scholarly journals Process Development and Synthesis of Process-Related Impurities of an Efficient Scale-Up Preparation of 5,2′-Dibromo-2,4′,5′-Trihydroxy Diphenylmethanone as a New Acute Pyelonephritis Candidate Drug

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 468
Author(s):  
Xiu E Feng ◽  
Ke Meng Cui ◽  
Qing Shan Li ◽  
Zi Cheng Wu ◽  
Fei Lei
Keyword(s):  
Acute Pyelonephritis ◽  
High Performance ◽  
Process Development ◽  
Scale Up ◽  
Preparation Process ◽  
Reaction Conditions ◽  
Related Impurities ◽  
Candidate Drug ◽  
Optimal Reaction ◽  
Impurity Profiles

Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49-API), a new acute pyelonephritis candidate drug, was developed and validated aiming to reduce by-products and achieve better impurity profiles. Meanwhile, the polymorph of LM49-API and process-related impurities were also investigated. Ultimately, the optimal reaction conditions were verified by evaluating the impurity profiles and their formation during the synthesis. Six process-related impurities were synthesized and identified, being useful for the quality control of LM49-API. Its finalized preparation process was further validated at 329–410 g scale-up production in 53.4–57.1% overall yield with 99.95–99.98% high-performance liquid chromatography (HPLC) purity, and it is currently viable for commercial production. LM49-API-imC and LM49-API-imX were identified as the main single impurities in LM49-API, with the content controlled to be less than 0.03%.

scholarly journals Software-guided microscale flow calorimeter for efficient acquisition of thermokinetic data

2021 ◽  
Author(s):  
Timothy Aljoscha Frede ◽  
Marlene Dietz ◽  
Norbert Kockmann
Keyword(s):  
Design Of Experiments ◽  
Process Development ◽  
Reaction Conditions ◽  
Experimental Conditions ◽  
Flow Calorimeter ◽  
Microscale Flow ◽  
Increased Sensitivity ◽  
Important Time ◽  
Optimal Reaction

AbstractFast chemical process development is inevitably linked to an optimized determination of thermokinetic data of chemical reactions. A miniaturized flow calorimeter enables increased sensitivity when examining small amounts of reactants in a short time compared to traditional batch equipment. Therefore, a methodology to determine optimal reaction conditions for calorimetric measurement experiments was developed and is presented in this contribution. Within the methodology, short-cut calculations are supplemented by computational fluid dynamics (CFD) simulations for a better representation of the hydrodynamics within the microreactor. This approach leads to the effective design of experiments. Unfavourable experimental conditions for kinetics experiments are determined in advance and therefore, need not to be considered during design of experiments. The methodology is tested for an instantaneous acid-base reaction. Good agreement of simulations was obtained with experimental data. Thus, the prediction of the hydrodynamics is enabled and the first steps towards a digital twin of the calorimeter are performed. The flow rates proposed by the methodology are tested for the determination of reaction enthalpy and showed that reasonable experimental settings resulted. Graphical abstract A methodology is suggested to evaluate optimal reaction conditions for efficientacquisition of kinetic data. The experimental design space is limited by thestepwise determination of important time scales based on specified input data.

scholarly journals Coordinating the in vivo processes for minicircle production - a novel approach to large scale manufacturing

2018 ◽  
Author(s):  
Peter Mayrhofer ◽  
Hana Jug ◽  
Aleš Štrancar ◽  
Alexandre Di Paolo ◽  
Laurent Jost ◽  
...  
Keyword(s):  
High Performance ◽  
Large Scale ◽  
Process Development ◽  
Scale Up ◽  
Hydrophobic Interaction Chromatography ◽  
Viral Gene ◽  
Novel Approach ◽  
Dna Production ◽  
Minicircle Dna

ABSTRACTSafety as well as efficiency issues in connection with bacterial backbone sequences should be carefully considered when designing new DNA vaccines or non-viral gene therapy approaches. Bacterial backbone sequences like antibiotic resistance markers or regulatory bacterial elements constitute biological safety risks and reduce the overall efficiency of the DNA agent. To overcome these problems the minicircle technology has been developed. But, despite all the obvious advantages, minicircles have so far not replaced their problem laden conventional counterpart in gene transfer applications what can be contributed to efficiency issues in large scale manufacturing. In this article we describe the combined efforts of experts in the field of minicircle development, large scale biomanufacturing and downstream process development to provide a new approach. The Recombination Based Plasmid Separation (RBPS) Technology, which has already solved crucial problems associated with minicircle-DNA production, has been developed further for this purpose. A novel parental plasmid exploiting advanced in vivo process coordination for restriction and subsequent degradation of miniplasmid-DNA will be introduced. Furthermore we describe the scale-up of minicircle-DNA production by fermentation in combination with high performance downstream processes including purification by ion exchange and hydrophobic interaction chromatography on monolithic material.

