Dom Hebrault presented on using real time in situ FTIR analytics to enhance development and control of continuous processes. He discussed three case studies: [1] rapidly optimizing a Doebner modification reaction using inline FTIR to monitor concentrations in real time; [2] safely monitoring a hazardous indazole synthesis using hydrazine in flow; and [3] improving product quality of a Grignard reaction for drug synthesis from 40% to 1% impurity using inline FTIR process control. The case studies demonstrated how inline FTIR can provide major benefits for continuous flow reaction optimization, monitoring hazardous substances, and process quality control.
This document discusses using in-line IR spectroscopy to analyze reactions in continuous flow systems. It describes challenges in analyzing continuous reactions and how ReactIR can provide real-time monitoring without sampling. Case studies are presented where ReactIR was used to optimize a Doebner modification reaction in a few hours, monitor a hazardous reaction involving hydrazine for safety, and troubleshoot a multi-step synthesis. ReactIR allows rapid screening and optimization of reaction conditions as well as safer handling of dangerous chemicals through continuous monitoring.
Application Note: Gross Alpha Measurements in Aqueous Samples Using Extractio...PerkinElmer, Inc.
A new approach to the measurement of gross alphas in liquid samples, which combines Eichrom's extraction technology with PerkinElmer's liquid scintillation analysis technology, is presented. Difficulties with sample preparation and detection efficiency have always been problematic with the traditional method of gas flow proportional counting (GPC). The use of Eichrom's extraction resins and alpha liquid scintillation counting (LCS) has resolved the sample preparation problems, associated with drying the sample on a planchet. With its superior detection efficiency over GPC, this combination provides a better counting platform. Thus, many of the inherent limitations associated with the traditional GPC method are overcome by using this new approach and results demonstrate faster sample preparation, lower detection limits and shorter counting times.
This document discusses the use of in situ FTIR spectroscopy for monitoring organic synthesis reactions in real time. It describes how ReactIR, a flow cell accessory, allows for non-destructive analysis of reactions under normal operating conditions. This enables continuous monitoring of reaction kinetics, pathways and intermediates. The document presents examples of using the real-time spectral data from ReactIR to control reaction parameters and optimize multi-step continuous flow processes. Specifically, it shows how reactant addition can be automatically controlled based on measured intermediate concentrations to improve efficiency and reduce waste. Overall, the document illustrates how in situ FTIR spectroscopy is enhancing the development, analysis and control of continuous chemical synthesis.
This document is an air quality analysis certificate for a sample taken from a compressor owned by I-Dive Tec Rec Centres PLC. The sample passed specifications for breathing air. Key findings include:
- The sample was taken on 10/16/2012 and analyzed on 10/29/2012.
- Results showed the sample met specifications for oxygen, nitrogen, carbon monoxide, carbon dioxide, total hydrocarbons and oil/particulate levels.
- The certificate is valid until the next semi-annual sample is due on 4/16/2013.
This document discusses using in-line infrared (IR) spectroscopy to monitor and control multi-step continuous flow chemical reactions. It describes how ReactIR in-situ IR spectroscopy can provide real-time analysis of reaction kinetics and intermediates. The document also shows how ReactIR data can be used to automatically control the addition of a third reagent stream in stoichiometric amounts, improving reaction efficiency and product purity compared to manual control. ReactIR can be applied to microscale, mesoscale, and kilolab flow reactors.
Scale-up Systems India Mettler RC1 Sanket SalgaonkarScale-up Systems
This document discusses the use of DynoChem software for modeling chemical processes. DynoChem can be used to develop process models based on experimental data from sources like reaction calorimeters. It allows modeling heat flows and predicting temperature profiles. This helps understand the process and enables process safety evaluations through what-if scenario analysis, like investigating the impact of loss of cooling capacity. DynoChem facilitates scale-up and process optimization by predicting large scale process performance based on the developed models.
This document describes a new method for extracting trace amounts of mercury from natural waters using silver and gold nanoparticles impregnated in nylon membrane filters. Water samples are treated to convert all mercury species to Hg2+ and then reduced to elemental Hg0. The mercury is then collected on the nanoparticle-coated membrane filters during filtration. Mercury levels are then determined by thermal desorption from the filters using a mercury analyzer. This new method achieves a lower limit of detection of 0.04 ng compared to the traditional cold vapor generation method, and avoids additional sample treatment and contamination risks. Mercury was also found to be stable on the filters for at least 5 months without loss.
Investigation into the design and application of solid core stationary phases has led to a better understanding of how the phases work and has resulted in their design aligned to the structure of the analytes being separated. The current range of columns available is discussed both in terms of selectivities, and also morphologies, allowing informed decisions to be made by the chromatographer. Using real life examples, coupled with advanced modeling, the effects of the particle size and morphology will be given for both small and large molecules, offering an insight into what the future holds for solid core products.
This document discusses using in-line IR spectroscopy to analyze reactions in continuous flow systems. It describes challenges in analyzing continuous reactions and how ReactIR can provide real-time monitoring without sampling. Case studies are presented where ReactIR was used to optimize a Doebner modification reaction in a few hours, monitor a hazardous reaction involving hydrazine for safety, and troubleshoot a multi-step synthesis. ReactIR allows rapid screening and optimization of reaction conditions as well as safer handling of dangerous chemicals through continuous monitoring.
Application Note: Gross Alpha Measurements in Aqueous Samples Using Extractio...PerkinElmer, Inc.
A new approach to the measurement of gross alphas in liquid samples, which combines Eichrom's extraction technology with PerkinElmer's liquid scintillation analysis technology, is presented. Difficulties with sample preparation and detection efficiency have always been problematic with the traditional method of gas flow proportional counting (GPC). The use of Eichrom's extraction resins and alpha liquid scintillation counting (LCS) has resolved the sample preparation problems, associated with drying the sample on a planchet. With its superior detection efficiency over GPC, this combination provides a better counting platform. Thus, many of the inherent limitations associated with the traditional GPC method are overcome by using this new approach and results demonstrate faster sample preparation, lower detection limits and shorter counting times.
This document discusses the use of in situ FTIR spectroscopy for monitoring organic synthesis reactions in real time. It describes how ReactIR, a flow cell accessory, allows for non-destructive analysis of reactions under normal operating conditions. This enables continuous monitoring of reaction kinetics, pathways and intermediates. The document presents examples of using the real-time spectral data from ReactIR to control reaction parameters and optimize multi-step continuous flow processes. Specifically, it shows how reactant addition can be automatically controlled based on measured intermediate concentrations to improve efficiency and reduce waste. Overall, the document illustrates how in situ FTIR spectroscopy is enhancing the development, analysis and control of continuous chemical synthesis.
This document is an air quality analysis certificate for a sample taken from a compressor owned by I-Dive Tec Rec Centres PLC. The sample passed specifications for breathing air. Key findings include:
- The sample was taken on 10/16/2012 and analyzed on 10/29/2012.
- Results showed the sample met specifications for oxygen, nitrogen, carbon monoxide, carbon dioxide, total hydrocarbons and oil/particulate levels.
- The certificate is valid until the next semi-annual sample is due on 4/16/2013.
This document discusses using in-line infrared (IR) spectroscopy to monitor and control multi-step continuous flow chemical reactions. It describes how ReactIR in-situ IR spectroscopy can provide real-time analysis of reaction kinetics and intermediates. The document also shows how ReactIR data can be used to automatically control the addition of a third reagent stream in stoichiometric amounts, improving reaction efficiency and product purity compared to manual control. ReactIR can be applied to microscale, mesoscale, and kilolab flow reactors.
