Kinetic Modeling to De-Risk Process Changes As a Part of Life-Cycle Management
During drug substance development, project teams invent, optimize, and thoroughly characterize manufacturing processes to make the drug substance in a safe, sustainable, and robust manner. Many of the overall goals are set by projected commercial demand.
2023-Nov-08

Selected highlights at AIChE Annual Meeting 2023
Links to abstracts of presentations featuring use of Scale-up Suite by Amgen, BMS, Hovione, Lilly, MSD (Merck), Sarafinas, Seagen, Snapdragon (Cambrex), Veranova.
2023-Oct-27

Development of a Mechanistic Amino Acid Activation Reaction Kinetics Model for Safe and Efficient Solid Phase Peptide Synthesis
Amino acid pre-activation is a critical reaction step during solid phase peptide synthesis due in part to the formation of impurities such as isomer, N,N′-diisopropylcarbodiimide-adduct and single amino acid addition.
2023-Sep-08

Kinetic Barriers to Disproportionation of Salts of Weakly Basic Drugs
Disproportionation is a major issue in formulations containing salts of weakly basic drugs. Despite considerable interest in risk assessment approaches for disproportionation, the prediction of salt-to-base conversion remains challenging.
2023-Jul-26

New Scale-Up Technologies for Multipurpose Pharmaceutical Production Plants: Use Case of a Heterogeneous Hydrogenation Process
Minimizing the effort associated with the pilot and laboratory-scale experiments needed for a successful scale-up of a process from laboratory to production scale is a significant challenge in process development.
2023-Jul-06

Copper-Catalyzed Racemization-Recycle of a Quaternary Center and Optimization Using a Combined Kinetics-DoE/MLR Modeling Approach
The copper-catalyzed racemization of a complex, quaternary center of a key intermediate on route to lanabecestat has been identified.
2023-Apr-17

Multivariate curve resolution for kinetic modeling and scale-up prediction
This paper describes the investigation of an imine synthesis reaction in an oscillating segmented flow microreactor. The reaction is profiled using in-line Raman spectroscopy, and the reaction kinetic modelled using Dynochem.
2023-Jan-31

Kinetic and Mechanistic Investigations to Enable a Key Suzuki Coupling for Sotorasib Manufacture─What a Difference a Base Makes
The process to manufacture sotorasib (AMG 510) employs a Suzuki–Miyaura reaction as a key step in the synthetic sequence.
2022-Dec-27

Selected highlights at AIChE Annual Meeting 2022
Links to abstracts of presentations featuring use of Scale-up Suite by BMS, Continuus, Gilead, GSK, Lilly, Merck, On Demand Pharma, Sanofi, Teich Process Development, Vertex, US Army
2022-Nov-03

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution
This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons.
2022-Jun-07

Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone
Sterically hindered chiral ketones are useful intermediates in the synthesis of active pharmaceutical ingredients.
2022-May-17

Advances in Continuous Flow Calorimetry
Calorimetric data from chemical reactions such as reaction enthalpy, adiabatic temperature rise, and activation energy are essential for reaction safety and scale-up from laboratory investigations to reactor design and operation.
2022-Jan-19

Scalable Synthesis of (R,R)-N,N-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis
Hydrogen bonding phase-transfer catalysis offers a convenient solution to activate safe and economical metal alkali fluorides for enantioselective nucleophilic fluorination.
2021-Dec-03

Development of a High-Throughput Kinetics Protocol and Application to an Aza-Michael Reaction
A case study is presented with a transition metal salt/TMSCl-catalyzed aza-Michael reaction to showcase the performance and robustness of the high-throughput kinetic platform.
2021-Nov-24

Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control
A scalable and efficient synthesis of hydroxyindanone, a key intermediate for belzutifan (MK-6482), is described.
2021-Nov-15

Manufacturing Process Development for Belzutifan, Part 6: Ensuring Scalability for a Deoxyfluorination Reaction
The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities.
2021-Nov-15

New Scale-up Technologies for Hydrogenation Reactions in Multipurpose Pharmaceutical Production Plants
With only a few laboratory-scale experiments and information about the production-scale reactor, a chemical
process model is developed. Collaboration between Siegfried and University of Applied Sciences and Arts Northwestern Switzerland.
2021-Nov-11

Selected highlights at AIChE Annual Meeting 2021
Links to abstracts of presentations featuring use of Dynochem or Reaction Lab by AbbVie, BMS, Hovione, Lilly, Merck, Sarafinas Process & Mixing Consulting.
2021-Nov-03

Step Up: Gas–Liquid Mass-Transfer Characterization at Plant Scale Using the Pressure Step Method
Gas–liquid reactions (such as aqueous phase hydrogenations) are frequently mass transport limited. Characterization of reactor overall mass transport performance is key to the successful transfer of reactions across scales or between plants.
2021-Oct-28

Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates
Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes.
2021-Oct-28

Evidence of Rate Limiting Proton Transfer in an SNAr Aminolysis in Acetonitrile under Synthetically Relevant Conditions
An early synthetic step in the synthesis of adavosertib, AZD1775, is the SNAr reaction between 4-fluoronitrobenzene and 1-methylpiperazine in acetonitrile.
2021-Oct-25

Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad
The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex.
2021-Oct-25

Investigating the Activation Kinetics of Phosphoramidites for Oligonucleotide Synthesis
Solid-phase synthesis of oligonucleotides relies on a repeating cycle of rapid and well-defined synthetic steps to generate the target sequence.
2021-Oct-08