Preparation and Characterization of PA6-PEG/Li High Performance Static Dissipation Composites

2017 ◽  
Vol 70 (6) ◽  
pp. 669
Author(s):  
Chongling Yang ◽  
Shouzai Tan ◽  
Gengen Chen ◽  
Litao Guan
Keyword(s):  
High Performance ◽  
Condensation Reaction ◽  
Polyamide 6 ◽  
Decomposition Temperature ◽  
Reaction Conditions ◽  
Comprehensive Properties ◽  
Ft Ir ◽  
Optimal Reaction ◽  
Resistivity Testing

A copolymer of PA6 (polyamide 6) and PEG (polyethylene glycol) was synthesized by a condensation reaction. The optimal reaction conditions were determined as the following: a reaction temperature of 255°C, –0.04 MPa vacuum, and a condensation time of 40 min. A series of novel PA6-PEG/Li composites were developed by melt blending the PA6-PEG copolymer (10 wt-% PEG) with three different kinds of colourless lithium salts (LiCl, C18H35LiO2, LiAc). FT-IR, NMR, thermogravimetric (TGA), electronic universal testing, and resistivity analyses were employed to investigate the comprehensive properties of the copolymers and composites. The results of FT-IR and 1H NMR analyses revealed that the PEG was copolymerized with PA6 successfully. TGA results indicated that the decomposition temperature of the PA6-PEG copolymer was above 350°C. Resistivity testing revealed that the surface resistivity (Rs) of the copolymer decreased from 1 × 1014 to 5.67 × 109 Ω square–1 with an increase of the content of PEG. The PA6-PEG/LiCl composite showed an excellent static dissipation performance of 2.71 × 108 Ω square–1.

scholarly journals The Synthesis of Mannose-6-Phosphate Using Polyphosphate-Dependent Mannose Kinase

Catalysts ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 250
Author(s):  
Wenlong Zhu ◽  
Miaomiao Gao ◽  
Biqiang Chen ◽  
Tianwei Tan ◽  
Hui Cao ◽  
...  
Keyword(s):  
Scale Up ◽  
Enzymatic Reaction ◽  
Synthesis Method ◽  
Cost Effective ◽  
Industrial Applications ◽  
Key Factors ◽  
Reaction Conditions ◽  
Mannose 6 Phosphate ◽  
Arthrobacter Species ◽  
Optimal Reaction

Mannose-6-phosphate (M6P) is involved in many metabolic pathways in life, and it has important applications in the treatment of diseases. This study explored a cost-effective enzyme catalytic synthesis method of M6P, using polyphosphate-dependent mannose kinase from Arthrobacter species. This synthesis uses polyphosphate to replace expensive ATP, and it is greener and safer than chemical synthesis. This study investigated the effects of key factors such as metal ions, temperature, and substrate addition on this enzymatic reaction, and improved the conversion efficiency. We moreover take advantage of the response surface method to explore the best catalytic conditions synthetically. The conversion was 99.17% successful under the optimal reaction conditions. After a series of optimizations, we carried out a 200 mL scale-up experiment, which proved that the method has good prospects for industrial applications.

scholarly journals Mathematical Model, Simulation and Scale up of Batch Reactor Used in Oxidative Desulfurization of Kerosene

2021 ◽  
Vol 22 (3) ◽  
pp. 11-17
Author(s):  
Ghazwan Ahmed ◽  
Jasim Humadi ◽  
Ahmad Aabid
Keyword(s):  
Mathematical Model ◽  
Kinetic Parameters ◽  
Batch Reactor ◽  
Scale Up ◽  
Oxidative Desulfurization ◽  
Reaction Conditions ◽  
Exponential Factor ◽  
Simulation And Optimization ◽  
The Mathematical Model ◽  
Optimal Reaction

