Gradient Mode Research Articles

Extension of Global Gyrokinetic Code for Tokamak Edge Turbulence Simulation

A field-aligned coordinate system using a shifted metric technique has been implemented to a global gyrokinetic code GKNET. This coordinate system allows for simulations with lower resolution in the direction along the magnetic field line, which is especially effective in the outer core regions with higher q values. Realistic tokamak geometries, including up-down asymmetric equilibria, have also been implemented by using a newly developed interface code that connects GKNET and a free-boundary 2D Grad-Shafranov equation solver. This is essential for tokamak edge simulations, which will be developed in the future. As an application, the nonlinear simulation of the ion temperature gradient (ITG) mode with the JT-60SA ITER-like plasma [M. Nakata et al., Plasma Fusion Res. 9, 1403029 (2014)] has been performed. The result shows that the linear ITG instability with high poloidal modes and resultant zonal flow generation are properly traced. In this case, it is estimated that the number of computational grids can be reduced to 1/94 compared to that of the flux surface coordinate system.

A new stability indicating HPLC and LC-APCI-MS methods for the estimation of Clofarabine in pharmaceutical dosage forms

Clofarabine is an anti-cancer drug. A new stability indicating isocratic RP-HPLC and LC-APCI-MS methods have been developed and validated for the quantification of Clofarabine as per ICH guidelines. Thermo scientific-TSQ Quantis with Vanquish HPLC coupled with MS was employed for the present study. Simpack C18 column was used for chromatographic resolution and a triple quadrupole mass spectrometer with atmospheric pressure chemical ionization (APCI) source, running in the positive mode (as well as negative mode) was used for detection. A mixture of 0.1% Formic acid: Acetonitrile was used as mobile phase on gradient mode and a mixture of Methanol: Water (50:50, v/v) was used as diluent. A wide linearity concentration range 5.0-150 μg/mL was shown by the proposed method. The proposed methods are simple, precise, and accurate are used to quantify the marketed formulations of Clofarabine. Stress degradation studies were performed and the method is found to be selective and specific.

Deep learning method of stochastic reconstruction of three-dimensional digital cores from a two-dimensional image.

Digital cores can characterize the true internal structure of rocks at the pore scale. This method has become one of the most effective ways to quantitatively analyze the pore structure and other properties of digital cores in rock physics and petroleum science. Deep learning can precisely extract features from training images for a rapid reconstruction of digital cores. Usually, the reconstruction of three-dimensional (3D) digital cores is performed by optimization using generative adversarial networks. The training data required for the 3D reconstruction are 3D training images. In practice, two-dimensional (2D) imaging devices are widely used because they can achieve faster imaging, higher resolution, and easier identification of different rock phases, so replacing 3D images with 2D ones avoids the difficulty of acquiring 3D images. In this paper, we propose a method, named EWGAN-GP, for the reconstruction of 3D structures from a 2D image. Our proposed method includes an encoder, a generator, and three discriminators. The main purpose of the encoder is to extract statistical features of a 2D image. The generator extends the extracted features into 3D data structures. Meanwhile, the three discriminators have been designed to gauge the similarity of morphological characteristics between cross sectionsof the reconstructed 3D structure and the real image. The porosity loss function is used to control the distribution of each phase in general. In the entire optimization process, a strategy using Wasserstein distance with gradient penalty makes the convergence of the training process faster and the reconstruction result more stable; it also avoids the problems of gradient disappearance and mode collapse. Finally, the reconstructed 3D structure and the target 3D structure are visualized to ascertain their similar morphologies. The morphological parameter indicators of the reconstructed 3D structure were consistent with those of the target 3D structure. The microstructure parameters of the 3D structure were also compared and analyzed. The proposed method can achieve accurate and stable 3D reconstruction compared with classical stochastic methods of image reconstruction.