Guest: James Murray, Amgen: “Kinetic Modelling of Complex Organic Reactions; A Minimalist Approach"
Complex kinetic models often require extensive experimentation to provide predictive capabilities. Our approach to minimizing experimentation and producing simple yet functional models to accelerate process optimization will be discussed.
2021-Sep-08

Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations
The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated.
2021-Aug-06

Boron Trifluoride-Mediated Cycloaddition of 3-Bromotetrazine and Silyl Enol Ethers: Synthesis of 3-Bromo-pyridazines
Pyridazines are important scaffolds for medicinal chemistry or crop protection agents, yet the selective preparation of 3-bromo-pyridazines with high regiocontrol remains difficult.
2021-Aug-03

Augmenting Adaptive Machine Learning with Kinetic Modeling for Reaction Optimization
We combine random sampling and active machine learning (ML) to optimize the synthesis of isomacroin, executing only 3% of all possible Friedländer reactions.
2021-Jul-08

Development of a Scalable Synthetic Route to BMS-986251. Part 1: Synthesis of the Cyclohexane Dicarboxylate Fragment
The cyclohexane dicarboxylate unit of BMS-986251 (1), a potent and efficacious RORγt inverse agonist, was synthesized starting from Hagemann’s ester in seven chemical transformations with five isolated intermediates.
2021-Jun-15

Development of the Late-Phase Manufacturing Process of ZPL389: Control of Process Impurities by Enhanced Process Knowledge
The development of the late-phase manufacturing process of the drug candidate ZPL389 and the strategies for the control of impurities are outlined in detail. Selective salt formation at several stages was pivotal to controlling the process impurities.
2021-Apr-14

Distance Teaching in Chemistry: Opportunities and Limitations
Remote teaching in the tertiary education sector is a relatively common practice, and the implementation of digital solutions in chemistry teaching offers many new opportunities and tools.
2021-Feb-28

Characterization of Propionyl Phosphate Hydrolysis Kinetics by Data-Rich Experiments and In-Line Process Analytical Technology
In-depth characterization of reaction kinetics often requires a considerable amount of experimental results under various conditions.
2021-Feb-17

Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2-Chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline
A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (1), a key intermediate in the synthesis of an immuno-oncology asset, is described.
2020-Dec-23

Guest: Cheryl Teich, Teich Process Development: “Process Schemes and the 'Yoga of Process Development'"
Cheryl Teich (former AIChE President, Yoda of Process Schemes and yoga enthusiast) shows how to use a simple diagram to start your journey to process understanding on the right foot, as opposed to the left foot.
2020-Dec-09

Guest: Keith Mattern, Merck: “End-to-End Automation: Characterizing volumetric mass transfer coefficient (kLa) across process scales using Dynochem"
Application of automated platform for experimental execution and model regression of gas-liquid mass transfer for reactor characterization, scale-up of biocatalytic oxidation. Review of Dynochem model development to capture unique system dynamics. mAbs.
2020-Nov-11

Activation of C–O and C–N Bonds Using Non-Precious Metal Catalysis
Activation of C–O and C–N Bonds Using Non-Precious Metal Catalysis
2020-Sep-10

Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate
During development of a radical benzylic bromination, observation of polymerized byproducts and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process understanding and robustness.
2020-Jul-15

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation
This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3.
2020-Jul-14

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process
This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1.
2020-Jul-14

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration
This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib.
2020-Jul-14

Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate
We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant.
2020-May-18

Efficient Kinetic Data Acquisition and Model Prediction: Continuous Flow Microreactors, Inline Fourier Transform Infrared Spectroscopy, and Self-Modeling Curve Resolution
This work presents and evaluates an approach to obtain and model kinetic data by combining a microreactor setup and real-time reaction monitoring through inline Fourier transform infrared spectroscopy with nonsteady-state conditions and SMCR.
2020-Apr-14

Guest: Lauren McCullough, Dow: "Using DynoChem to Advance Process Insight with Limited Data"
Lauren will discuss using DynoChem to squeeze process insight from limited plant and experimental data for performance and safety evaluations.
2019-Oct-23

Optimization of an Azaindazole Series of CCR1 Antagonists and Development of a Semicontinuous-Flow Synthesis
Chemotactic cytokine receptor 1 (CCR1) is involved in trafficking of immune cells to sites of inflammation. Antagonism of CCR1 has been extensively explored as an approach to treat inflammatory and autoimmune disease.
2019-Sep-27

Follow the Silyl Cation: Insights into the Vorbrüggen Reaction
To succeed in the development of a mechanistic model for the Vorbrüggen reaction of thymine with an advanced furanose intermediate, a range of spectroscopic techniques were applied and found essential to understanding kinetically relevant.
2019-Aug-21

Guest: Flavien Susanne, GSK: "How Process Simulation can Influence the Process Development and Control Strategy of a Drug Substance Asset"
At GSK, supported by a new modelling strategy, we are now embedding mechanistic and first principal models to support the process development phase and the control strategy of drug substance continuous processes from laboratory to manufacture.
2019-Jul-22

Guest: James Marek and Eric Moschetta, AbbVie: "Improving Process Development Workflows and Kinetic Understanding through PAT"
Please see (https://aiche.confex.com/aiche/2018/meetingapp.cgi/Paper/529180) and (https://aiche.confex.com/aiche/2018/meetingapp.cgi/Paper/529073)
2019-Jul-10

Development of an Operational Space Using Mechanistic Models for a Pd-Catalyzed Amidation Reaction Used in the Synthesis of ABT-530
Rigorous understanding of the impact of reaction parameters on the formation and rejection of impurities in a reaction is a critical part of process development.
2019-Jul-01

