Latest ArticlesTo establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of atorvastatin, two activity-related hydroxy statin metabolites and three toxicity-related statin lactones in human plasma, and its application to the study of pharmacokinetics in healthy subjects and the analysis of concentrations in patients.
After acidification, plasma samples were treated by protein precipitation. The LC separation was performed on a Zorbarx SB-C18(50 mm×2.1 mm, 5 μm) column. Methanol-acetonitrile (1∶1) water-methanol-acetonitrile (9∶0.5∶0.5) containing 0.05% formic acid were used as the mobile phases for gradient elution, and the flow rate was 0.35 mL·min-1. The electric spray ionization source, positive ion mode and multi-reaction monitoring scanning were adopted for MS detection. The m/z of each targeted analyte was 559.3→440.2 for atorvastatin, 575.1→440.3 for 2-hydroxy atorvastatin acid (2-HAT) and 4-hydroxy atorvastatin acid (4-HAT), 540.9→448.2 for atorvastatin lactone (ATL), 557.2→448.2 for 2-hydroxy atorvastatin lactone (2-HATL) and 4-hydroxy atorvastatin lactone (4-HATL), and 422.2→290.0 for the internal standard of pitavastatin. After a full method validation, the developed LC-MS/MS method was used to determine the plasma samples of healthy subjects and patients after taking atorvastatin calcium tablets, and the pharmacokinetic characteristics of atorvastatin and five metabolites were analyzed.
The calibration curves of atorvastatin and its metabolites presented a good linear relationship in the range of 0.1-25 nmol·L-1. The RSD of intra-and inter-day precision and the RE of accuracy were all less than 15%, and the stability was well tolerated under different conditions. In healthy subjects after oral administration of 20 mg atorvastatin calcium tablets, the respective mean values of Cmax for atorvastatin, 2-HAT, 4-HAT, ATL, 2-HATL and 4-HATL were 11.48, 4.71, 0.28, 1.71, 2.52 and 2.31 nmol·L-1, AUC0-∞ were 87.31, 58.79, 8.60, 28.75, 45.76, 31.49 nmol·h·L-1, t1/2 were 7.96, 7.93, 19.58, 8.76, 8.98 and 21.37 h. After 12 h of administration, the average blood concentrations of atorvastatin, 2-HAT, 4-HAT, ATL, 2-HATL and 4-HATL in the patient were (4.16±1.31) nmol·L-1, (2.65±1.33) nmol·L-1, (1.15±1.16) nmol·L-1, (2.96±1.83) nmol·L-1, (4.27±2.00) nmol·L-1 and (3.70±1.74) nmol·L-1.
The method for the simultaneous quantitative determination of atorvastatin and five metabolites in human plasma established in this study is accurate, rapid, sensitive and stable, and can be used for clinical pharmacokinetics research and plasma drug concentration monitoring. The clinical studies revealed that toxicity related lactone metabolites have a high level of exposure in humans, which requires attention to the possible risk of side effects.
To establish a suitable method to determine the structure and source of impurities of colistimethate sodium (CMS) for drug quality control studies.
Frist-dimensional system: using Acquity UPLC® Peptide CSH C18(150 mm×2.1 mm, 1.7 μm) column, the mobile phase A was phosphate buffer (7.8 g·L-1 sodium dihydrogen phosphate, adjusted to pH 6.4 with 1 mol·L-1 sodium hydroxide)- acetonitrile (19∶1), the mobile phase B was phosphate buffer-acetonitrile (1∶1). Gradient elution was performed at a flow rate of 0.3 mL·min-1. The column temperature was 30 ℃. Second-dimensional system: the Acquity BEH C18 column (50 mm×2.1 mm, 1.7 μm) column was used with ammonium formate(A)-acetonitrile mixture as mobile phase with gradient elution. The flow rate was 0.2 mL·min-1. The column temperature was 40 ℃. The detection wave length was 210 nm. The ESI source was used in negative ion mode.
The 2D-LC-Q TOF MS method was used to infer the structure of the 55 impurities in CMS, and the main sources were polymyxin E1-I, polymyxin E1-7MOA, polymyxin E3 and polymyxin E6.