Scale-up Systems India Mettler RC1 Sanket SalgaonkarScale-up Systems
This document discusses the use of DynoChem software for modeling chemical processes. DynoChem can be used to develop process models based on experimental data from sources like reaction calorimeters. It allows modeling heat flows and predicting temperature profiles. This helps understand the process and enables process safety evaluations through what-if scenario analysis, like investigating the impact of loss of cooling capacity. DynoChem facilitates scale-up and process optimization by predicting large scale process performance based on the developed models.
This document describes a new method for extracting trace amounts of mercury from natural waters using silver and gold nanoparticles impregnated in nylon membrane filters. Water samples are treated to convert all mercury species to Hg2+ and then reduced to elemental Hg0. The mercury is then collected on the nanoparticle-coated membrane filters during filtration. Mercury levels are then determined by thermal desorption from the filters using a mercury analyzer. This new method achieves a lower limit of detection of 0.04 ng compared to the traditional cold vapor generation method, and avoids additional sample treatment and contamination risks. Mercury was also found to be stable on the filters for at least 5 months without loss.
Investigation into the design and application of solid core stationary phases has led to a better understanding of how the phases work and has resulted in their design aligned to the structure of the analytes being separated. The current range of columns available is discussed both in terms of selectivities, and also morphologies, allowing informed decisions to be made by the chromatographer. Using real life examples, coupled with advanced modeling, the effects of the particle size and morphology will be given for both small and large molecules, offering an insight into what the future holds for solid core products.
Dr. Reddy's Development of Kinetic Model and Process Prediction. Keerthi Pemula.Scale-up Systems
This document discusses two case studies using kinetic modeling and DynoChem software to improve pharmaceutical synthesis processes. In the first case, three mechanisms were evaluated to predict an anti-bacterial reaction and reduce impurities. Mechanism 3 best fit the data and parameters from it improved yield. The second case developed a kinetic model for an API synthesis to minimize impurities and maximize yield through simulation and optimization. Process changes based on the mechanisms reduced reaction time and improved purity and yield. Overall, kinetic modeling with DynoChem helped analyze reaction mechanisms and improve two industrial synthesis processes.
Enzyme Based Analytical Chemistry - Nitrate and the U.S. EPAAnna-Marie Davidson
This document discusses the use of nitrate reductase enzymes for analytical chemistry applications such as nitrate analysis. It provides background on how enzymes work and their advantages for analysis, including selectivity, sensitivity, specificity, and safety. It then focuses on the production and use of nitrate reductase enzymes, including their validation for nitrate testing according to EPA standards. The document promotes the use of these enzymes as a non-toxic alternative to cadmium-based methods for nitrate analysis in areas like water quality monitoring.
21st International Conference Organic Process Research & Development 2010 San...dominev
This document discusses using real-time calorimetry to improve operational efficiency. It presents case studies where ReactIR, FBRM, PVM and RTCal were used:
1) ReactIR developed kinetic models to minimize byproducts in pharmaceutical reactions and improve crystallization processes.
2) FBRM and PVM helped optimize a crystallization to reduce impurities below 0.5%.
3) RTCal validated switching to a low copper acrylamide grade for polymerization, showing a shorter induction period but similar maximum heat output. Real-time calorimetry provided process safety evaluation.
A Combined Ozone Remedy for a Mixed VOC DNAPL Source ZoneChapman Ross, P.E.
Background/Objectives. In 2003, 1,300 drums and over 3,000 tons of soil were excavated from a drum disposal area in New England. Residual DNAPL created a 2,500 foot long plume that includes chlorobenzenes, toluene, and chlorinated ethenes. The plume discharges to a wetland and has led to vapor intrusion concerns at downgradient properties. Full-scale source zone remediation has been implemented to mitigate potential risks to ecological and human receptors.
Approach/Activities. Following extensive site characterization, bench-scale testing, and a successful field pilot test, the full-scale source zone remedy began in November 2010. The combined remedy approach uses physical, chemical, and biological treatment mechanisms to destroy the residual DNAPL in the vadose and saturated zones. Soil vapor extraction (SVE) and air sparging target the more volatile compounds, while in situ ozone injection (IOI) targets the less volatile compounds such as chlorobenzenes. Aerobic biological activity is also likely enhanced as a result of oxygen injection from IOI and air sparging. Three ozone injection systems deliver a total of 100 lbs of ozone per day to the subsurface; the SVE system extracts soil vapor at a rate of 650 scfm; the air sparge system continuously sparges air at 50 scfm at approximately 30 psi.
Results/Lessons Learned. Performance monitoring includes analysis of VOC concentrations in soil, soil gas, and groundwater. Quarterly low-flow groundwater sampling has shown substantial decreases in groundwater VOC concentrations relative to baseline. In the first six months of operation, 18 of the 20 monitoring wells sampled showed decreases in total VOC concentrations ranging from 14 to 97% with an average decrease of 57%. Furthermore, the mass discharge of total VOCs in groundwater from the source area has decreased from approximately 105 g/day before pilot-test start-up to less than 4 g/day. Concentrations of VOCs in soil gas are monitored in real-time by an automated soil gas monitoring system equipped with a photoionization detector (PID), and on a periodic basis with Waterloo Membrane Samplers™ that provide a speciated analysis of VOCs in soil gas. Of the 47 soil gas monitoring points that were sampled during the first six months of operation, 36 show decreasing trends in soil gas TVOC concentrations. Minimal rebound was observed in soil gas concentrations after treatment was temporarily suspended. Performance monitoring data have informed periodic system optimization to increase the efficiency of the remedy. These results indicate that the combined remedial technologies are effectively reducing source mass and mass discharge, and that the aggressive two year remedial time-frame will likely be met.
CPEG-40 and PVP-40 silver nanoparticles were found to be the most stable based on characterization of size, zeta potential, and UV-Vis absorption over 8 months of aging. 2CPEG-5 silver nanoparticles also showed good stability. These stabilized nanoparticles exhibited over 90% viability when tested on MCF-7 and HEP-2 cell lines. Zinc oxide nanoparticles were assembled using Heliotropium crispum plant extract and characterized as near spherical particles with organic capping. These particles showed good biocompatibility on Huh7 cells. The zinc oxide nanoparticles were used to fabricate an electrochemical sensor with carbon dots for hydrogen peroxide detection, exhibiting a low detection limit of 2.4 nM
Use of DynoChem in Process Development. Wilfried Hoffmann.Scale-up Systems
1) Process modeling allows prediction of interactions between chemical and physical rates as a function of scale and equipment to enable safe and cost-effective scale-up from lab to production.
2) A case study reaction is used to demonstrate how kinetic data, heat of reaction, and process safety data can be combined in a model to optimize temperature profiles and process conditions at different scales.
3) Process safety is considered by simulating what would happen in case of cooling failure, and including a thermal risk metric in the optimization to safely transfer the process across scales.
In the pharmaceutical arena there is great interest in solid core technology, where there is a broad range of sample types as well as requirements throughout the process of developing new chemical entities. The presentation looks at how solid core technology can be readily adapted to cope with the challenges associated with the pharmaceutical sector, looking at various sample matrices and molecular entities, from small molecules to large biomolecules. The presentation gives an insight into how varying the solid core to porous layer allows the user to optimize separation performance by reducing extra band broadening. Data presented demonstrates how this technology is more robust than fully porous systems when analyzing biological extracts, routinely used in DMPK departments, resulting in longer column lifetimes.
This document describes several mass spectrometry products from Thermo Scientific, including several triple quadrupole and Orbitrap models. It provides specifications for each model such as mass range, resolution, scan speed, and fragmentation capabilities. Application areas are also listed for several of the products, such as proteomics, metabolomics, and food safety. Key features are highlighted for technologies like segmented quadrupoles, collision cells, and ion optics that enhance performance.