Definitive screening designs for multistep kinetic models in flow
Currently, rate-based understanding of organic reactions employed in the manufacture of active pharmaceutical ingredients (APIs) is often not obtained.
2019-Jun-06

An Introduction to Closed‐Loop Process Optimization and Online Analysis
An Introduction to Closed‐Loop Process Optimization and Online Analysis
2019-Jan-24

Continuous‐flow Synthesis of Aryl Aldehydes by Pd‐catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen
A continuous‐flow protocol utilizing syngas (CO and H2) was developed for the palladium‐catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes.
2018-Oct-09

Guest: Tom Corrie, Syngenta: “Accelerating Active Ingredient Development with Early Stage DynoChem Simulations”
This talk will cover the implementation of DynoChem in agrochemical process development as a resource for knowledge generation and project direction in time-restricted projects, where extensive experimentation is not possible.
2018-Jul-11

Process design methodology for organometallic chemistry in continuous flow systems
This publication summarises the methodology applied in the process design and scale up of fast, exothermic reactions using organometallic reagents for synthesis of intermediates in the production of Active Pharmaceutical Ingredient (API).
2018-Apr-07

Development of a Robust and Reusable Microreactor Employing Laser Based Mid-IR Chemical Imaging for the Automated Quantification of Reaction Kinetics
A robust, reusable microreactor coupled with laser based mid-IR chemical imaging and automated analysis is reported, for the first time, with its application to monitor and quantify fast organometallic chemistry in flow.
2017-Oct-13

Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate
The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area.
2017-Oct-09

Development of a Leuckart-Wallach Reaction in Flow for the Synthesis of Abemaciclib
The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart–Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. PFR.
2017-Aug-16

Screwing NaBH4 through a Barrel without a Bang: A Kneaded Alternative to Fed-Batch Carbonyl Reductions
In this work the application of green chemistry principles such as process intensification and the replacement of reagents and solvents to more benign alternatives were coupled with the advantages of continuous manufacturing.
2017-Jul-22

Modeling reduces nickel needed in catalytic reactions
Nickel catalysts are much less expensive than precious metal catalysts, but the large amounts of nickel catalyst used in many catalytic cross-coupling reactions still discourage industrial adoption.
2017-Jun-19

Guest: Bruno De Kort, Monsanto "Evaluating runaway reaction scenarios during scale up to large scale using DynoChem"
Slides from guest webinar of 14 June 2017
2017-Jun-14

Kinetic Modeling of the Nickel-Catalyzed Esterification of Amides
Nickel-catalyzed coupling reactions provide exciting tools in chemical synthesis. However, most methodologies in this area require high catalyst loadings, which commonly range from 10–20 mol % nickel.
2017-May-22

The Development of a Dimroth Rearrangement Route to AZD8931
Recently, the aminoquinazoline motif has been highly prevalent in anticancer pharmaceutical compounds. Synthetic methods are required to make this structure on a multikilo scale and in high purity.
2017-Feb-01

Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
A concise catalytic asymmetric synthesis of idasanutlin (1) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction.
2016-Oct-31

Development of a Control Strategy for a Final Intermediate to Enable Impurities Control
This manuscript describes the development of a control strategy for impurities in the final intermediate step of the asunaprevir drug substance utilizing the concepts outlined in the International Conference on Harmonisation guidelines.
2016-Oct-07

Rapid multistep kinetic model generation from transient flow data
oday, the generation of kinetic models is still seen as a resource intensive and specialised activity. We report an efficient method of generating reaction profiles from transient flows using a state-of-the-art continuous-flow platform.
2016-Oct-03

The scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions: methodology and reactor design
Biphasic liquid/liquid reactions are commonplace, however their scale-up under super-heating conditions is not.
2016-Sep-02

Guest: Marimuthu Andiappan, Lilly: Use of DynoChem Modeling for Process Design: Mitigating the Risk of Coprecipitation
How Lilly used process modeling to develop an effective control strategy to mitigate the unexpected precipitation of pinacol while telescoping a class of reactions.
2016-Jun-08

O-Phenylisourea Synthesis and Deprotonation: Carbodiimide Elimination Precludes the Reported Chapman Rearrangement
The kinetics of the addition of phenol to diisopropylcarbodiimide, and reaction of the resulting N,N′-diisopropyl-O-phenylisourea with hydroxide, are reported.
2016-May-23

Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling
This manuscript focuses on the SNAr coupling between aminopyridine 3 and chloropyrimidine 7.
2016-May-12

Investigation of Variable Impurity Profile from a Mitsunobu Reaction Using Insights from Kinetic Modeling, Multi-Phase Interactions, and Computational Fluid Dynamics
A drug substance intermediate synthesis involving a Mitsunobu coupling reaction using triphenylphosphine and diisopropyl azodicarboxylate was investigated to understand the variable levels of an impurity.
2016-Apr-11

Guest: Daniel Caspi, AbbVie: Development and Scale-up of Acrylamide Formation Using an Impinging Jet
Reaction kinetics and response surface simulations were used to reduce the chloro impurity to acceptable levels in a fit-for-purpose flow chemistry solution.
2016-Feb-10

Guest: Samrat Mukherjee, AbbVie: Model-Based Process Control in API Manufacturing: A QbD-Vantage!
In this guest webinar, Samrat Muhjerjee, Associate Director at AbbVie, discusses how Quality-by-Design in API synthesis is facilitated by the use of DynoChem models.
2015-Dec-09