The structure and source of impurities in CMS are determined by 2D-LC-Q TOF MS, and the changes in the content of impurities such as manufacturers and production processes are evaluated, which is conducive to improving the production process and controlling drug quality at the source.
To explore the prepararation methods and rules of hair quality control samples which contained ketamine, norketamine or fluoroketamine, and the effects of different preparation and storage conditions on the performance of hair quality control samples.
Different preparation conditions were compared, such as different types of soaking solutions, solutions with different target contents, different amount of blank hair etc. The performances of hair quality control samples which were prepared in different conditions were systematically analyzed, and eighteen kinds of hair quality control samples with different contents of targets and different forms were prepared according to the rules, ACN-DMSO (1∶1, v/v, added 0.02 mol·L-1 hydrochloric acid) was used to soak blank hair in different time periods to prepare hair quality control samples with a wide coverage. HPLC-MS/MS instruments and BEH C18(100 mm×2.1 mm, 1.7 μm) column were used to test the content of targets in hair. Column temperature was 40 ℃, the mobile phases were aqueous solution with 0.1%(v/v) formic acid (A)-acetonitrile aqueous solution with 0.1%(v/v) formic acid (B), gradient elution (0-9 min, 5% B→100% B; 9-11 min, 100% B; 11-11.1 min, 100% B→5% B; 11.1-13 min, 5% B, a flow rats of 0.4 mL·min-1, inject volume of 1 μL. The homogeneity, short term and long term stability in different storage conditions (temperature, humidity, light conditions, etc.) were also investigated.
The influences of different preparation conditions on the hair quality control samples were determined, soaking solutions had strong influences on the hair quality control samples, however the amount of blank hair had nearly no effects. All the samples prepared were uniform, F of each sample was lower than F0.05(table) (3.02) according to the F-test method, and all the samples were stable, during storage at room temperature, refrigerated or frozen conditions for 6 months, the contents of the target substances in each sample were monitored, all of RSDs were <12%, and the t values of each sample were < t(0.05)(table) (2.131 8) according to the T-test method.
This study provides preparation rules of hair quality control samples and also provides detailed reference data for subsequent preparation and storage of related hair quality control samples.
To study and analyze rapid evaporative ionization mass spectrometry (REIMS) fingerprints of samples of Fritillariae Thunbergii Bulbus and Fritillariae Hupehensis Bulbus in different forms for authenticity discrimination with machine learning.
Aerosol formations from the samples by high temperature of dry burning method were ionized and determined by REIMS with m/z 50-1 200 as scanning range in sensitive mode and positive ion mode. The scanning time was 0.2 s and data was recorded as continuous mode. Then the basic situation of REIMS data distribution was studied and analyzed through the methods of cluster analysis, correlation analysis, similarity analysis and principal component analysis. And then logistic regression model with ridge regression (l2) as penalty parameter and quasi-Newton method (lbfgs) as optimization algorithm was established.
The REIMS fingerprints of the samples showed the characteristics of variety differences. Both cross validation and test set validation had an accuracy of 1.0, and the logistic regression model could accurately predict and distinguish the varieties of the samples.
The application prospect of REIMS technique combined with machine learning in the field of traditional Chinese medicine is very broad.
To develop a high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method for the determination of vildagliptin in human anticoagulant plasma with ethylenediamine tetra acetic acid and apply it to the study of pharmacokinetics.
13C-15N-vildagliptin was used as internal standard (IS). After extraction from human plasma by protein precipitation with acetonitrile, all components were separated by a Hypurity C18 column (150 mm×2.1 mm, 5 μm), using a gradient elution procedure consisting of methanol and 5 mmol·L-1 ammonium formate at a flow rate of 0.5 mL·min-1, and the column temperature was 40 ℃. Injection volume was just 2 μL. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 304.3→154.2 for vildagliptin and m/z 310.3→160.3 for internal standard. Specificity, standard curve, lower limit of quantification, precision, recovery, matrix effect and stability were examined. Then this method was used to determine the plasma concentration of veragliptin in healthy subjects.