Linear instabilities in the hot-ion regime in a high-field spherical tokamak

The present operating high-field compact spherical tokamak ST40 is an important step toward an ST-based fusion reactor (Gryaznevich and Asunta 2017 Fusion Eng. Des. 123 177; McNamara 2023 Nucl. Fusion 63 054002). Temperature and density profiles and their uncertainties in recent hot ion ST40 plasmas with central ion temperatures exceeding 8.6 keV, have been inferred using an integrated analysis of several diagnostics including line-of-sight integration and volume average measurements, as well as limited profile information from a charge-exchange-recombination spectrometer. A linear gyrokinetic stability analysis has been carried out to identify the most unstable micro-instabilities in these hot ion plasmas. In one of these plasmas, it is found that linear growth rates of both ion- and electron-scale ( where k θ is the poloidal wavenumber and ρ s is the ion gyro-radius with sound speed) modes decrease from the edge toward the core of the plasma (i.e. from ρ = 0.8 to 0.3 where ρ is the square root of the normalized magnetic flux), while the change of linear growth rates at is non-monotonic. In particular, at ρ = 0.3 no unstable mode was found at , and about an order of magnitude reduction in the maximum linear growth rate in the ion-scale wavenumber range of is seen at ρ = 0.3 compared with the ρ = 0.8 location. It is found through parametric scans that while the ion temperature gradient (ITG) mode/trapped electron mode (TEM) and kinetic ballooning mode (KBM)/kinetic shear Alfvén (KSA) mode are more important in the plasma core, ubiquitous mode (UM) is found to be the important ion-scale instability at . At ρ = 0.8, two instabilities are found at the electron scale, with one being the typical electrostatic electron temperature gradient (ETG) mode at ρ e scale and beyond and the other being an unidentified low-real-frequency instability (at the intermediate scale between electron and ion gyroradii) which can propagate in the ion direction and is driven by ETG. The existence of UM at the ion scale and the low-real-frequency instability and ETG mode at the electron scale at ρ = 0.8 is supported by an extensive linear gyrokinetic stability analysis of another ST40 hot ion plasma in a wider parametric range, taking into account the uncertainties in the experimental profiles.

Determination of Pinoresinol 4-O-beta-D-glucopyranoside and Vladinol F as Markers in Pandanus tonkinensis Fruits by High Performance Liquid Chromatography

According to the traditional know-how, the Northern wild pineapple (Pandanus tonkinensis) has been used efficiently as a major component of oriental remedies for liver protection. Based on the experimentally found chemical composition of Pandanus tonkinensis and their obtained biological activities in terms of the hepatoprotection purpose, two structure-elucidated compounds pinoresinol 4-O-beta-D-glucopyranoside and vladinol F were selected as potential markers for this medical plant. This paper is aiming to present the validation of proposed HPLC method for simultaneous quantification of the both pinoresinol 4-O-beta-D-glucopyranoside and vladinol F in the fruits of Pandanus tonkinensis with the following conditions: using RP-C18 (250 mm × 4.6 mm; 5 μm) column, detection wavelength measured at 228 nm, the mobile phases consisting of acetonitrile and 0.1% acetic acid in gradient mode with a flow rate of 1mL/min and injection volume was 10 mL. Method validation showed a high specificity, linear calibration ranging from 25.5 to 76.4 mg/ml (r= 0.9991) and from 26.0 to 77.9 mg/ml (r= 0.9987) for two markers, respectively. Besides, a good repeatability and intermediate precisions (RSD < 2%), a reliable accuracy (recovery efficiency between 99.4 and 101.5%, RSD < 1.73%) as well as the obtained limits of quantification in values of 2.55 m/g and 2.60 mg/g for the two mentioned markers were received. Using the above validated method, the content of two markers - pinoresinol 4-O-beta-D-glucopyranoside and vladinol F in Pandanus tonkinensis fruits collected from different locations (Thanh Hoa, Hoa Binh, Thai Nguyen) had been determined falling in the range of 0.0250 - 0.0435 mg/g and 0.0243 - 0.0371 mg/g, respectively.
 Keywords: pinoresinol 4-O-beta-D-glucopyranoside, vladinol F, markers, Pandanus tonkinensis, HPLC