Mono- and tri-ester hydrogenolysis using tandem catalysis. Scope and mechanism
The scope and mechanism of thermodynamically leveraged ester RC(O)O–R′ bond hydrogenolysis by tandem metal triflate + supported Pd catalysts are investigated both experimentally and theoretically by DFT and energy span analysis.
2015-Nov-26

Guest: Shujauddin Changi, Eli Lilly: Model and Experimental Driven Approach to Develop and Innovate Batch & Continuous Process Development for Grignard Reactions
Changi describes a strategy for using experiments and DynoChem kinetic models to develop Grignard reactions for batch and continuous operation, and shares an example where this approach was used to deliver a safe, robust process at commercial scale.
2015-Nov-04

Kinetics Model for Designing Grignard Reactions in Batch or Flow Operations
This paper describes the development of a “fit for use” model for a Grignard reaction, which was used to produce an intermediate compound during the manufacture of API for edivoxetine hydrochloride.
2015-Oct-29

Guest: Chris Pink, GSK: Ensuring consumption of a genotoxic starting material in API manufacture through kinetics and mixing studies
Slides from webinar on Ensuring Consumption of a Genotoxic Starting Material in API Manufacture through the use of Kinetics and Mixing Studies
2015-Oct-14

Guest: Chris Hone, University of Leeds: Evolution and Validation of Kinetic Motifs using Continuous-Flow Reactors
Chris Hone presents an example of how DynoChem is used for continuous flow reactor (PFR) design from his PhD work in Chemical Process Research and Development at iPRD, University of Leeds.
2015-Oct-07

A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors
The control of mutagenic impurities is of crucial interest to pharmaceutical companies and regulatory agencies alike.
2015-Oct-05

Impurity Profiling, Kinetics, and Representative Sampling from Reaction Slurries.
Adobe Presenter format presentation featuring use of the EasySampler with DynoChem.
2015-Sep-24

Guest: Shane Grosser, Merck: Development and Scale up of Gas-Liquid Systems Facilitated through Process Modeling
Case studies using DynoChem to develop and scale up gas-liquid systems: pressure swings to dry and degas solvents; solvent evaporation to reduce reaction by-products; vessel characterization and optimization of a biocatalytic oxidation.
2015-Aug-12

Guest: Georges Assaf, UCB: Modelling Acid-Base Equilibria using DynoChem: Acid-Catalysed Condensation
A case study demonstrating the use of DynoChem to generate better understanding of acid-catalysed reaction from a mechanistic basis and optimization of yield.
2015-Aug-12

Application of Safety by Design Methodology in Evaluating Process Safety for a Duff Reaction Using Predictive Process Simulators
This work presents a Safety by Design (SbD)-driven approach to the evaluation of process safety and reaction modeling that was effective in obtaining enhanced process knowledge and defining a design space for chemical reaction hazards.
2015-Jul-30

Design of Safe Energetic Process Using the Advanced Flow Reactor
Conventional manufacturing of energetic materials includes the use of batch and semi-batch reactors. These methods offer flexibility at the cost of safety, reproducibility and often times higher cost products.
2015-Jun-16

Using Data-Rich Experimentation to Enable the Development of Continuous Processes

2015-May-20

IR and NMR Reaction Monitoring Techniques for Nucleophilic Addition Reactions: In Situ Monitoring of the Addition of Benzimidazole to a Pyridinium Salt
This study centers on the use of in situ FTIR spectroscopy and online NMR to study the nucleophilic addition of benzimidazole analogues to an N-methylpyridinium salt. The reaction consists of two stages.
2015-Mar-30

Mechanism of Phosphine Borane Deprotection with Amines: The Effects of Phosphine, Solvent and Amine on Rate and Efficiency
The kinetics of borane transfer from simple tertiary phosphine borane adducts to a wide range of amines have been determined.
2015-Feb-20

Guest: Mannheim University of Applied Science: Kinetic Studies in Microreactors - Requirements for reliable data and successful reactor scale-up
Slides from DynoChem Guest Webinar by Thorsten Roder of Hochschule Mannheim, held on 19 November 2014
2014-Dec-10

Development of Flow Processes for the Syntheses of N-Aryl Pyrazoles and Diethyl Cyclopropane-cis-1,2-dicarboxylate
N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine.
2014-Nov-20

Kinetic and Scale-up Investigations of a Michael Addition in Microreactors
Process development using microreactors (PFR) for an exothermic Michael addition is presented using DynoChem tools. This includes consideration of the assumption of ideal plug flow, local mixing at the feed point and heat transfer.
2014-Oct-14

Development of a Continuous Plug Flow Process for Preparation of a Key Intermediate for Brivanib Alaninate
A continuous (PFR) process was developed using both Qr and composition data to mitigate the potential thermal runaway and allow for safer scale-up.
2014-Oct-14

Guest: Nick Falco, GSK: Development of an ammonolysis reaction kinetics model for improved process understanding and parametric flexibility
Development of an ammonolysis reaction kinetics model in Dynochem and use of the model to improve the manufacturing process and define parametric flexibility in the operating space
2014-Sep-17

Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions
A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions.
2014-Aug-30

Guest: Sarah Rothstein, Nalas Engineering: Kinetic and manufacturing evaluations of 2,6-diaminopyrazine-1-oxide (DAPO) production
Development of a DynoChem kinetic model to study starting material decomposition, impurity formation, evaluate manufacturing options, and compare batch vs. continuous operation
2014-Aug-20

In-situ Analyses of Unstable Compounds in Batch and Flow Conditions
In-situ analyses using React-IR were applied to several reactions. Kinetics were fitted using DynoChem.
2014-Jul-31

Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly Selective Hydrolysis of a Nitrile to an Amide
A combination of mechanism-guided experimentation and kinetic modeling was used to optimise a reaction and eliminate the major reaction impurity. The model was then used to check process robustness on a 90 kg scale.
2014-Jul-16

Guest: Chris Mitchell, Takeda: Development of a modeling-based strategy for the safe and effective scale-up of highly energetic hydrogenation reactions
Development of DynoChem model to take into consideration kinetics, reactor heat transfer capabilities and gas-liquid mass transfer for scale-up of highly energetic hydrogenation reactions
2014-Jul-16

Guest: Andrew Cosbie, Amgen: Building Value into Process Understanding and Engineering Assessments
How Amgen uses process schemes as a living document to communicate among engineers, scientists, management and CMOs; to capture key process parameters, rates, ranges and references; to facilitate engineering assessments and risk assessments
2014-Jul-16

Guest: Flavien Susanne, Novartis: Application of QbD in Continuous Processing: Approach Supported by DynoChem Process Simulation
A methodology based on process simulation using DynoChem was used to develop three consecutive continuous transformations, transfer them to kilogram scale facilities and generate the design space based on the QbD ICH Q8 guidelines
2014-Jun-18

Application of In Situ Raman Spectroscopy To Facilitate Use of Hydrogen Peroxide on Kilogram Scale
The safe implementation of a hydrogen-peroxide-mediated oxidation of a poorly reactive sulfide to the corresponding sulfone is described.
2014-Jun-09

Guest: Franjo Jovic, Pliva: Modelling based approach to process development for the API synthesis hydrogenation step
Franjo Jovic of Pliva presents the design space for an API hydrogenation reaction step defined using DynoChem and model predictions verified with experimental results.
2014-May-21

Guest: Bernhard Berger, Siegfried AG: Applications of DynoChem in Thermal Process Safety – Optimization of Accumulation and Time to Maximum Rate
Working with a highly exothermic oxidation reaction, it is shown how a DC model for heat flow / Qr can be created from a few RC1 experiments, to evaluate a parameter space and assure thermal process safety
2014-Mar-20

Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low Temperature Reactions by Kinetic Fitting of Nonisothermal Heat Data from Reaction Calorimeter (RC1e)
A new approach to determine the adiabatic decomposition temperature is presented here, using a combination of nonisothermal heat data and DynoChem kinetic modeling for the low temperature decomposition of a lithiated halogenated aromatic intermediate.
2014-Jan-10

Use of Modeling and Process Analytical Technologies in the Design of a Catalytic Amination Reaction: Understanding Oxygen Sensitivity at the Lab and Manufacturing Scales
An experimental mechanistic study was undertaken to understand the effect of oxygen on the reaction. A reactor model was then used to control dissolved oxygen levels on scale.
2013-Nov-28

Guest: Andrew Derrick, Pfizer: DynoChem applications in a busy commercial plant
Applications: Scale-up of laboratory heat flow data to pilot and production scale to assist validation based on maximum temperature Assumptions: well mixed phases, dosing controlled reaction
2013-Nov-21

Guest: Ed Delaney, Reaction Science: Application of DynoChem in CMC Regulatory Support
Ed shows how DynoChem kinetic models can be used to address concerns related to control of genotoxic impurities (for example sulfonate ester) in Pharmaceutical APIs
2013-Sep-25

Modeling-based Development of an Enantioselective Hydrogenation Reaction of a Sitagliptine Intermediate
This work presents a quality by design (QbD) driven approach to experiments and DynoChem modeling that was effective in obtaining enhanced process knowledge and defining a design space.
2013-Sep-09

Guest: Dan Hallow, BMS: Application of DynoChem Reaction Modeling to Quality by Design
Dan Hallow of BMS describes how DynoChem was used in a QbD approach for commercialization of an API step, especially to control formation of a critical impurity.
2013-Aug-14

Optimization of the Manufacturing Route to PF-610355 ( 1 ): Synthesis of Intermediate 5
Tertiary carbinamine 5 is an isolated intermediate in the synthesis of a novel, inhaled β-2 adrenoreceptor agonist PF-610355. Process development for the key amide-formation and Ritter reactions, together with reaction understanding studies are discussed.
2013-Feb-05

Optimization of the Manufacturing Route to PF-610355 (1): Synthesis of Intermediate 5
Tertiary carbinamine 5 is an isolated intermediate in the synthesis of a novel, inhaled β-2 adrenoreceptor agonist PF-610355. Process development for the key amide-formation and Ritter reactions, together with reaction understanding studies are discussed.
2013-Feb-05

Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor
Two routes to the chiral indazolyl amino ester subunit were developed - either a Rh-catalyzed asymmetric hydrogenation or a biocatalytic process to install the single chiral center. The advantages and disadvantages of each process route are discussed.
2012-Dec-21

Mechanism of Metal-Free Hydrogen Transfer between Amine−Boranes and Aminoboranes
The kinetics of the metal-free hydrogen transfer from amine–borane Me2NH•BH3 to aminoborane iPr2N═BH2, yielding iPr2NH•BH3 and cyclodiborazane [Me2N-BH2]2 via transient Me2N═BH2, have been investigated in detail
2012-Sep-27

Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation
A mechanistic model based on thermodynamics was built to predict disproportionation.
2012-Aug-24

Intermolecular Alkyne Hydroacylation. Mechanistic Insight from the Isolation of the Vinyl Intermediate That Precedes Reductive Elimination
The isolation of the branched alkenyl intermediate that directly precedes reductive elimination of the final α,β-unsaturated ketone product is reported for the hydroacylation reaction between two alkyne.
2012-Jul-26