The calibration curve of vildagliptin in human plasma was linear over the concentration range of 1.11 to 534.0 ng·mL-1. The lower limit of quantitation was 1.11 ng·mL-1. The intra-and inter-day precisions at four quality control levels were within 0.9%-8.5%, and the accuracy was within 99.8%-109.3%. The data of short-term stability at room temperature displayed that the accuracy percentage of LQC samples was 92.0% for 0.5 h exposure, 87.6% for 1 h exposure, 71.2% for 2 h exposure. These of LQC samples chilled on ice was 102.0% for 0.5 h exposure, 94.5% for 1 h exposure, 86.6% for 2 h exposure. These results showed a phenomenon that there was a possible degradation of vildagliptin in plasma. The results of extraction recovery and matrix effect and other stability met the requirements of biological sample analysis. The pharmacokinetic study results of 8 healthy subjects showed that t1/2 was (1.49±0.37) h, tmax was (2.06±1.11) h, Cmax was (290.94±100.36) ng·mL-1, AUC0-24 h was (1 343.46±186.89) ng·h·mL-1, AUC0-∞ was (1 351.31±188.79) ng·h·mL-1.
This method is easy to operate, has high specificity, and sensitivity. It has been successfully applied to the pharmacokinetic study of 8 healthy subjects after oral administration of 50 mg vigagliptin tablets on an empty stomach. Therefore, it can be used as a reliable detection method for human pharmacokinetic research and therapeutic drug monitoring.
To establish an HPLC method for the determination of the related substances in telmisartan.
Waters Symmetry Shield RP8 (150 mm×4.6 mm, 3.5 μm) column was adopted. The mobile phase A was 0.1% phosphoric acid solution (pH was adjusted to 3.0 with triethylamine), and the mobile phase B was acetonitrile. The gradient elution was performed. The flow rate, column temperature and wavelength were 0.8 mL·min-1, 25 ℃ and 230 nm, respectively.
The resolutions between the peaks of telmisartan and nine known impurities were greater than 1.5. The limits of quantitation of all impurities were less than 40 ng·mL-1, and the limits of detection of all impurities were less than 10 ng·mL-1. The standard curves of telmisartan and its impurities were linear within the range 30-600 ng·mL-1, and the correlation coefficients were all greater than 0.999 5. The average recovery rates of impurities Ⅰ-Ⅸ were 93.8%, 99.8%, 97.5%, 99.2%, 99.8%, 98.3%, 98.4%, 99.2% and 99.7%, respectively, and the RSDs of 9 results were all less than 2.0%. Changing the flow rate, column temperature, wavelength, mobile phase ratio and pH did not affect the detection results of the related substances. The results of maximum single impurity were 0.02% in three batches of telmisartan, and the results of total impurities were less than 0.10%.
The method is highly specific, sensitive, precise and accurate, and can be used for the determination of related substances of telmisartan.
Gas chromatography-Orbitrap mass spectrometry (GC-Orbitrap/MS), a developing gas chromatography-high resolution mass spectrometry approach, allows for high throughput qualitative and quantitative analysis of volatile and semi-volatile components. It has the advantages of high sensitivity, selectivity, and a wide linear dynamic range, which makes it well suitable for the analysis of a wide range of trace substances in complex matrices. In recent years, this technology has been applied in environmental science, industry, food analysis, pharmaceutical analysis, forensic science, clinical medicine and other fields. This paper presents the first review of GC-Orbitrap/MS, which not only describes the basic principles and technical characteristics, but also introduces the progress of the technique in food and pharmaceutical research. Applications in food analysis include the inspection of pesticide residues, detection of persistent organic compounds and analysis of flavor substances. In pharmaceutics, the analysis of chemical impurities and quality evaluation of traditional Chinese medicine are introduced. It is noteworthy that this technique is particularly advantageous for the identification of unknown compounds and the determination of ultra-trace components. Lastly but importantly, this review summarizes the challenges encountered in the current development of this technique, including the establishment of high-resolution standard databases, the selection and optimization of sample pre-treatment method and the application of GC-Orbitrap/MS in the field of traditional traditional Chinese medicine. A few solutions are also proposed, such as the application of variable electron voltage technique, the combination of two-dimensional gas chromatography and electrostatic field Orbitrap mass spectrometry and the integrated analysis comprehensively using multiple scan modes. These strategies are aimed to provide more advanced and accurate solutions to food, pharmaceutical, and other relevant analysis.