In this paper, a mathematical model for the oxidative desulfurization of kerosene had been developed. The mathematical model and simulation process is a very important process due to it provides a better understanding of a real process. The mathematical model in this study was based on experimental results which were taken from literature to calculate the optimal kinetic parameters where simulation and optimization were conducted using gPROMS software. The optimal kinetic parameters were Activation energy 18.63958 kJ/mol, Pre-exponential factor 2201.34 (wt)-0.76636. min-1 and the reaction order 1.76636. These optimal kinetic parameters were used to find the optimal reaction conditions which used to obtain a high conversion (≥ 99%). These optimal reaction conditions were reaction temperature 379.4 oK and reaction time 160 min. A scale up to batch reactor was conducted using these optimal kinetic parameters and optimal reaction conditions and the results showed the best reactor size that can be used at a diameter of 1.2 m.

The Structure and Properties of MoSi2 Thin Film in Mos Process

1980 ◽  
Vol 38 ◽  
pp. 326-327
Author(s):  
C.K. Wu ◽  
P. Chang ◽  
N. Godinho
Keyword(s):  
Thin Film ◽  
Integrated Circuits ◽  
High Performance ◽  
Large Scale ◽  
Process Development ◽  
Structure And Properties ◽  
Metal Silicides ◽  
High Oxidation ◽  
Important Approach ◽  
High Oxidation Resistance

Recently, the use of refractory metal silicides as low resistivity, high temperature and high oxidation resistance gate materials in large scale integrated circuits (LSI) has become an important approach in advanced MOS process development (1). This research is a systematic study on the structure and properties of molybdenum silicide thin film and its applicability to high performance LSI fabrication.

Synthesis of Phosphonates via Michaelis-Arbuzov Reaction

2017 ◽  
Vol 14 (6) ◽  
pp. 883-903 ◽  
Author(s):  
Boppudi Hari Babu ◽  
Gandavaram Syam Prasad ◽  
Chamarthi Naga Raju ◽  
Mandava Venkata Basaveswara Rao
Keyword(s):  
Reaction Times ◽  
Biologically Active ◽  
Fine Tuning ◽  
Arbuzov Reaction ◽  
Reaction Conditions ◽  
Solvent Type ◽  
Potential Applications ◽  
Synthetic Methodologies ◽  
Optimal Reaction ◽  
The Arbuzov Reaction

Background: Michaelis–Arbuzov reaction has played a key role for the synthesis of dialkyl or diaryl phosphonates by reacting various alkyl or aryl halides with trialkyl or triaryl phosphite. This reaction is very versatile in the formation of P-C bond from the reaction of aliphatic halides with phosphinites or phosphites to yield phosphonates, phosphinates, phosphine oxides. The Arbuzov reaction developed some methodologies, possible mechanistic pathways, selectivity, potential applications and biologically active various phosphonates. Objective: The synthesis of phosphonates via Michaelis–Arbuzov reaction with many new and fascinating methodologies were developed and disclosed in the literature, and these are explored in this review. Conclusion: This review has discussed past developments and vast potential applications of Arbuzov reaction in the synthesis of organophosphonates. As presented in this review, various synthetic methodologies were developed to prepare a large variety of phosphonates. Improvements in the reaction conditions of Lewis-acid mediated Arbuzov rearrangement as well as the development of MW-assisted Arbuzov rearrangement were discussed. Finally, to achieve high selectivities and yields, fine-tuning of reaction conditions including solvent type, temperature, and optimal reaction times to be considered.

Determination of Impurities in Perampanel Bulk Drugs by High-Performance Liquid Chromatography and Gas Chromatography

2020 ◽  
Vol 16 ◽  
Author(s):  
Yun-Yan Xia ◽  
Qiao-Gen Zou ◽  
Yu-Fei Yang ◽  
Qian Sun ◽  
Cheng-Qun Han
Keyword(s):  
Gas Chromatography ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
High Performance ◽  
Quantitative Detection ◽  
Dihydrogen Phosphate ◽  
Phosphate Solution ◽  
Related Impurities ◽  
Bulk Drug