Enquiry-based Learning in Engineering Curriculum: are we preparing graduates ready to face future challenges?
The School initiated a substantial curriculum redesign leading to introduction of an Enquiry Based Learning approach via industrially relevant case studies throughout the curriculum, using industry standard software packages (DynoChem and HYSYS).
2012-Jun-19

ReactNMR and ReactIR as Reaction Monitoring and Mechanistic Elucidation tools
ReactNMR and ReactIR as Reaction Monitoring and Mechanistic Elucidation tools
2012-Apr-11

Modeling-Based Approach Towards Quality by Design (QbD) for the Ibipinabant API Step
Modeling-Based Approach Towards Quality by Design (QbD) for the Ibipinabant API Step
2012-Apr-11

Kinetic and Mechanistic Insight into the Thermodynamic Degradation of Saxagliptin
Kinetic and Mechanistic Insight into the Thermodynamic Degradation of Saxagliptin
2012-Apr-11

Kinetic Understanding Using NMR Reaction Profiling
Kinetic Understanding Using NMR Reaction Profiling
2012-Apr-04

Understanding and Control of Dimethyl Sulfate in a Manufacturing Process: Kinetic Modeling of a Fischer Esterification Catalyzed by H2SO4
Understanding and Control of Dimethyl Sulfate (sulfonate ester formation) in a Manufacturing Process: Kinetic Modeling of a Fischer Esterification Catalyzed by H2SO4. Control of genotoxic impurities.
2012-Apr-04

Safe, Convenient ortho-Claisen Thermal Rearrangement Using a Flow Reactor
Presents a process that utilized a tube reactor to make 80 g of an early phase intermediate in a short time while mitigating the potential chemistry hazards. Continuous. PFR.
2012-Apr-04

Guest: Wilfried Hoffmann, Pfizer: Use of DynoChem in Process Developmentt
Presentation of how DynoChem has been used in process development at Pfizer
2012-Feb-07

Development of a Generic Mechanism for the Dehydrocoupling of Amine-Boranes: A Stoichiometric, Catalytic, and Kinetic Study of H3B·NMe2H Using the [Rh(PCy3)2]+ Fragment
The multistage Rh-catalyzed dehydrocoupling of the secondary amine-borane H3B•NMe2H, to give the cyclic amino-borane [H2BNMe2]2, has been explored using catalysts based upon cationic [Rh(PCy3)2]+ (Cy = cyclo-C6H11)
2012-Jan-19

Kinetic Modeling and Optimization of Operating Parameters for Transvinylation of Lauric Acid
The kinetic parameters and the thermodynamic parameters of the transvinylation of lauric acid were estimated using DynoChem. The optimum operating parameters were then predicted using the model and verified by performing the corresponding experiments.
2012-Jan-04

ReactNMR and ReactIR as Reaction Monitoring and Mechanistic Elucidation Tools: The NCS Mediated Cascade Reaction of α-Thioamides to α-Thio-β-chloroacrylamides
On-flow ReactIR and 1H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide.
2011-Oct-26

Discovery of a Novel, Efficient, and Scalable Route to Bendamustine Hydrochloride: The API in Treanda
Process Research and Development activities leading to a new and efficient route to bendamustine hydrochloride, the active ingredient in Treanda, a treatment for blood cancers, are disclosed.
2011-Aug-13

Model-Guided Design Space Development for a Drug Substance Manufacturing Process
Model-Guided Design Space Development for a Drug Substance Manufacturing Process
2011-Jul-26

A Data Driven Model Based Approach to Scale up of Hydrogenation Reactions in the API Industry
A Data Driven Model Based Approach to Scale up of Hydrogenation Reactions in the API Industry
2011-May-30

Applications in Kilo Lab Flow Chemistry and Scale-up
Includes examples of modeling reactions in a PFR and centrifugation.
2011-May-30

Scaling Up and Plant-to-Plant Transfer of Safety Data for an Exothermic Reaction
Scaling Up and Plant-to-Plant Transfer of Safety Data for an Exothermic Reaction. Calorimetry. Gas evolution. Qr. Rc1, ARC.
2011-May-30

Kinetics of a SnAr Reaction
Kinetics of a SnAr Reaction
2011-May-30

Models, Mass Balance, and Analytical Data
Models, Mass Balance, and Analytical Data
2011-May-30

Reaction Kinetics as a tool to underpin Control Strategy
Reaction Kinetics as a tool to underpin Control Strategy
2011-May-30

Pilot Scale Design and Continuous Manufacture of Novel Explosives Using Kinetic Modelling
Pilot Scale Design and Continuous Manufacture of Novel Explosives Using Kinetic Modelling
2011-May-11

Development of Kinetic Model and Process Prediction
Development of Kinetic Model and Process Prediction
2011-Apr-28

Kinetic Model Development for Reversible Reactions
Kinetic Model Development for Reversible Reactions
2011-Apr-28

Genotoxic Impurities: Strategies for Identification and Control
Modeling of reactions that can produce genotoxic impurities; comparison of model results with experimental data. Using the model to indicate the risk associated with using certain reagents. Work completed in PQRI collaborative project.
2011-Mar-29

An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design
An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design
2010-Nov-19

A Mechanistic Insight into a Simple C−N Bond Formation via SN2 Displacement: A Synergistic Kinetics and Design of Experiment (DoE) Approach
A Mechanistic Insight into a Simple C−N Bond Formation via SN2 Displacement: A Synergistic Kinetics and Design of Experiment Approach
2010-Oct-04

