n=13, 32.5%) than spray fixed smears (n=27, 67.5%). However, other parameters such as cytological and nuclear morphology, staining of cytoplasm and nucleus were found to be not significant when compared between the two methods of fixation (p<0.05). The study shows that wet-fixed smears have better cellular distribution and relatively fewer impurities when compared to the spray fixed smears. The method of wet-fixed smears may be used as an alternative to spray fixed smears. A larger sample size may be required for further validation.
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OBJECTIVE：To de termine unknown impurities in Cefprozil suspension ，and to identify its structure. METHODS ： LC-HR-MS/MS method was used to detect and identify unknown impurities in Cefprozil suspension. The determination was performed on Thermo HyPURITY TM C18 with mobile phase consisted of acetonitrile- 0.013％ formic acid solution （gradient elution ） at the flow rate of 1.0 mL/min. The detection wavelength was set at 230 nm，and column temperature was 40 ℃. The sample size was 20 μL. ESI+ full scanning was carried out with electrospray ion source scanning range was mass-charge ratio （m/z）100-1 500 with spray voltage of 3.8 kV，metal capillary temperature of 320 ℃，sheath gas pressure of 60 Arb，auxiliary gas pressure of 10 Arb，spray temperature of 280 ℃. RESULTS ：Under this condition ，the detection limit of impurity K was 0.202 μg/mL. RSDs of precision and reproducibility tests were both lower than 4％. Three unknown impurities were found around impurity K ，which were isomers of each other. The retention time of ions were 17.83-19.31 min，and the secondary parent ion were all m/z 436.150 0[M+ H]+，which may be the product of ring opening and dehydration of cefpropene. CONCLUSIONS ：Three unknown impurities near impurity K in Cefprozil suspension were detected by this method.
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The present article reviews the challenges and hurdles in the development of an analytical method for aminoglycosides(AG). The article emphasizes on the attempts made to develop analytical methods based on HPLC and othersophisticated techniques, such as LC-MS, radioimmunoassay, microbial assay, enzyme linked immunosorbentassay (ELISA), extractive colorimetry, anion-exchange chromatography with pulsed amperometric detection, highperformance thin layer chromatography, densitometry, and microbial agar diffusion assay. The various media mostlyused for the in vitro as well as in vivo estimation of AG by HPLC and LC-MS are heptafluorobutyric acid, ammoniumacetate, ammonium formate and formic acid. Estimation of AG by radioimmunoassay and ELISA can be suitably doneby using TRIS-HCl and saline phosphate buffer. The buffer media used for ex vivo analysis mostly include MEM,TRIS and saline phosphate. The presence of AG in food from the animal sources, water bodies, and its prolongedexposure may result in serious health issues. The present article outlined the various sensitive, robust and preciseanalytical techniques for the estimation of the various aminoglycosides in many sources, and discussed the hurdlesfaced during the development of the analytical techniques.
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Objective: Separation and identification of the process impurities in the manufacture of temsirolimus drug viz., rapamycin, temsirolimus regioisomer (monoester) (TS monoester), and temsirolimus diester (TS diester). Methods: During the process development of temsirolimus (TS), three process impurities-rapamycin, temsirolimus regioisomer (monoester) and temsirolimus diester-were detected by high-performance liquid chromatography (HPLC). Impurities were isolated by medium pressure liquid Chromatography (MPLC) and characterized by ESI-MS/MS, 1H NMR, FT-IR spectral data. Results: These impurities are characterised with the help of ESI MS/MS, 1H NMR, and FT-IR data. The impurities are identified and characterised as the process impurities. One of them is the starting material i.e. rapamycin and the other two are formed during the manufacture of the drug. This method offers advantages over using photodiode-array UV detection (LC-PDA) for the determination of peak purity, viz. components with similar UV spectra can be distinguished. Conclusion: The structures of these impurities were characterized as rapamycin, TS Monoester, and TS Diester. Out of these process impurities, rapamycin has been previously identified while the other two are previously unreported.
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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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There are safety problems in traditional Chinese medicine(TCM) injections. Most of the adverse reactions of TCM injections are very similar to those of hypersensitivity reactions. The hypersensitivity reaction of macromolecular substances in TCM injections has also been confirmed by experiments. Polysorbate 80 (trade name of tween-80) is a solubilizing excipient commonly used in TCM injections. Polysorbate 80 contains macromolecular impurities and the material basic research is not clear enough, and its quality problems need to be solved urgently. Based on this, the authors concluded that the macromolecular impurities in polysorbate 80 were the important material basis for the safety of TCM injections contained polysorbate 80. In this paper, the research progress of application of polysorbate 80 as a solubilizing excipient in TCM injections was reviewed and analyzed, so as to provide ideas for improving the safety of TCM injections contained polysorbate 80 and to promote the healthy development of TCM injections.
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OBJECTIVE: To establish a high performance size exclusion chromatography(HPSEC) method for the separation and analysis of polymers in cefotaxime sodium and cefotaxime sodium for injection, and determine the structures of the impurities by LCMS. METHODS: HPSEC was performed by using Sepax SRT SEC-150(7.8 mm × 300 mm, 5 μm) column. The mobile phase was 0.1 mol•L-1 disodium hydrogen phosphate and 0.1 mol•L-1 phosphate buffer solution. The flow rate was 0.8 mL•min-1, the detection wavelength was set at 235 nm, the injection volume was 10 μL, and the column temperature was maintained at 35 ℃. The concentration of polymers was quantified by external standard method. The LC-MS/MSn system conditions were as following: the mobile phase was 20 mmol•L-1 amonium acetate, the flow rate was 0.8 mL•min-1, ESI source with positive and negative ion scan was utilized, the scanning range was m/z 200 - 1 600, and the post-column diversion ratio was 1:4. RESULTS: Eight impurity peaks were obtained in total; the resolutions were all greater than 1. 5. The linear range of cefotaxime was 1 - 100 μg•mL-1 (r = 1.000 0). The RSD repeatability was 1.2%(n = 6). The limit of detection was 0.2 μg and the limit of quantitation was 0.4 μg. Three polymers were identified by LC-MS. CONCLUSION: The HPSEC method can be used for the quantitative and qualitative analyses of individual polymer impurities. It is also sensitive for the control of polymers in cefotaxime.
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The bodies found in water are one of the most common types in forensic practice. The dis-covery site of the body is often not the drowning site. However, the determination of drowning site is vital for the identification of victim. Inorganic particles and planktons, such as granular impurities, diatoms and bacteria, are valuable markers for the diagnosis of drowning. By comparing the granular impurities and planktons in tissues and suspicious drowning mediums, the drowning site can be concluded based on their similarity of types and distribution, which has practical applied value. In this paper, the research progress on determination of drowning site is summarized to provide reference for the peers.