Validated stability-indicating RP-HPLC assay method for fesoterodine fumarate in pharmaceutical products

The goal of the current study was to develop a precise, sensitive and validated reverse phase HPLC method for determination of fesoterodine fumarate (FST). The current investigation was performed for a stability indicating method in order to obtain both assay and impurity profiles of FST. All the experiment was done on HPLC Shimadzu Prominence 20A having stainless steel ACE5 C18 column with a particle size of 5µm and a dimension of 4.6 mm X 150 mm. The mobile phase was in gradient mode with mobile phase A (0.03M ammonium acetate buffer : acetonitrile : methanol (55:30:15 v/v) pH 3.8) and mobile phase B (water) . The flow rate was 1.2 mL/min and the wavelength 208 nm was selected for detection. This method was validated for linearity and range, accuracy, precision and robustness in accordance with ICH requirements. The retention time of fesoterodine was found as 11.0 min. The main degradation product 5-hydroxymethyltolterodine (5-HMT; active metabolite of FST) and the other process impurities; aldehyde, benzylated hydroxy, tolterodine ester, diester impurities were detected easily at the retention times 3.8, 13.5, 16.7, 21.5, 37.1 minutes, respectively. It was observed that the retention times of the main peak and its impurities were not affected and the selectivity of the method was proved under the applied stress conditions. With this developed method, FST and its impurities can easily be detected. It is also stable, simple, accurate, and completely validated RP-HPLC technique for the analysis of FST and related impurities that meets with ICH standards.

Secondary metabolites of Schisandra chinensis in homeostasis regulator adaptogen herbal formula for preventive oncology

The original herbal formula of homeostasis regulator Multiphytoadaptogen (MPhA) for preventive oncology developed by the N.N. Blokhin Center of Oncology containing phytocomponents from Schizandra chinensis has been investigated in vitro, in vivo and in clinical studies. The MPhA multi-target effects are achieved by optimizing the functioning of the nervous, immune and endocrine defense systems that regulate homeostasis under stress. Everything that has been previously studied for MPhA can be considered as preclinical testing, including clinical research, which can be regarded as the pilot studies. This was allowed because MPhA in Russia is registered as a parapharmaceutical agent and therefore standardized according to established requirements. However, due to the high efficiency of MPhA, a detailed study of the chemical composition and standardization of it is required, including the composition of Schisandra chinensis Baill (Schisandraceae) active components, which turned out to be translocated into MPhA as a result of the extraction technology developed. So, for MPhA identification and standardization we detected the secondary metabolites in the herbal formula MPhA as well as in fruits extract of Schisándra chinénsis using high-performance liquid chromatography in combination with mass spectrometry. Chromatography was performed on an ACQUITY UPLC BEH C18 column in a gradient mode. A TSQ Vantage triple quadrupole mass spectrometer with electrospray ionization was used. Lignans Schizandrin and Schizantherin A were identified in the MPhA as well as in Schisándra chinénsis fruits extract obtained by the technology developed. The determined secondary metabolites can be used for standardization and quality testing of the herbal formula MPhA. In addition, we performed in silico analyzes of Schizandrin and Schizantherin A biological activity spectra using computer program PASS (Prediction of Activity Spectra for Substances). Schizandrin and Schizantherin A activities, according the scientific literature and in silico analysis, correspond to the properties studied for MPhA which therefore fits into the concept of a drug – homeostasis regulator adaptogen for preventive oncology.