A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes
A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes. From PQRI project on genotoxic impurities.
2010-Mar-31

Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride
Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride
2010-Feb-28

Up-front Thinking to Design a Better Lab Scale DoE
David Place and colleagues discuss use of a basic kinetic model to help design a more informative and valuable set of experiments.
2009-Nov-01

Use of Mechanistic Models to Develop Design Spaces for Drug Substance Production
Peter Clark of Scale-up Systems discussed the use of mechanistic models with explanations and examples selected for pharmaceutical scientists.
2009-Nov-01

Feasibility study for a passive trip system to prevent a runaway reaction in a batch reactor
Feasibility study for a passive trip system to prevent a runaway reaction in a batch reactor
2009-Aug-31

Highly efficient asymmetric synthesis of Sitagliptin
A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed.
2009-Jun-01

DynoChem Applications in Abbott's Process Safety Laboratory
DynoChem Applications in Abbott's Process Safety Laboratory. Calorimetry. ARC, Rc1, Qr, Hydrogenation, UA.
2009-May-01

Why Study a Synthetically Useless Reaction? - Unravelling Sulphonate Ester Formation using DynoChem
Review of lab and modeling work carried out in a PQRI project to establish the kinetics of sulphonate ester formation. Includes interesting and useful remarks on the 'wheel of life' of a Dynochem project.
2009-May-01

Optimization and Scale Up of chemical reaction during an API project development
Reviews application of a combination of experiments and modeling to ensure successful scale-up.
2009-May-01

An Example from GSK's Design for Manufacture Initiative: Use of Dynochem in Conjunction with Lab and Pilot Scale Data to Advance Process Understanding
DynoChem was used to develop a kinetic model for the main and side reactions using mechanistic understanding and lab/pilot scale data and to establish a suitable mechanism for the reaction to enable troubleshooting throughout lifecycle management.
2009-May-01

Pilot Plant Unit Operations Modeling as a Process Scale Tool
Mixing calculations were performed to estimate mass transfer effects for a fit-for-purpose heterogeneous reaction. Lab scale calorimetry data was scaled-up to determine required addition rates. These rates were implemented and resulted in success.
2009-May-01

Roles of mechanistic and empirical modeling / DOE in achieving Quality by Design
Mechanistic models can enhance DoE models, either indirectly or directly by inclusion in the DoE by numerical response. Response models have the potential to be used to generate the
design space predictively - “dynamic design space”.
2009-May-01

Using DynoChem to Scale Up Data from Various Calorimeters
Data from various calorimeters can be used to develop kinetic models. Potential pitfalls exist when stretching and scaling calorimetry data – obtain thermokinetic models if possible. Carefully plan lab experiments to get the most appropriate data.
2009-May-01

How Process Safety and Environmental lab can guide Process Development
Merck Environmental and Process Safety lab organization. Integration of Environment and Safety to Process Development. Three examples of how Environment and Process Safety can guide process development.
2009-May-01

DynoChem Modelling of 3 Continuous Stirred Tank Reactors
How to Pretend to be an Engineer using
DynoChem’s User Support Group. Able to demonstrate that the model reliably predicted the results in the laboratory. Reassured the plant manager that the continuous process would provide throughput and quality.
2009-May-01

Modeling is the Easy Part! : Getting the right data and getting the data right is the challenging part!
A good understanding of the reaction concentration with external analytical methods is needed to convert in situ analytical data into concentration.
2009-May-01

Using DynoChem to determine a suitable sampling endpoint for reaction analysis in a DoE
If an adequate Kinetic model of the mechanism can be elucidated, DoE factor ranges can be investigated prior to committing time & resource. Dynochem is a powerful tool that enables the process chemist to leverage data collected from 4 “shake- down” runs.
2009-May-01

N,N′-Carbonyldiimidazole-Mediated Amide Coupling: Significant Rate Enhancement Achieved by Acid Catalysis with Imidazole·HCl
Over a series of 10 aromatic amines we show the rate of CDI mediated amidation to be significantly enhanced upon introduction of imidazole·HCl as a proton source for acid catalysis.
2008-Dec-05

An Example from GSK's Design for Manufacture Initiative: Use of Dynochem In Conjunction with Lab and Pilot Scale Data to Advance Process Understanding
An Example from GSK's Design for Manufacture Initiative: Use of Dynochem In Conjunction with Lab and Pilot Scale Data to Advance Process Understanding
2008-Nov-01

Process Modeling Based Approach towards Quality by Design for An API Synthetic Step
Process Modeling Based Approach towards Quality by Design for An API Synthetic Step
2008-Nov-01

Use of In-Line FTIR for the Kinetic Study of the Reaction and Degradation of Propylene Oxide In the Synthesis of a Pharmaceutical Intermediate
Use of In-Line FTIR for the Kinetic Study of the Reaction and Degradation of Propylene Oxide In the Synthesis of a Pharmaceutical Intermediate
2008-Nov-01

Understanding the Impact of Magnesium to Grignard Reaction Kinetic through on-Line Monitoring
Understanding the Impact of Magnesium to Grignard Reaction Kinetic through on-Line Monitoring
2008-Nov-01

Integration of PAT for the Development and Scale-up of a Hydrogenolysis Reaction
Integration of PAT for the Development and Scale-up of a Hydrogenolysis Reaction
2008-Nov-01

An Application of Reaction Engineering and Modeling In Quality by Design
An Application of Reaction Engineering and Modeling In Quality by Design
2008-Nov-01