NYSAS Seminar LC-IR To Characterize Polymeric Excipients In Pharmaceutical F...mzhou45
This document describes an LC-IR technique for characterizing polymeric excipients in pharmaceutical formulations. The LC-IR system combines liquid chromatography separation with online infrared spectroscopy detection. It is used to characterize copolymer compositions, detect excipient degradation from hot melt extrusion processes, and study the stability of excipients like PEG. The LC-IR technique provides compositional information and identifies degradation products with molecular weight distributions. This allows understanding of excipient properties, degradation mechanisms, and process effects to ensure quality and stability of pharmaceutical formulations.
The Dependence of Indoor PAH Concentrations on Outdoor PAHs and Traffic Volum...REY DECASTRO
The document presents the results of a study on indoor PAH concentrations and their relationship to outdoor PAH levels and traffic volume. Key findings include:
1) Indoor PAH levels depend on both traffic volume and outdoor PAH concentrations.
2) Outdoor PAH levels depend on traffic volume.
3) Season was the strongest predictor of indoor and outdoor PAH levels, with higher levels observed in spring and summer.
Global BioSciences sells sustainable remediation technologies through business partners. Their Butane Biostimulation technology uses butane gas to stimulate microbial growth and degradation of contaminants like chlorinated solvents, petroleum hydrocarbons, and MTBE in soil and groundwater. It is a low-cost solution that is easy to implement and has treated contamination at numerous pilot and full-scale sites internationally.
Tsvaygboym, J Phys Chem C 2008 v112 pp 695-700nanotech2masses
This document summarizes research on the reaction of single-walled carbon nanotubes (SWNTs) with organic peroxides. The main findings are:
1) SWNTs induce the decomposition of benzoyl peroxide, p-methoxybenzoyl peroxide, phthaloyl peroxide, and trifluoroacetyl peroxide through single electron transfer, accelerating their decomposition rates.
2) Phthaloyl peroxide showed the greatest functionalization of SWNTs of the four peroxides tested.
3) t-Butoxy radicals were found to add to SWNTs, but SWNTs did not inhibit the autoxidation of cumene by alkylper
1) The document discusses using viscosifying surfactants for enhanced oil recovery (EOR). It introduces surfactant mesophases and how their rheological properties can increase fluid viscosity.
2) Rhodia and Poweltec's methodology for developing and testing viscosifying surfactant formulations is described. This includes measuring viscosity under reservoir conditions, fluid propagation tests in porous media, and core flood tests to evaluate oil recovery.
3) An example application to a field case demonstrates good thermal stability of a surfactant formulation and its ability to further increase oil recovery compared to polymer flooding alone.
Determination of Carbohydrates in Various Matrices by Capillary High-Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection (HPAE-PAD)
This presentation describes the combined advantages of a reagent-free capillary format Ion Chromatography (IC) to determine monosaccharides and disaccharides in various applications, from low concentrations in synthetic urine samples to high concentrations in beverage samples. In a reagent-free IC system, the hydroxide eluent is electrolytically generated inline to deliver accurate and precise concentrations for isocratic or gradient separations by only adding deionized water. Eluent generation eliminates carbonate contamination and errors from manual preparation. A capillary scale system with µL/min flow rates can run 24/7, always on and always ready for samples.
The document summarizes research comparing the disinfection of wastewater using peracetic acid (PAA) and sodium hypochlorite. It discusses two case studies - jar testing of PAA and sodium hypochlorite at a wastewater facility in Cincinnati, and a study comparing the two disinfectants at a combined sewer overflow facility in Steubenville, Ohio. The research found that PAA was generally as effective as sodium hypochlorite at inactivating bacteria, but required a higher dose. PAA also produced fewer harmful byproducts and had lower aquatic toxicity than sodium hypochlorite. An ongoing study is evaluating the two disinfectants further at a CSO facility in
The document proposes starting a new M.Tech program in Biochemical Engineering at the National Institute of Technology, Tiruchirappalli. It justifies the need for the program by explaining how biochemical engineering contributes to important economic activities in India and is an emerging field with good job demand. The proposal requests approval and additional staff/faculty from the Ministry of Human Resource Development. It includes tables outlining the proposed course details, equipment requirements, and equipment costing over Rs. 5 lakhs needed to establish laboratories for the new program.
Using THGA and Zeeman Background Correction for Blood-Lead Determination in C...PerkinElmer, Inc.
Validated applications determining whole blood levels are generally performed using graphite furnace atomic absorption spectroscopy (GFAAS). GFAAS is cost effective, allows for detection limits well under the blood-lead level action guideline, and requires less operator training than more advanced elemental techniques.2 In this study, we will demonstrate the applicability of the PerkinElmer® PinAAcle™ 900T atomic absorption spectrometer (Figure 1) using the stabilized temperature platform furnace (STPF) and transversely-heated graphite atomizer (THGA), for use in customer-validated applications to determine lead amounts in blood samples.
Learn more about our solutions: http://bit.ly/IG2kI1
Method for HCL Monitoring by FTIR Analysisjimbelanger33
This document describes an analytical method for determining HCl concentration in gases using Fourier transform infrared spectroscopy (FTIR). It involves calibrating the FTIR using certified gas standards and then applying the calibration model to analyze sample gases. Key aspects discussed include using classical least squares to predict concentrations, selecting appropriate analysis regions, accounting for spectral interferences like water, and requirements for the sampling system such as heated lines and filtering. The method is intended for continuous emission monitoring applications like those required at Portland cement plants under EPA regulations.
Crystallization process improvement driven by dynochem process modeling. Flav...Scale-up Systems
The original continuous crystallization process used anti-solvent crystallization with heptanes and IPAc to crystallize an API. This led to varying composition, supersaturation and volumes, producing small primary particles prone to agglomeration. The process had long cycle times, low throughput and yielded primarily agglomerated particles. Dynochem modelling was used to improve the process by controlling crystallization parameters.
The purpose of this webinar is to highlight GSK's approach to:
- create a simple, mechanistically descriptive model
- verify its utility with clarity of objectives, and
- communicate understanding via creative but aligned metrics
... for a challenging chemical reaction.
Dr. Reddy's Development of Kinetic Model and Process Prediction. Keerthi Pemula.Scale-up Systems
This document discusses two case studies using kinetic modeling and DynoChem software to improve pharmaceutical synthesis processes. In the first case, three mechanisms were evaluated to predict an anti-bacterial reaction and reduce impurities. Mechanism 3 best fit the data and parameters from it improved yield. The second case developed a kinetic model for an API synthesis to minimize impurities and maximize yield through simulation and optimization. Process changes based on the mechanisms reduced reaction time and improved purity and yield. Overall, kinetic modeling with DynoChem helped analyze reaction mechanisms and improve two industrial synthesis processes.
Enzyme Based Analytical Chemistry - Nitrate and the U.S. EPAAnna-Marie Davidson
This document discusses the use of nitrate reductase enzymes for analytical chemistry applications such as nitrate analysis. It provides background on how enzymes work and their advantages for analysis, including selectivity, sensitivity, specificity, and safety. It then focuses on the production and use of nitrate reductase enzymes, including their validation for nitrate testing according to EPA standards. The document promotes the use of these enzymes as a non-toxic alternative to cadmium-based methods for nitrate analysis in areas like water quality monitoring.