Patch refers to a thin sheet flexible preparation made of raw drug and suitable material for sticking on the skin, which can produce systemic or local effects. In vitro release test (IVRT) and in vitro permeation test (IVPT) are important contents of preclinical pharmaceutical research for formulation process optimization, quality control and safety and effectiveness evaluation of patch. The experimental equipment and methods used are different, the obtained experimental samples and data are different from each other, and the accuracy and precision of the experimental data are also different. Therefore, the selection of experimental equipment and the establishment of experimental methods in the in vitro experiment of IVRT & IVPT is a problem worthy of attention. In this paper, the research status of patch was summarized, the requirements of pharmacopoeia of different countries for IVRT experiments were briefly introduced, and the differences of different methods were reviewed. For IVPT experiments that have not yet been prescribed by relevant standards, the common types of experimental equipment and experimental conditions were introduced in detail, the applicability of different equipment and the influence of main experimental conditions (temperature, stirring speed, composition of acceptor solution, selected skin, etc.) on the experimental results were summarized, and the research progress of in vivo and in vitro correlation was introduced. At the same time, the validity of the experimental data was discussed, hoping to provide a useful reference for the development and research of the in vitro experimental methodology of the patch.
To identify the structures of the related substances in penciclovir cream by two-dimensional liquid chromatography quadrupole time-of-flight tandem mass spectrometry (2D-LC-Q TOF/MS) technique.
The first-dimension separation of the related substances in penciclovir cream and its stressed samples according to ICH were carried out on an ODS (250 mm×4.6 mm, 5 μm) column with gradient elution by 0.15% formic acid 10 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases, and each related substance was enriched separately. The second-dimension gradient elution was performed on a Phenomenex Luna SCX (250 mm×4.6 mm, 5 μm) column with 0.1% formic acid 20 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases for each of the related substances to achieve good separation with the matrix of penciclovir cream. The accurate mass and elemental composition of the parent ions and their product ions of the related substances were determined by positive electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry, and the structures of all the related substances were elucidated.
Under the established 2D-LC-Q TOF/MS analytical conditions, penciclovir and its related substances were adequately separated, and 21 major related substances were detected and identified in the penciclovir cream and its stressed samples. According to their chromatographic retention behavior, spectral characteristics, mass spectrometry characteristics and their differences from other known related substances of nucleoside drugs and combing with synthesis and formulation process route, their structures can be identified all of which were identified for the first time.
The results can provide reference for the quality control of penciclovir cream.
To establish an immunochromatographic method suitable for the rapid detection of residues of triazine herbicide prometryn in Chinese medicine, based on self-made prometryn antigen and monoclonal antibody.
An antibody conjugate amount of 7 μg and dilution configuration of 0.1 mol·L-1 PBS with 1% OVA, 0.1% Tween-80 were determined, and dry test strips with a T-line scribing concentration of 0.05 mg·mL-1 and a C-line scribing concentration of 0.5 mg·mL-1 were used. The suitable method was selected to improve the sensitivity of colloidal gold immunochromatography test strip, reduce the matrix effect of traditional Chinese medicine in different parts, and detect a large number of traditional Chinese medicine.
The detection sensitivity of the test strip could reach 1 ng·mL-1, and the detection limit of the actual sample could reach 0.1 mg·kg-1. The established method was suitable for the detection of prometryn residues in 40 kinds of Chinese medicinal materials such as Citri Reticulatae Pericarpium, Taraxaci Herba, Notoginseng Radix et Rhizoma andLonicerae Japonicae Flos.
This method has the advantages of rapid and accurately detection, simple pretreatment, simple operation and strong generalization, and can be used as an effective method for rapid screening of prometryn residues in the field, so as to ensure the quality and safety of traditional Chinese medicine. At the same time, this study has a certain reference significance for the development of rapid detection of agricultural residues in many kinds of traditional Chinese medicine.
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