Three-dimensional characteristic chromatogram by online comprehensive two-dimensional liquid chromatography: Application to the identification and differentiation of ginseng from herbal medicines to various Chinese patent medicines

One bottleneck problem in the quality control of traditional Chinese medicine (TCM) is the accurate identification of easily confused herbal medicines from Chinese patent medicine (CPM). Ginseng products derived from the multiple parts (e.g., root/rhizome, leaf, and flower bud) of multiple Panax species (P. ginseng, P. quinquefolius, P. notoginseng, P. japonicus, and P. japonicus var. major) are globally popular; however, their authentication is very challenging. Using online comprehensive two-dimensional liquid chromatography (LC × LC), we propose the concept of a three-dimensional characteristic chromatogram (3D CC) by integrating enhanced LC × LC separation and a contour plot that visualizes the stereoscopic chromatographic peaks and examine its performance in authenticating various ginseng products. Targeted at the resolution of 17 ginsenoside markers, an online LC × LC/UV system with a 56 min analysis time was constructed: a CORTECS UPLC Shield RP 18 column running at 0.1 mL/min for the first-dimensional chromatography and a Poroshell SB-Aq column at 2.0 mL/min in shift gradient mode in the second dimension of separation. In particular, ginsenosides Rg1/Re and Rc/Ra1 were well resolved. According to the presence/absence of stereo peaks consistent with the main ginsenoside markers in the 3D CC and the depth of shade (depending on peak volume), it was feasible to use a single method to identify and distinguish among 12 different ginseng species as the drug materials and the use of ginseng simultaneously from 21 CPMs. Conclusively, a practical solution enabling the accurate identification of easily confused TCMs was provided, covering both the drug materials and the compound preparations.

Simultaneous Quantification RP-HPLC Method Development and Validation for Atorvastatin and Tadalafil in Bulk Form

Background: Tadalafil and Atorvastatin together have been shown to significantly enhance hemodynamics and sexual performance in middle-aged and older patients with hyperlipidemia. Despite of the number of techniques for estimating tadalafil and atorvastatin calcium, the Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) technique for simultaneous determination of Atorvastatin calcium and Tadalafil has not yet been disclosed. Purpose: A sensitive, simple, rapid, reverse phase high pressure liquid chromatography (RP-HPLC) method has been developed and validated for the simultaneous estimation of Tadalafil and Atorvastatin in bulk form. Methods: The method was carried out utilizing the C-18 column (Sapphirus, 5 x 250 mm) and mobile phase at 1 ml/min flow rate. 0.05M phosphate buffer (30:70 v/v gradient mode) and acetonitrile were the ideal mobile phase conditions. The pH was changed with glacial acetic acid to 4.0. Results: Tadalafil and Atorvastatin had retention times of 3.517 and 4.117, respectively, according to data collected concurrently. The linearity range for Atorvastatin and Tadalafil (15 µg/ml to 90 µg/ml) was established using an external standard calibration method. It was calculated that the recovery rate ranges from 98.09 to 101.44 percent, and it was discovered that all values fall within this range. The limits of detection for Atorvastatin and Tadalafil are 0.318 µg/ml and 0.672 µg/ml, respectively. Conclusion: The method was found to be robust, durable, accurate and linear for validated parameters. The % RSD observed for flow rate, wavelength, and analyst variation was found to be below 2, which was considered acceptable in the robustness investigation.

Gyrokinetic simulations of core turbulence and thermal transport in the high-β P discharge on EAST

The properties of core turbulence and thermal transport are investigated for EAST high-β P (β P ∼ 3.1) plasmas with dominant electron heating (T e/T i > 1) via gyrokinetic simulation with the NLT code. Linear simulations identify that the electrostatic -driven trapped electron mode (-TEM) dominates in the core region (ρ< 0.7) and the ion temperature gradient (ITG) mode dominates in the out region (ρ⩾ 0.7), consistent with the linear threshold analysis of micro-instabilities. Sensitivity analysis shows that the normalized electron density gradient (R/L ne) and ITG (R/L Ti) are two effective parameters to stabilize TEM instability. Nonlinear simulations are also carried out and compared with the experimental results, which show that the electron thermal internal transport barrier (ITB) in EAST high-β P plasma is determined by the TEM-induced turbulence. A higher zonal flow shearing rate is observed in the ITB region (0.2 < ρ < 0.34), which can regulate energy transport induced by TEM turbulence and facilitate the formation of e-ITB. A plausible positive feedback mechanism to mitigate turbulence transport and improve energy confinement via enhanced ion heating is proposed for future experiments.