21st International Conference Organic Process Research & Development 2010 San...dominev
This document discusses using real-time calorimetry to improve operational efficiency. It presents case studies where ReactIR, FBRM, PVM and RTCal were used:
1) ReactIR developed kinetic models to minimize byproducts in pharmaceutical reactions and improve crystallization processes.
2) FBRM and PVM helped optimize a crystallization to reduce impurities below 0.5%.
3) RTCal validated switching to a low copper acrylamide grade for polymerization, showing a shorter induction period but similar maximum heat output. Real-time calorimetry provided process safety evaluation.
A Combined Ozone Remedy for a Mixed VOC DNAPL Source ZoneChapman Ross, P.E.
Background/Objectives. In 2003, 1,300 drums and over 3,000 tons of soil were excavated from a drum disposal area in New England. Residual DNAPL created a 2,500 foot long plume that includes chlorobenzenes, toluene, and chlorinated ethenes. The plume discharges to a wetland and has led to vapor intrusion concerns at downgradient properties. Full-scale source zone remediation has been implemented to mitigate potential risks to ecological and human receptors.
Approach/Activities. Following extensive site characterization, bench-scale testing, and a successful field pilot test, the full-scale source zone remedy began in November 2010. The combined remedy approach uses physical, chemical, and biological treatment mechanisms to destroy the residual DNAPL in the vadose and saturated zones. Soil vapor extraction (SVE) and air sparging target the more volatile compounds, while in situ ozone injection (IOI) targets the less volatile compounds such as chlorobenzenes. Aerobic biological activity is also likely enhanced as a result of oxygen injection from IOI and air sparging. Three ozone injection systems deliver a total of 100 lbs of ozone per day to the subsurface; the SVE system extracts soil vapor at a rate of 650 scfm; the air sparge system continuously sparges air at 50 scfm at approximately 30 psi.
Results/Lessons Learned. Performance monitoring includes analysis of VOC concentrations in soil, soil gas, and groundwater. Quarterly low-flow groundwater sampling has shown substantial decreases in groundwater VOC concentrations relative to baseline. In the first six months of operation, 18 of the 20 monitoring wells sampled showed decreases in total VOC concentrations ranging from 14 to 97% with an average decrease of 57%. Furthermore, the mass discharge of total VOCs in groundwater from the source area has decreased from approximately 105 g/day before pilot-test start-up to less than 4 g/day. Concentrations of VOCs in soil gas are monitored in real-time by an automated soil gas monitoring system equipped with a photoionization detector (PID), and on a periodic basis with Waterloo Membrane Samplers™ that provide a speciated analysis of VOCs in soil gas. Of the 47 soil gas monitoring points that were sampled during the first six months of operation, 36 show decreasing trends in soil gas TVOC concentrations. Minimal rebound was observed in soil gas concentrations after treatment was temporarily suspended. Performance monitoring data have informed periodic system optimization to increase the efficiency of the remedy. These results indicate that the combined remedial technologies are effectively reducing source mass and mass discharge, and that the aggressive two year remedial time-frame will likely be met.
CPEG-40 and PVP-40 silver nanoparticles were found to be the most stable based on characterization of size, zeta potential, and UV-Vis absorption over 8 months of aging. 2CPEG-5 silver nanoparticles also showed good stability. These stabilized nanoparticles exhibited over 90% viability when tested on MCF-7 and HEP-2 cell lines. Zinc oxide nanoparticles were assembled using Heliotropium crispum plant extract and characterized as near spherical particles with organic capping. These particles showed good biocompatibility on Huh7 cells. The zinc oxide nanoparticles were used to fabricate an electrochemical sensor with carbon dots for hydrogen peroxide detection, exhibiting a low detection limit of 2.4 nM
Use of DynoChem in Process Development. Wilfried Hoffmann.Scale-up Systems
1) Process modeling allows prediction of interactions between chemical and physical rates as a function of scale and equipment to enable safe and cost-effective scale-up from lab to production.
2) A case study reaction is used to demonstrate how kinetic data, heat of reaction, and process safety data can be combined in a model to optimize temperature profiles and process conditions at different scales.
3) Process safety is considered by simulating what would happen in case of cooling failure, and including a thermal risk metric in the optimization to safely transfer the process across scales.
In the pharmaceutical arena there is great interest in solid core technology, where there is a broad range of sample types as well as requirements throughout the process of developing new chemical entities. The presentation looks at how solid core technology can be readily adapted to cope with the challenges associated with the pharmaceutical sector, looking at various sample matrices and molecular entities, from small molecules to large biomolecules. The presentation gives an insight into how varying the solid core to porous layer allows the user to optimize separation performance by reducing extra band broadening. Data presented demonstrates how this technology is more robust than fully porous systems when analyzing biological extracts, routinely used in DMPK departments, resulting in longer column lifetimes.
This document describes several mass spectrometry products from Thermo Scientific, including several triple quadrupole and Orbitrap models. It provides specifications for each model such as mass range, resolution, scan speed, and fragmentation capabilities. Application areas are also listed for several of the products, such as proteomics, metabolomics, and food safety. Key features are highlighted for technologies like segmented quadrupoles, collision cells, and ion optics that enhance performance.
NYSAS Seminar LC-IR To Characterize Polymeric Excipients In Pharmaceutical F...mzhou45
This document describes an LC-IR technique for characterizing polymeric excipients in pharmaceutical formulations. The LC-IR system combines liquid chromatography separation with online infrared spectroscopy detection. It is used to characterize copolymer compositions, detect excipient degradation from hot melt extrusion processes, and study the stability of excipients like PEG. The LC-IR technique provides compositional information and identifies degradation products with molecular weight distributions. This allows understanding of excipient properties, degradation mechanisms, and process effects to ensure quality and stability of pharmaceutical formulations.
The Dependence of Indoor PAH Concentrations on Outdoor PAHs and Traffic Volum...REY DECASTRO
The document presents the results of a study on indoor PAH concentrations and their relationship to outdoor PAH levels and traffic volume. Key findings include:
1) Indoor PAH levels depend on both traffic volume and outdoor PAH concentrations.
2) Outdoor PAH levels depend on traffic volume.
3) Season was the strongest predictor of indoor and outdoor PAH levels, with higher levels observed in spring and summer.
Global BioSciences sells sustainable remediation technologies through business partners. Their Butane Biostimulation technology uses butane gas to stimulate microbial growth and degradation of contaminants like chlorinated solvents, petroleum hydrocarbons, and MTBE in soil and groundwater. It is a low-cost solution that is easy to implement and has treated contamination at numerous pilot and full-scale sites internationally.
Tsvaygboym, J Phys Chem C 2008 v112 pp 695-700nanotech2masses
This document summarizes research on the reaction of single-walled carbon nanotubes (SWNTs) with organic peroxides. The main findings are:
1) SWNTs induce the decomposition of benzoyl peroxide, p-methoxybenzoyl peroxide, phthaloyl peroxide, and trifluoroacetyl peroxide through single electron transfer, accelerating their decomposition rates.
2) Phthaloyl peroxide showed the greatest functionalization of SWNTs of the four peroxides tested.
3) t-Butoxy radicals were found to add to SWNTs, but SWNTs did not inhibit the autoxidation of cumene by alkylper
1) The document discusses using viscosifying surfactants for enhanced oil recovery (EOR). It introduces surfactant mesophases and how their rheological properties can increase fluid viscosity.
2) Rhodia and Poweltec's methodology for developing and testing viscosifying surfactant formulations is described. This includes measuring viscosity under reservoir conditions, fluid propagation tests in porous media, and core flood tests to evaluate oil recovery.
3) An example application to a field case demonstrates good thermal stability of a surfactant formulation and its ability to further increase oil recovery compared to polymer flooding alone.