Background: High-performance liquid chromatography (HPLC) method has been used to detect related impurities of perampanel. However, the detection of impurities is incomplete, and the limits of quantification and detection are high. A sensitive, reliable method is in badly to be developed and applied for impurity detection of perampanel bulk drug. Objective: Methodologies utilising HPLC and gas chromatography (GC) were established and validated for quantitative determination of perampanel and its related impurities (a total of 10 impurities including 2 genotoxic impurities). Methods: The separation was achieved on a Dikma Diamonsil C18 column (250 mm × 4.6 mm, 5 μm) with the mobile phase of 0.01 mol/L potassium dihydrogen phosphate solution (A) and acetonitrile (B) in gradient elution mode. The compound 2-bromopropane was determined on an Agilent DB-624 column (0.32 mm × 30 m, 1.8 μm) by electron capture detector (μ-ECD) with split injection ratio of 1:5 and proper gradient temperature program. Result: Both HPLC and GC methods were established and validated to be sensitive, accurate and robust according to International Council for Harmonization (ICH) guidelines. The methods developed were linear in the selected concentration range (R 2≥0.9944). The average recovery of all impurities was between 92.6% and 103.3%. The possible production mechanism of impurities during the synthesis and degradation processes of perampanel bulk drug was also discussed. Five impurities were analyzed by liquid chromatography–mass spectrometry (LC-MS). Moreover, two of them were simultaneously characterized by LC-MS, IR and NMR. Conclusion: The HPLC and GC methods were developed and optimized, which could be applied for quantitative detection of the impurities, and further stability study of perampanel.

Amperometric assay of vitamin C using an ascorbate oxidase enzyme electrode

1979 ◽  
Vol 44 (11) ◽  
pp. 3395-3404 ◽  
Author(s):  
Pavel Posádka ◽  
Lumír Macholán
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
Oxygen Electrode ◽  
Ascorbate Oxidase ◽  
Current Response ◽  
Reaction Conditions ◽  
Long Term Storage ◽  
Oxidase Enzyme ◽  
Optimal Reaction

An oxygen electrode of the Clark type, coated by a thin, active layer of chemically insolubilized ascorbate oxidase from squash peelings specifically detects by measuring oxygen uptake 10 to 400 μg of ascorbic acid in 3 ml of phosphate buffer. The record of current response to substrate addition lasts 1-2 min. The ascorbic acid values determined in various samples of fruit juices are in good agreement with the data obtained by titration and polarography. The suitable composition of the membrane and its lifetime and stability during long-term storage are described; optimal reaction conditions of vitamin C determination and the possibilities of interference of other compounds are also examined. Of the 35 phenols, aromatic amines and acids tested chlorogenic acid only can cause a positive error provided that the enzyme membrane has been prepared from ascorbate oxidase of high purity.

scholarly journals A Novel Pseudomonas geniculata AGE Family Epimerase/Isomerase and Its Application in d-Mannose Synthesis

Foods ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1809
Author(s):  
Zhanzhi Liu ◽  
Ying Li ◽  
Jing Wu ◽  
Sheng Chen
Keyword(s):  
3D Structure ◽  
Three Dimensional ◽  
Optimal Temperature ◽  
Reaction Conditions ◽  
Enzymatic Production ◽  
Physiological Properties ◽  
Potential Applications ◽  
Kinetics Of ◽  
Optimal Reaction ◽  
Gene Age

d-mannose has exhibited excellent physiological properties in the food, pharmaceutical, and feed industries. Therefore, emerging attention has been applied to enzymatic production of d-mannose due to its advantage over chemical synthesis. The gene age of N-acetyl-d-glucosamine 2-epimerase family epimerase/isomerase (AGEase) derived from Pseudomonas geniculata was amplified, and the recombinant P. geniculata AGEase was characterized. The optimal temperature and pH of P. geniculata AGEase were 60 °C and 7.5, respectively. The Km, kcat, and kcat/Km of P. geniculata AGEase for d-mannose were 49.2 ± 8.5 mM, 476.3 ± 4.0 s−1, and 9.7 ± 0.5 s−1·mM−1, respectively. The recombinant P. geniculata AGEase was classified into the YihS enzyme subfamily in the AGE enzyme family by analyzing its substrate specificity and active center of the three-dimensional (3D) structure. Further studies on the kinetics of different substrates showed that the P. geniculata AGEase belongs to the d-mannose isomerase of the YihS enzyme. The P. geniculata AGEase catalyzed the synthesis of d-mannose with d-fructose as a substrate, and the conversion rate was as high as 39.3% with the d-mannose yield of 78.6 g·L−1 under optimal reaction conditions of 200 g·L−1d-fructose and 2.5 U·mL−1P. geniculata AGEase. This novel P. geniculata AGEase has potential applications in the industrial production of d-mannose.

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