Global gyrofluid simulations of turbulence in tokamak plasmas

We develop a tokamak plasma turbulence simulation code based on a fluid model using the BOUT++ framework. The model corresponds to a global extension of the local gyrofluid model (Beer and Hammett, 1996 [11]), where external sources and neoclassical equilibrium flows are included but some higher-order kinetic effect terms are ignored for the global nonlinear simulation. Hyper-viscous damping terms are introduced to compensate for the stabilizing effect of the missing kinetic terms. With an appropriate hyper-viscosity, we obtain reasonable linear and nonlinear results on ion temperature gradient modes compared to global gyrokinetic simulations. We perform global flux-driven simulations with self-consistently evolving profiles with external heat sources/sinks. A spectral analysis of heat flux in flux-driven turbulence exhibits a broad 1/f (f is the frequency) spectrum observed in gyrokinetic simulations, indicating the prevalence of self-organized criticality-like heat avalanches. We also investigate the effect of an externally imposed vorticity source on turbulence suppression and transport barrier formation. It is shown that internal transport barrier can form even for a monotonic safety factor profile when a sufficiently strong vorticity source is applied.

The internal transport barrier formation on EAST tokamak during the fishbone instability

The internal transport barrier (ITB) which is related to the fishbone instability has been observed on the Experimental Advanced Superconducting Tokamak (EAST) in ELMy H-mode discharges. An interpretation of the formation of the ITB on EAST tokamak is provided, based on both analytical and numerical calculations. The fishbone instability induces the redistribution of fast ions and leads to the accumulation of fast ions in a local region where the ITB is going to appear. Correspondingly, the gradients of fast ions are enhanced, where the ion temperature gradient (ITG) mode exists. Fast ions can interact with the ITG mode through the dilution, Shafranov shift and wave-particle resonance mechanisms. It is found that the ITG mode is stabilized by fast ions and the stabilizing effects are determined mainly by the density, temperature and their gradients of fast ions. The enhanced density and temperature gradients of fast ions lead to a stronger stabilizing effect on ITG mode. Compared with the stabilizing effect before the appearance of fishbone instability, the stabilization on ITG mode is enhanced after the fishbone instability, which is beneficial to the formation of the ITB.

Electrostatic turbulence in EAST plasmas with internal transport barrier

Based on first-principles nonlinear gyrokinetic simulations, the electrostatic turbulence properties in the internal transport barrier (ITB) region of an Experimental Advanced Superconducting Tokamak discharge (#93890) are investigated. Specifically, ITBs with steep density and temperature gradients are located in the weakly negative magnetic shear region at the plasma center. In the linear stage, the growth rate and frequency of the ion temperature gradient (ITG) mode increase significantly due to resonant excitation by trapped electrons. That is, the resonance between trapped electrons and the ITG becomes strong due to the precession drift reversal of trapped electrons by the negative magnetic shear and Shafranov shift. Meanwhile, the trapped electron mode is stable in the ITB region due to only a very small fraction of electrons precessing in the direction of the electron diamagnetic drift. Nonlinear simulations show that, after considering the non-adiabatic effect of trapped electrons, the heat conductivity of ions and the turbulence intensity increase by at least a factor of 7 compared with the results only considering the adiabatic effect of electrons. The zonal charge density of trapped electrons can partially cancel that of ions, which weakens the intensity of the zonal flow, and consequently reduces the zonal flow regulation and enhances the turbulent transport.

Multileveled Hierarchical Hydrogel with Continuous Biophysical and Biochemical Gradients for Enhanced Repair of Full-Thickness Osteochondral Defect.