Determination of Carbohydrates in Various Matrices by Capillary High-Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection (HPAE-PAD)
This presentation describes the combined advantages of a reagent-free capillary format Ion Chromatography (IC) to determine monosaccharides and disaccharides in various applications, from low concentrations in synthetic urine samples to high concentrations in beverage samples. In a reagent-free IC system, the hydroxide eluent is electrolytically generated inline to deliver accurate and precise concentrations for isocratic or gradient separations by only adding deionized water. Eluent generation eliminates carbonate contamination and errors from manual preparation. A capillary scale system with µL/min flow rates can run 24/7, always on and always ready for samples.
The document summarizes research comparing the disinfection of wastewater using peracetic acid (PAA) and sodium hypochlorite. It discusses two case studies - jar testing of PAA and sodium hypochlorite at a wastewater facility in Cincinnati, and a study comparing the two disinfectants at a combined sewer overflow facility in Steubenville, Ohio. The research found that PAA was generally as effective as sodium hypochlorite at inactivating bacteria, but required a higher dose. PAA also produced fewer harmful byproducts and had lower aquatic toxicity than sodium hypochlorite. An ongoing study is evaluating the two disinfectants further at a CSO facility in
The document proposes starting a new M.Tech program in Biochemical Engineering at the National Institute of Technology, Tiruchirappalli. It justifies the need for the program by explaining how biochemical engineering contributes to important economic activities in India and is an emerging field with good job demand. The proposal requests approval and additional staff/faculty from the Ministry of Human Resource Development. It includes tables outlining the proposed course details, equipment requirements, and equipment costing over Rs. 5 lakhs needed to establish laboratories for the new program.
Using THGA and Zeeman Background Correction for Blood-Lead Determination in C...PerkinElmer, Inc.
Validated applications determining whole blood levels are generally performed using graphite furnace atomic absorption spectroscopy (GFAAS). GFAAS is cost effective, allows for detection limits well under the blood-lead level action guideline, and requires less operator training than more advanced elemental techniques.2 In this study, we will demonstrate the applicability of the PerkinElmer® PinAAcle™ 900T atomic absorption spectrometer (Figure 1) using the stabilized temperature platform furnace (STPF) and transversely-heated graphite atomizer (THGA), for use in customer-validated applications to determine lead amounts in blood samples.
Learn more about our solutions: http://bit.ly/IG2kI1
Method for HCL Monitoring by FTIR Analysisjimbelanger33
This document describes an analytical method for determining HCl concentration in gases using Fourier transform infrared spectroscopy (FTIR). It involves calibrating the FTIR using certified gas standards and then applying the calibration model to analyze sample gases. Key aspects discussed include using classical least squares to predict concentrations, selecting appropriate analysis regions, accounting for spectral interferences like water, and requirements for the sampling system such as heated lines and filtering. The method is intended for continuous emission monitoring applications like those required at Portland cement plants under EPA regulations.
Crystallization process improvement driven by dynochem process modeling. Flav...Scale-up Systems
The original continuous crystallization process used anti-solvent crystallization with heptanes and IPAc to crystallize an API. This led to varying composition, supersaturation and volumes, producing small primary particles prone to agglomeration. The process had long cycle times, low throughput and yielded primarily agglomerated particles. Dynochem modelling was used to improve the process by controlling crystallization parameters.
The purpose of this webinar is to highlight GSK's approach to:
- create a simple, mechanistically descriptive model
- verify its utility with clarity of objectives, and
- communicate understanding via creative but aligned metrics
... for a challenging chemical reaction.
Scale-up of Safety Data using Dynochem. Tom Vickery.Scale-up Systems
This document summarizes two case studies where Dynochem, a process modeling and simulation tool, was used to analyze experimental safety data and scale-up risks. In the first case, Dynochem was used to model the temperature-dependent decomposition of an unstable cryogenic reaction. The tool fitted the experimental heat flow data and allowed modeling of different reaction scenarios. In the second case, Dynochem fitted gas generation data from a reaction and allowed simulation of varying heat rates to understand their effect on runaway risks. The tool provided a consistent model for safety scale-up evaluations in both cases.
Using Dynochem to determine a suitable sampling endpoint in a DoE. David Place.Scale-up Systems
The document discusses using Dynochem software to determine suitable sampling endpoints for design of experiments (DOEs) investigating chemical reactions. It provides a case study of a Finkelstein alkylation reaction where an impurity forms. Dynochem is used to fit rate constants and activation energies to the reaction mechanism. This allows simulating different experimental conditions to identify suitable reaction times that control impurity formation before committing resources to a DOE. The kinetic model can then refine the factor ranges investigated in the DOE to efficiently establish critical process parameters.
AiChE National Meeting 2012 Pittsburgh Presentation Flow Continuousdominev
1) In-situ FTIR spectroscopy using a ReactIR flow cell allows for real-time monitoring and analysis of continuous chemical reactions without interrupting flow.
2) Case studies demonstrated its use in optimizing a continuous ozonolysis reaction for safer API production, achieving a 2.7kg yield in 4 days.
3) Rapid screening and optimization of a Doebner modification reaction was also demonstrated, identifying optimal conditions within hours using on-the-fly variation of temperature and residence time analyzed via the in-situ FTIR.
Applications in Kilo Lab Flow Chemistry and Scale-up. Edel Hughes.Scale-up Systems
This presentation discusses Pfizer's Kilo Technology Lab (KTL) facility and its use of DynoChem software. The KTL uses modular equipment to develop and scale up processes from kg to commercial scale. The presentation characterizes the KTL's static mixer reactor using DynoChem and validates the model, shows how DynoChem was used to model centrifugation of a product, and outlines future plans to further characterize KTL equipment using DynoChem to enhance process understanding and better scale up processes.
Practical aspects of distillation modeling in DynoChem. Carolyn Cummings.Scale-up Systems
The document discusses using DynoChem software to model and optimize distillation processes. It presents two case studies:
1) Modeling an azeotropic distillation of MTBE and methanol to determine the endpoint. The model accurately predicted the distillation time.
2) Modeling a batch concentration distillation to assess premature crystallization. The model was used to reproduce a manufacturing process, determine the optimal operating pressure to avoid crystallization, and predict batch properties over time. The optimized process incorporated additional solvent charges to control temperature and maintain solubility.
Using DynoChem to Inform Experimental Design of Batch Crystallization. Rahn M...Scale-up Systems
The document discusses using modeling software to inform experimental design of batch crystallization processes. It presents two models - Model A acts as a "nucleation detector" to predict peak supersaturation without considering nucleation, while Model B solves the cooling or antisolvent addition curve. Case studies demonstrate how the models were used for optimization, robustness analysis, and scoping of new compounds. The models provide a simple tool to aid experimental design for scientists unfamiliar with crystallization kinetics.
This document discusses several studies utilizing continuous flow microreactors for organic synthesis. One study produced an unstable Vilsmeier-Haack formylation intermediate in a safe and controlled manner using inline infrared analysis to optimize reaction conditions. Another used inline infrared to study gas-liquid homogeneous catalysis kinetics at high pressures. A third demonstrated automated optimization of a Pall-Knorr reaction using online infrared data in a microfluidic system.
The document summarizes Robert Woodward's presentation on the kinetics of an SnAr (nucleophilic aromatic substitution) reaction. The presentation covered the reaction chemistry, experiments conducted using two substrates at varying temperatures and conditions, kinetic data collected, and a kinetic scheme and assumptions for modeling the reaction using iterative simulation and optimization in Dynochem software. The goal was to better understand the reaction mechanism and develop predictive chemistry to improve conversion and reduce impurities within timelines for a diabetes medication synthesis.