A catalyzed and highly selective ester reduction in the synthesis of an N-Acylpyrrolidine: Safe design through reaction calorimetry and modeling
A catalyzed and highly selective ester reduction in the synthesis of an N-Acylpyrrolidine: Safe design through reaction calorimetry and modeling
2008-Oct-01

Process Safety Testing and Process Modeling in the PSL Using DynoChem
Process Safety Testing and Process Modeling in the PSL Using DynoChem. Calorimetry. ARC, Rc1, Qr, Hydrogenation.
2008-Oct-01

Scale-up of Safety Data using Dynochem
Scale-up of Safety Data using Dynochem. Calorimetry. Gas evolution. Qr. Rc1, Omnical, ARC.
2008-Oct-01

Overview of DynoChem for safety applications
Overview of DynoChem for safety applications
2008-Oct-01

Modeling-Based Approach towards On-Scale Implementation of a Methanethiol-Emitting Reaction
Modeling-Based Approach towards On-Scale Implementation of a Methanethiol-Emitting Reaction
2008-Mar-08

Development of a scalable synthesis of GSK183390A, a PPAR alpha / gamma agonist
Development of a scalable synthesis of GSK183390A, a PPAR alpha / gamma agonist
2007-Nov-01

Application of Modeling in a Qbd Context
Application of Modeling in a Qbd Context
2007-Nov-01

Modeling Based Approach towards on-Scale Implementation of a Methanethiol Emitting Reaction
Modeling Based Approach towards on-Scale Implementation of a Methanethiol Emitting Reaction
2007-Nov-01

Optimising reaction performance in the pharmaceutical industry by monitoring with NMR
Optimising reaction performance in the pharmaceutical industry by monitoring with NMR
2007-May-01

Application of DynoChem to kinetics in the laboratory and pilot plant.
Application of DynoChem to kinetics in the laboratory and pilot plant.
2007-May-01

Modeling based approach towards on-scale implementation of a methanethiol emitting reaction
Modeling based approach towards on-scale implementation of a methanethiol emitting reaction
2007-May-01

Using DynoChem to reduce batch cycle time in a gas-liquid reactor and commission a new unit.
Using DynoChem to reduce batch cycle time in a gas-liquid reactor and commission a new unit.
2007-May-01

Optimizing a multiphase reaction using DynoChem
Optimizing a multiphase reaction using DynoChem
2007-May-01

Modeling and optimizing adiabatic multiphase, multisolid reaction systems with DynoChem
Modeling and optimizing adiabatic multiphase, multisolid reaction systems with DynoChem
2007-May-01

Scale-up optimization using simulation experiments.
Scale-up optimization using simulation experiments.
2007-May-01

GSK approach to enhancing process understanding using DynoChem: reaction kinetics examples
GSK approach to enhancing process understanding using DynoChem: reaction kinetics examples
2007-May-01

A case study of data-driven and model-based scaleup approach for API process development
A case study of data-driven and model-based scaleup approach for API process development
2007-May-01

Facilitating late stage development through integrated process modeling
Facilitating late stage development through integrated process modeling
2007-May-01

Discovery and development of a novel asymmetric hydrogenation of an unprotected enamine in the synthesis of Januvia: process improvements via mechanistic insight.
Discovery and development of a novel asymmetric hydrogenation of an unprotected enamine in the synthesis of Januvia: process improvements via mechanistic insight.
2007-May-01

Scale-up from RC1 and ARC safety tests using DynoChem
Scale-up from RC1 and ARC safety tests using DynoChem. Calorimetry. Gas evolution. Qr. Rc1, Omnical, ARC.
2007-May-01

Comparative evaluation of commercial software for kinetic parameter estimation.
Comparative evaluation of commercial software for kinetic parameter estimation.
2007-May-01

DynoChem and homogeneous mixing: an example
DynoChem and homogeneous mixing: an example
2007-May-01

DynoChem case studies in the safety lab
DynoChem case studies in the safety lab. Calorimetry. ARC, Rc1, Qr, kinetics.
2007-May-01

A kinetic investigation into the removal of carbobenxyloxy group from protected amines via hydrogenolysis reaction
A kinetic investigation into the removal of carbobenxyloxy group from protected amines via hydrogenolysis reaction
2007-Apr-01

Screening Adiabatic calorimetry: Simulation phi=1 in glass test cells by increasing the concentration
Screening Adiabatic calorimetry: Simulation phi=1 in glass test cells by increasing the concentration
2006-Jul-01

Emerging Technologies Supporting Chemical Process R&D and Their Increasing Impact on Productivity in the Pharmaceutical Industry
Review of parallel experiments (DoE), reaction kinetic modelling, kinetic analysis, QbD (design space) and new technologies (e.g. continuous reactions)
2006-May-27

Modeling and Reactor Design for a highly Exothermic Reaction System
To identify safe operating conditions, a three step kinetic rate expression is postulated. The fitted model is used to select the best reactor configuration. Validation by successfully running both glass-plant and pilot plant scale batches.
2005-Nov-01

Identification of New Catalysts to Promote Imidazolide Couplings and Optimisation of Reaction Conditions Using Kinetic Modelling
Identification of New Catalysts to Promote Imidazolide Couplings and Optimisation of Reaction Conditions Using Kinetic Modelling
2004-Oct-01

Scale-up of homogeneous and heterogeneous reaction systems based on kinetic modelling and RC1 data in DynoChem
Scale-up of homogeneous and heterogeneous reaction systems based on kinetic modelling and RC1 data in DynoChem
2003-Sep-01

Characterisation of the scalability of hydrogenation reactions
Characterisation of the scalability of hydrogenation reactions
2002-Sep-01