The repair of hierarchical osteochondral defect requires sophisticated gradient reestablishment; however, few strategies for continuous gradient casting consider the relevance to clinical practice regarding cell adaptability, multiple gradient elements, and precise gradient mirroring native tissue. Here, a hydrogel with continuous gradients in nano-hydroxyapatite (HA) content, mechanical, and magnetism is developed using synthesized superparamagnetic HA nanorods (MagHA) that easily respond to a brief magnetic field. To precisely reconstruct osteochondral tissue, the optimized gradient mode is calculated according to magnetic resonance imaging (MRI) of healthy rabbit knees. Then, MagHA are patterned to form continuous biophysical and biochemical gradients, consequently generating incremental HA, mechanical, and electromagnetic cues under an external magnetic stimulus. To make such depth-dependent biocues work, an adaptable hydrogel is developed to facilitate cell infiltration. Furthermore, this approach is applied in rabbit full-thickness osteochondral defects equipped with a local magnetic field. Surprisingly, this multileveled gradient composite hydrogel repairs osteochondral unit in a perfect heterogeneous feature, which mimics the gradual cartilage-to-subchondral transition. Collectively, this is the first study that combines an adaptable hydrogel with magneto-driven MagHA gradients to achieve promising outcomes in osteochondral regeneration.

Mitoxantrone Quantification by HPLC-MS/MS in Caco-2 Culture Media

Mitoxantrone is a marker substrate of breast cancer resistance protein (BCRP). BCRP is involved in a number of pharmacokinetic drug-drug interactions. The transporter’s possible saturability makes it advisable to use low concentrations of mitoxantrone for in vitro studies. Consequently, mitoxantrone quantification requires a method with high sensitivity.The aim of the study was to develop and validate a procedure for mitoxantrone quantification in Caco-2 culture media by HPLC-MS/MS.Materials and methods. The authors used an Ultimate 3000 HPLC system and a TSQ Fortis triple quadrupole mass spectrometer by Thermo Fisher Scientific and a Selectra C18 column (4.6×100 mm, 5 μm, 100 Å) by United Chemical Technologies. The elution ran in a gradient mode with a mobile phase of 1% formic acid solution and methanol. Experimental parameters were as follows: eluent flow rate, 0.3 mL/min; separation column temperature, 35 °C; injection volume, 5 μL; ana lysis time, 10 min; approximate mitoxantrone retention time, 5.51 min. The sample preparation involved protein precipitation from the culture medium with methanol, followed by centrifugation at 13,000 g for 10 min. The detection was performed using electrospray ionisation in the positive ion mode. Detection parameters were as follows: electrospray voltage, 3700 V; sheath gas flow rate, 50 L/min; auxiliary gas flow rate, 10 L/min; sweep gas flow rate, 1 L/min; ion-transfer tube temperature, 300 °C; and evaporator temperature, 350 °C. The detection was set at mass transitions of m/z 455 to 88.2 and m/z 455 to 358.1, with the collision energy for these transitions amounting to 25 V and 18 V, respectively. The source fragmentation was at 0, and the CID gas pressure was at 2 mTorr.Results. The analytical procedure showed selectivity, high sensitivity (limit of detection, 10 nmol/L; lower limit of quantification, 50 nmol/L), accuracy, precision, and linearity in the concentration range of 50–1000 nmol/L. The authors observed no carryover or matrix effects. A simulation of real-life storage conditions demonstrated high stability of mitoxantrone samples. Thus, the analytical procedure enables preclinical evaluation of medicinal product effects on the functional activity of BCRP, based on assessing the transcellular mitoxantrone transport in the presence of a test product.Conclusion. The authors developed and validated the analytical procedure for mitoxantrone quantification in Caco-2 culture media by HPLC-MS/MS.