Scale Up Challenges in Chemical Engineering: The Role of Chemical Engineers i...jodoua
This document discusses challenges in scaling up chemical processes from the laboratory to the industrial scale. It emphasizes the importance of a systematic approach using models informed by experiments at different scales. Dimensionless groups allow insights from small-scale experiments and models to be applied at larger scales by capturing key relationships unaffected by scale. Process design challenges include variability in feedstocks, utilizing waste streams, energy costs, regulations, and rapid time to market.
Scale-up and scale-down of chemical processesSeppo Karrila
Explains the path from for example synthesizing a useful appearing material in the lab to actual production of the same. Also explains what pilot machines are, how they are used, and why sometimes down-scaling of a unit operation is done to experiment in bench-scale.
The document discusses how particle size affects the scale-up of solid/liquid separations. It defines key terms used in filtration and presents equations showing how specific cake resistance, which depends on particle size, surface area, and volume, impacts filtration pressure and rate. Test results demonstrate that smaller mean particle sizes lead to significantly higher specific cake resistance and slower filtration. The document concludes that particle size distribution and compressibility must be considered for successful filtration scale-up between lab and production scales.
Modeling of Granular Mixing using Markov Chains and the Discrete Element Methodjodoua
The document presents a method for modeling granular mixing using Markov chains and the discrete element method (DEM). It motivates the use of Markov chains to efficiently simulate granular mixing as an alternative to computationally expensive DEM simulations. The theory and definitions of Markov chains and operators are provided. The method is applied to simulate mixing in a cylindrical drum, and the effects of the number of states, time step, and learning time are investigated. Properties of the resulting operator like the invariant distribution and mixing rates are analyzed to characterize the mixing dynamics.
The document discusses the role of process analytical technology (PAT) in green chemistry and green engineering. It provides an overview of the speaker's past and current involvement with green chemistry, including conference presentations and publications. Several case studies are presented that illustrate how PAT tools like calorimetry, ATR-FTIR spectroscopy, and continuous processing can make chemical processes safer, minimize hazards, and enable more nature-like bioprocesses.
The document discusses the use of real-time in situ Fourier transform infrared spectroscopy (FTIR) for kinetic investigation of organic synthesis reactions using a ReactIR flow cell. It provides examples of using the flow cell to monitor a palladium-catalyzed cross-coupling reaction in both continuous flow and batch modes. Reaction progress kinetic analysis of the cross-coupling revealed it to be zero-order in both reactants and first-order in the palladium catalyst, indicating the rate-limiting step is likely reductive elimination.
1) In-situ FTIR spectroscopy using a ReactIR flow cell allows for real-time monitoring and analysis of continuous chemical reactions without the need for offline sampling.
2) A case study demonstrated the use of in-situ FTIR to develop a continuous process for the ozonolysis of styrene and an API intermediate, allowing characterization of reaction kinetics, intermediates, and optimization of flow rate and reactor size.
3) This led to the safe, efficient production of 2.7 kg of an API intermediate over 4 days with 99% conversion and 85% ozone efficiency. In-situ FTIR enabled continuous monitoring and ensured high product quality and yield.
1) Recent advances in continuous flow chemistry allow for safer and more efficient reactions through the use of inline monitoring techniques like ATR-FTIR.
2) A Strecker reaction was optimized in a flow reactor using ATR-FTIR to monitor the reaction in situ which allowed for safer operation and higher yields through rapid stoichiometric optimization.
3) A chemoenzymatic sequence for the stereoselective synthesis of lactones was developed using a single-operation protocol combining continuous flow hydrogenation and biocatalyzed Baeyer-Villiger oxidation which provided a safer and simpler procedure.
ReactIR as a Diagnostic Tool for Developing Robust, Scalable Synthetic Processesplaced1
The document discusses using ReactIR technology to provide insights into chemical reactions and processes. It presents three case studies where ReactIR was used: (1) monitoring an unstable acid chloride intermediate in a Vilsmeier reaction, (2) studying mixed anhydride formation with unstable intermediates, and (3) gaining understanding of a chiral resolution process. ReactIR allowed observing reaction components in real-time, identifying side reactions, and gaining mechanistic insights in all three cases.
This document describes the development and validation of an RP-HPLC method for the simultaneous analysis of diclofenac sodium and rabeprazole sodium without the need for an internal standard. The method utilizes a C8 column with a mobile phase of triethyl amine buffer (pH 5):acetonitrile (50:50 v/v) at a flow rate of 2 mL/min. Validation showed the method to be linear, accurate, precise, sensitive and stable. The method was applied to a pharmaceutical formulation containing both drugs with recoveries from 98-100%.
UHPLC has proven to be an effective way to reduce analysis times without losing separation efficiency through the use of small particle and core-shell column technologies. The use of higher column temperatures and shorter column lengths has allowed the analysis speed of UHPLC to be further increased. A number of high-speed UHPLC applications and conditions will be presented which now allow up to four analytical runs to be completed in only a one-minute timeframe.
The document provides information on charged aerosol detection (CAD) technology. It discusses the evolution of CAD products, how CAD works, comparisons to other detection methods like ELSD, and example applications. Key points covered include how CAD provides a uniform response for analytes independent of chemical structure, its wide dynamic range of up to four orders of magnitude, and how it can detect both non-volatile and semi-volatile compounds on HPLC and UHPLC systems without the need for reference standards.
Virtual Reaction Service Using Chem Axon Reactor July06DanielSButler
The document discusses implementing chemical reactions virtually using a software called Reactor. It provides examples of developing aromatic, heterocyclic, and amide reactions virtually and applying charge and pKa plugins. It also discusses considerations for accurately translating real reactions to the virtual world, including regioselectivity, stereochemistry, and resolving molecules to comprehensively cover chemical space.
This document discusses the calibration of various analytical instruments used in pharmaceutical analysis. It begins with an introduction to calibration and the need for calibrating instruments. It then provides details on calibrating UV-Vis spectrophotometers, IR spectrophotometers, spectrofluorimeters, HPTLC, and gas chromatography. For each instrument, it describes the parameters checked during calibration such as wavelength accuracy, resolution, photometric accuracy, linearity, and acceptance criteria. The document aims to explain the calibration process for key analytical tools to ensure accurate measurements.
This document summarizes a study that investigated the effects of water content and temperature on the reaction mechanism and crystal properties of paracetamol produced via reactive crystallization. The researchers first optimized the solubility of paracetamol by examining mixtures of acetic acid and water at different ratios and temperatures. They found the highest solubility occurred with a 7:3 ratio of acetic acid to water at 70°C. Based on this, they determined suitable amounts of reactants for the reaction. Experiments then examined how varying the water content (0, 10g, 20g) or temperature (50-80°C) impacted the reaction kinetics, products, and crystal properties. They found paracetamol form I crystals with 99
This document discusses the qualification and calibration of analytical instruments and glassware. It describes the components of analytical data quality including qualification, calibration protocols, and the need for calibration. It then provides details on calibrating specific instruments like electronic balances, pH meters, UV-visible spectrophotometers, FTIR, GC, HPLC, and HPTLC. It also covers calibrating various glassware items like volumetric flasks, pipettes, measuring cylinders, and beakers. The calibration procedures and acceptance criteria are outlined for ensuring the accuracy of measurements from analytical equipment.
Process monitoring – feedback for water treatment may improve the efficiency of the treatment process – use fewer chemicals to achieve require effluent emission limits
Measurement of Se, As for compliance with Steam Electric Generating Effluent Guidelines
Monitoring of treatment of wastewater by biological based treatment systems
Measurement of Corrosion Products (e.g. Fe, Ni, Cr and Mn) to improve operating efficiency
Measurement of Elements in Nuclear Power Plant Applications (e.g. Pb, Cu, Fe)
Reduce laboratory analysis costs
Viscol 10 series Fully Automatic Kinematic Viscometer OmarSARKAHIAH
Viscol 10 Series Fully Automatic Kinematic Viscometer
Wide-range (120 Fold) viscosity measurement with single viscometer tube
Eliminates operator effects and failures
Eliminates solvent interactions by full automated washing system
Increases time efficiency of operators
Eliminates calibration costs
Reduces analysis cycle time
Transfers data to USB & PC
Requires less sample and less solvent
The document describes research on extracting EPA/DHA from fish oil using a mini-fluidic reactor and comparing it to a batch reactor. Key findings include:
- The mini-fluidic reactor reached equilibrium concentration at 10°C in less than 36 seconds, while the batch reactor took over 15 minutes. Both systems extracted over 75% of omega-3 fatty acids from the fish oil feedstock.
- Flow patterns in the mini-fluidic reactor deviated from the expected slug flow due to the properties of the actual fish oil and silver nitrate solutions used.
- Hydrodynamic studies showed stratified flow occurred rather than slug flow, indicating practical fish oil processing with silver nitrate may require handling stratified flows
Improved Solid State Hydrogen-specific Analyzing SystemsISA Interchange
The document summarizes a presentation about improved solid-state hydrogen analyzing systems. It discusses a hydrogen sensor technology using palladium-nickel alloy films that can accurately measure hydrogen from 0.5% to 100% with a response time under 30 seconds. The presentation outlines the technology background, analyzer performance and specifications, tolerance to contaminants, field data from refinery installations, and applications in refineries and petrochemical plants.
The role of process analytical technology (pat) in green chemistry and green ...dominev
This document discusses the use of process analytical technology (PAT) tools in green chemistry and engineering. It presents case studies on using Fourier transform infrared spectroscopy (FTIR) and reaction calorimetry to monitor and develop continuous bioprocesses and chemical reactions. Specifically, it examines how FTIR was used to monitor a biotransformation reaction and develop a continuous multi-step synthesis. It also explores how reaction calorimetry helped classify reaction kinetics and screen conditions to optimize reactions. The document emphasizes how PAT tools can advance green chemistry principles by enabling real-time process monitoring, improving reaction understanding, and facilitating continuous process development and scale-up.
What is the Rate Law for the Crystal Violet Reaction327-43.docxalanfhall8953
This document summarizes an experiment to determine the rate law for the reaction between crystal violet (CV+) and sodium hydroxide. Students measured the absorbance of CV+ solutions over time using a spectrophotometer. The data showed the reaction was first order with respect to CV+ concentration. The pseudo-first order rate constant was determined to be 0.0066 s-1. The half-life of the reaction was calculated to be 226.923 seconds. In conclusion, the rate law for the crystal violet reaction is rate = 0.0066[CV+].
The document discusses optimizing the extraction process of phytochemicals from Eurycoma Longifolia, a plant known as Tongkat Ali. It aims to develop a mathematical model for the mass transfer during batch solid-liquid extraction to maximize yield. Preliminary experiments tested the effects of various processing parameters, including extraction duration, solvent ratio, particle size, and scale. The results provide parameter values and indicate longer duration, higher ratio, and smaller particle size increase yield, while scale has little effect. Further experiments are still optimizing the analysis method and effects of other parameters.
This experiment involves conducting a saponification reaction between sodium hydroxide (NaOH) and ethyl acetate (Et(Ac)) in a continuous stirred tank reactor (CSTR) to determine the effect of residence time on conversion. A calibration curve will be prepared to relate conductivity measurements to conversion values for the 0.1M NaOH and 0.1M Et(Ac) reaction. The objectives are to determine conversion, the reaction rate constant, and the effect of residence time on conversion.
Prasanna Kamat has over 8 years of experience as a laboratory supervisor in a gas-based power plant. He holds a B.Sc. and M.Sc. in Chemistry and additional qualifications in IT and medical laboratory technician. His responsibilities include sampling and analyzing water, steam, oil, fuel and other process materials to ensure safe and efficient plant operations. He is proficient in numerous analytical instruments and safety practices. Currently he works in the plant's environment department monitoring air quality, waste water and more.
No single liquid chromatography (LC) detector delivers ideal results. Often with LC detectors one analyte responds more strongly than another, or may not respond at all. What is most desired is the ability to accurately measure a wide range of analytes with consistent response simultaneously.
Charged Aerosol detection (CAD) is a mass sensitive technique for determining levels of any non-volatile and many semi-volatile analytes after separation by liquid chromatography. This technique provides consistent analyte response independent of chemical characteristics and gives greater sensitivity over a wider dynamic range. An analytes response does not depend on optical properties, like with UV-vis absorbance, or the ability to ionize, as with mass spectrometry (MS). The presence of chromophoric groups, radiolabels, ionizable moieties, or chemical derivatization is needed for detection.
Similar to Flow Chemistry Congress Boston 2012 Dh V4 (20)
Expanding Your High Performance Liquid Chromatography and Ultra High Performa...
Flow Chemistry Congress Boston 2012 Dh V4
1. Enhanced Development and Control of
Continuous Processes using
Real Time In Situ FTIR Analytics
Dom Hebrault, Ph.D.
Flow Chemistry Congress
April 24th 2012
4. Today’s Agenda
Continuous Flow Chemistry - Analysis Challenges
ReactIR™ In Situ IR Spectroscopy
Case studies:
- A Visual, Efficient, Method to Optimize Reaction Conditions: Case study on a Doebner
Modification
- Safer Use and Monitoring of Hazardous Substances: A General, One-Step Synthesis
of Substituted Indazoles using a Flow Reactor and a FlowIR
- Troubleshooting and Improving Product Quality of a Grignard Batch Process in a 6-
Step Drug Synthesis
5. Continuous Chemistry - Analysis Challenges
Today: Limited availability of convenient,
specific, in-line monitoring techniques
Chemical information
- Continuous reaction monitoring superior to traditional sampling for offline
analysis (TLC, LCMS, UV, etc.)
→ Stability of reactive intermediates
→ Rapid optimization procedures
Technical knowledge
- Dispersion and diffusion: Side effects of continuous flow – must be
characterized
6. In-Line IR Monitoring
Monitor Chemistry In Situ, Under Reaction Conditions
- Non-destructive
- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc.)
- Extremes in temperature or pressure
- No interference from bubbles, solid, color,…
Attenuated Total Reflectance (ATR)
Spectroscopy
7. In-Line IR Monitoring
Real-Time Analysis, “Movie” of the reaction
- Track instantaneous concentration changes (trends, endpoint, conversion)
- Minimize time delay in receiving analytical results
8. In-Line IR Monitoring
Determine Reaction Kinetics, Mechanism and Pathway
- Monitor key species as a function of reaction parameters
- Track changes in structure and functional groups
9. In-Line FTIR Micro Flow Cell in the Laboratory
ReactIRTM Flow Cell: An Analytical Accessory
for Continuous Flow Chemical Processing
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120 ºC
Wetted parts: HC276, Diamond, (Silicon) & Gold
Multiplexing
Spectral range 600-4000 cm-1
Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404
10. FlowIR: Flow chemistry and beyond…
FlowIRTM: A New Plug-and-Play
Instrument for Flow Chemistry and
Beyond
9-bounce ATR sensor
(SiComp, DiComp) and head
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120 ºC
Small size, no purge, no
Spectral range 600-4000 cm-1 alignment, no liquid N2
11. Rapid Analysis of Continuous Reaction Optimization
Optimization of a Doebner Modification of
Knoevenagel Reaction in a Continuous
Mode + CO2
Introduction
Vapourtec R2+/R4
Can reaction optimization and conditions
screening be conducted inline?