Development of HPLC-CAD method for simultaneous quantification of nine related substances in ursodeoxycholic acid and identification of two unknown impurities by HPLC-Q-TOF-MS

Ursodeoxycholic acid has gained increasing attention due to its recent discovery of the preventive effect on SARS-CoV-2 infection. Ursodeoxycholic acid has been included in various pharmacopoeias as an old drug, and the latest European Pharmacopoeia lists nine potential related substances (impurities A∼I). However, existing methods in pharmacopoeias and literature can only quantify up to five of these impurities simultaneously, and the sensitivity is inadequate, as the impurities are isomers or cholic acid analogues lacking chromophores. Herein, a novel gradient RP-HPLC method coupled to charged aerosol detection (CAD) was developed and validated for the simultaneous separation and quantification of the nine impurities in ursodeoxycholic acid. The method proved sensitive and allowed the quantification of the impurities as low as 0.02 %. Relative correction factors of the nine impurities were all within the range of 0.8–1.2 in the gradient mode by optimizing chromatographic conditions and CAD parameters. In addition, this RP-HPLC method is fully compatible with LC-MS due to the volatile additives and high percentage of the organic phase, which can be directly used for the identification of impurities. The newly developed HPLC-CAD method was successfully applied to commercial bulk drug samples, and two unknown impurities were identified by HPLC-Q-TOF-MS. The effect of CAD parameters on the linearity and correction factors was also discussed in this study. Overall, the established HPLC-CAD method can improve the methods in current pharmacopoeias and literature and contributes to understanding the impurity profile for process improvement.

Qualitative and Quantitative Determination of Dapagliflozin Propanediol Monohydrate and Its Related Substances and Degradation Products Using LC-MS and Preparative Chromatography Methods

Dapagliflozin is a novel sodium-glucose cotransporter type 2 inhibitor. This work aims to develop a new validated sensitive RP-HPLC coupled with a mass detector method for the determination of dapagliflozin, its alpha isomer, and starting material in the presence of dapagliflozin major degradation products and an internal standard (empagliflozin). The separation was achieved on BDS Hypersil column (length of 250mm, internal diameter of 4.6 mm and 5-μm particle size) at a temperature of 35℃. Water and acetonitrile were used as mobile phase A and B by gradient mode at a flow rate of 1 mL/min. A wavelength of 224nm was selected to perform detection using a photo diode array detector. The method met the requirement of the International Conference on Harmonisation for Registration of Pharmaceuticals for Human Use (ICH) for validation. The molecular weight of impurities and degradation products was estimated using positive ESI-MS. Fifteen impurities were detected during the analysis of dapagliflozin APIs and the brand Farxiga ® and some generic products. Three of fifteen detected impurities (H, J and K) exceeded the impurities acceptable limits 0.1%. Those impurities were isolated using new preparative chromatography then characterized using elemental analysis, FTIR and NMR.