How does dispersion affect fraction
collection? FlowIRTM
On-the-fly reaction optimization with
inline FTIR analytics
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
12. Rapid Analysis of Continuous Reaction Optimization
Results
100°C, 10’
Reference spectra of 4 main components
150°C, 10’ 120°C, 20’
3 main/unique bands
Cinnamic acid
(772cm-1) 4.5 h
Malonic
Acid
(1729cm-1) 80°C, 10’ 120°C, 10’ 100°C, 20’ 100°C, 30’
Benzaldehyde
(828cm-1)
7 reaction “plugs”, on-the-fly variation of
residence time and temperature (1:1.1
benzaldehyde/malonic acid ratio)
Few hours experiment only
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
13. Rapid Analysis of Continuous Reaction Optimization
Results
Development of an in-situ real time assay
method
- ReactIR algorithm: iC Quant and iC IR
- Simple univariate model (trans-
cinnamic acid 772 cm-1 with 2 baseline
points)
(0.1-0.5M)
Trans-cinnamic acid
(772 cm-1)
“Proof of concept” univariate model
Limited number of datapoints
Model used to predict concentration
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
14. Rapid Analysis of Continuous Reaction Optimization
Results 1:2
Development of an in-situ real time assay
method: 1:1.2
- Application to the previous screening
- 100°C, 20’ to 30’ represent an optimum
at (1:1.1 benzaldehyde / malonic acid
ratio)
[M]
120°C, 20’
3.5 h
100°C, 10’
0.35
150°C, 10’
1: 1.1 1:1.5 1:2
0.30 Steady state
0.25
0.20 Variation of benzaldehyde / malonic acid:
0.15
- From 1:1.1 to 1:2 (100°C, 20’)
0.10 - No significant improvement
- Real time FTIR provides confirmation of
80°C, 10’ 120°C, 10’ 100°C, 20’ 100°C, 30’
steady state and concentrations in the
plug
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
15. Rapid Analysis of Continuous Reaction Optimization
Conclusions
No issue with CO2 bubble
Faster, more efficient, optimization
Off-line analysis requires accurate
sampling when plugs are short, which can
be difficult
How about FlowIR for batch reaction?
Use of a recirculation loop, or a syringe
pump
Preliminary results promising
Goal is to cover 95% of standard chemical
conditions
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
16. Safer Use and Monitoring of Hazardous Substances
Vapourtec R2+/R4
A General, One-Step Synthesis of
Substituted Indazoles using a Flow
Reactor and a FlowIR
Introduction FlowIRTM
Time-efficient and safe production of
small amounts of pharma-relevant
fragments
Reduce inventory of hydrazine under
“forced” conditions in flow mode Real time monitoring of concentrations
NH2
N
O2N CHO O2N
• indazole
+ H2N
NH2
• azine
F F
Hydrazine Hydrazone
• hydrazone
Faster optimization of conditions
O2N NO2 O2N
• reagent excess
N N
+ N • temperature
N
F F
Azine (minor) Indazole (major)
• residence time
Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and
Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
17. Safer Use and Monitoring of Hazardous Substances
Results
Indazole
Screening (7 experiments in 2.5 h):
hydrazine excess, temperature, and
residence time 1:1.2, 150°C
15’
Intermediate
1:1, 150°C
15’
1:1.2, 100°C
15’
1:1, 100°C Azine
1:1, 50°C 15’
15’
1:1.2, 50°C
15’
1:1, 25°C No reaction at 25°C
15’
Hydrazone only at 50°C: 1st step is faster
No full conversion of hydrazone even at
150°C
0.2 eq. excess hydrazine: 4% more
indazole
2.5 h
Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and
Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
18. Safer Use and Monitoring of Hazardous Substances
Introduction
Is 150°C still too low?
Temperature more efficient than
increase of residence time
1:1.2, 200°C
15’
1:1.2, 150°C 1:1.2
30’ 200°C
1:1.2, 150°C 5’
5’
Integration of ReactIR software (iC IR)
with Flow CommanderTM software
Facilitates automated experiment
optimization
Allows accurate sampling of plugs for
fraction collection and analysis
Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and
Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
19. Real Time Product Quality Control for Flow Processes
Troubleshooting and Improving Product O OH
Quality of a Grignard Batch Process in a AcOH
Ar
6-Step Drug Synthesis Aldol
O OMgBr O
MeMgBr
Introduction AcOH
Ar OEt Ar Ar
Ketone
Impurity headache PhMe/THF
2-Me-THF
OMgBr OH
MeMgBr
• <10% aldol during development study Ar
AcOH
Ar
• 40% during 1000 L campaign
Alcohol
Challenges and Objectives
• Flow process
• Real time process quality control(*)
• Proof of concept on 40 Kg scale
• Aldol ≤ 1%
• Conversion ≥ 97%
(*) Off-line analysis (HPLC) takes 20-40’
“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012
20. Real Time Product Quality Control for Flow Processes
Toluene
at 730cm-1
Preliminary results in flow
Reference
spectra
• Eq. MeMgBr: 2 → 1.5 Ester carbonyl
2-Methyl-THF
at 1752cm-1 at 1383cm-1
• Eq. NEt3: 6 → 3.5 Ketone carbonyl
at 1721cm-1
• T°: -10 → 0°C
• Fast reaction < 20 s Product Grignard
Starting
reagent
material
Aldol: 40% → ≈ 1%
Reaction
spectra
Enolate
at 1252cm-1
No ester
starting material
No product
ketone!!
Alfa Laval ART® Plate Reactors
“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012
21. Real Time Product Quality Control for Flow Processes
[Ester]1752cm-1
10%
Excellent system stability upon flow
rate changes 3%
1%
Conversion measurement ≥ 97% with
Solvent, 2-Me-THF at 1383cm-1
2-Me-THF 2-Me-THF
2-Me-THF
14 mL/min 1 mL/min Stop flow
7 mL/min qualitative/quantitative peak height(*)
Starting material, ester at 1752cm-1 Conversion measurement ≥ 99%
requires quantitative model
(*) results within +10% versus IPC-HPLC
“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012
22. Real Time Product Quality Control for Flow Processes
Toluene, Grignard at 730 cm-1
Starting material, ester at 1752cm-1
Solvent, 2-Me-THF at 1383cm-1
Start Grignard Switch Increase Grignard Increase ester flow Increase ester, increase Grignard
reagent and off ester to 2 eq., switch rate, decrease increase to 1.1 eq.
ester pumps pump ester pump on Grignard to 0.8 eq. Grignard to 1 eq.
“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012
23. Real Time Product Quality Control for Flow Processes
Scale-up validation - Lab
• 500 g ketone product
• 4-5 s residence time
• 25 mL/min
• 4-6 h
Scale-up validation - KiloLab
• 30 kg ketone product
• Same residence time
• 72 mL/min
• 92 h
• Project timeline ≤ one week
“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012
24. Acknowledgements
Vapourtec Ltd. (U.K.)
- Chris Butters, Duncan Guthrie
Flow Chemistry Solutions (U.K.)
- Andrew Mansfield
AstraZeneca, Sodertalje (Sweden)
- Fabrice Odille, Mats Ridemark, Daniel Fahlen
Mettler Toledo Autochem
- Will Kowalchyk (USA), Jon Goode (U.K.)