DEVELOPMENT OF METHOD FOR QUANTITATIVE DETERMINATION OF CEFQUINOME SULFATE IN PIGLETS BLOOD PLASMA USING HPLC/DMD

This manuscript presents a developed method for determining cefquinome sulfate in piglets blood plasma intended for clinical and pharmaceutical research of veterinary drugs based on it. Blood plasma proteins were precipitated twice with a solution of trichloroacetic acid. The supernatant was further purified by a series of solid-phase extraction. Separation was performed on an inverted phase Kinetex EVO С18 column using acetonitrile and 0,1 % trifluoroacetic acide solusion as the mobile phase. The gradient mode of eluents was used during 10 min at a flow rate of 1,4 ml/min. The peak retention time of cefquinome sulfate is 4,2 min. The specificity of the analytical method was checked by comparing the chromatographic separation of a sample of blood plasma enriched with a standard solution of cefquinome sulfate and a sample of blood plasma placebo. The preparing loaded blood plasma samples procedure for building a calibration graph is described in the article. The validation parameters of the method “recovery” and “coefficient of variation” were considered in accordance with the criteria of Council Directive 2002/657/EC. The procedure of sample preparation of fortified blood plasma to construct calibration graph is described in the manuscript. The mean recovery from fortified blood plasma samples in the range of 0.1-2.0 μg/ml cefquinom sulfate was 102.3 %. The method is linear in the concentration range of 0.1 – 4.0 μg/ml of cefquinome sulfate. The correlation coefficient for the determination method is 0.9998. The results obtained in the study of the linearity of this technique were used to estimate the correctness and convergence. The accuracy of the measurements was evaluated by examining the known amounts of analyte added to the control blood plasma. Recovery data are acceptable because they are within ± 10% of the target value. The method has sufficient convergence (accuracy). The evaluation of the intermediate precision of cefquinome sulfate determination was assessed on three different days of analysis. The limit of detection for cefquinom sulfate is 0.05 μg/ml and limit of quantification - 0.10 μg/ml. The average CV for each compound was &lt;10%. The procedure was confirmed and then applied to determination cefquinome sulfate in the pig blood plasma obtained during the study of the pharmacokinetics of the veterinary drug. The HPLC/DMD method can be used for study of the pharmacokinetics of the veterinary drug.

The simultaneous quantification of Sitagliptin and Irbesartan in rat plasma using the validated LC-MS/MS method is applied to a pharmacokinetic study

Irbesartan (IRB), an angiotensin II receptor AT1 blocker, is an antihypertensive agent commonly used with Sitagliptin (STG), a novel antidiabetic agent in diabetes. A finalised and validated LC-MS/MS method was used for the bioanalytical quantification of STG and IRB to be applicable to studies on the P.K drug-drug interactions between STG and IRB. Using a YMC triart C18 column (50 mm × 4.6 mm i.d., 3 µm), both the drugs and the Tolbutamide were separated using a gradient mode with a flow rate of 1 ml/min with run time of 5 min. For analyte detection, an LC-MS/MS system with multiple reaction monitoring (MRM) was used. The technique was validated across a concentration range of 5–1000 ng/ml, with the LLOQ for both analytes being 5 ng/ml. At all QC levels accuracies from spiked samples were > 83% for both drugs and internal standards. The accuracy for STG within-batch and between-batch was found within 98.4–107.2%, and for IRB was found within 92.4–102.5%. The precision for STG within batch and between batches was less than 12.3% CV, and for IRB was less than 10.2% CV at all concentration levels. The pharmacokinetic profiles of STG and IRB were successfully applied on simultaneous oral administration to rats. This method applies to pharmacokinetic multidrug interaction studies.

Global linear stability analysis of kinetic trapped ion mode (TIM) in tokamak plasma using the spectral method

Trapped ion modes (TIMs) belong to the family of ion temperature gradient (ITG) modes, which are one of the important ingredients in heat turbulent transport at the ion scale in tokamak plasmas. A global linear analysis of a reduced gyro-bounce kinetic model for trapped particle modes is performed, and a spectral method is proposed to solve the dispersion relation. Importantly, the radial profile of the particle drift velocity is taken into account in the linear analysis by considering the magnetic flux ψ dependency of the equilibrium Hamiltonian in both the quasi-neutrality equation and equilibrium gyro-bounce averaged distribution function . Using this spectral method, linear growth rates of TIM instability in the presence of different temperature profiles and precession frequencies of trapped ions, with an approximated constant Hamiltonian and the exact ψ dependent equilibrium Hamiltonian, are investigated. The growth rate depends on the logarithmic gradient of temperature κ T , density κ n and equilibrium Hamiltonian . With the exact ψ dependent Hamiltonian, the growth rates and potential profiles are modified significantly, compared to the cases with an approximated constant Hamiltonian. All the results from the global linear analysis agree with a semi-Lagrangian based linear Vlasov solver with good accuracy. This spectral method is very fast and requires much less computation resources compared to a linear version of the Vlasov-solver based on a semi-Lagrangian scheme.