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Chemical process development and scale-up from the lab to a commercial scale presents challenges including engineering, safety, and economics. While personal experience and empirical data may be used to an extent, investigation requires the involvement of different disciplines, such as characterization of equipment, exploration of the thermodynamics of the process, mixing and mass transfer studies as well as the research of reaction kinetics and hazardous potential. Process scale-up is also governed by the heat transfer and heat removal. Reaction calorimetry combined with PAT inline monitoring accelerates the scale-up of a chemical process.
Mixing and Mass Transfer in Process Development & Scale-up
At the heart of scale-up in chemical process development is the fundamental understanding of the mixing process. Influencing mixing efficiency are the physical properties of the material being mixed, the design of the stirrer and the reactor, the mixing regime, and the position of the feed tube and the operating conditions. Chemical reactions in a stirred tank reactor may include reagents with more than one phase and/or state (liquid, gaseous or solid). These reactions require intensive interfacial contacting to facilitate optimal mass transfer. Improper or poor mixing may result in a low reaction rate, low yield, poor selectivity or increased concentration of impurities which increase the costs of manufacturing significantly.
Scale-up of Heat Transfer in Agitated Vessels
The heat dissipation in a stirred tank reactor is vital for the scale-up and safe operation of a chemical process. Batch and semi-batch reactors are still the most frequently applied type of reactors in the chemical and pharmaceutical industries. Variations of heat transfer may impact the scaling of a chemical process, design of the plant vessel, cooling system and potential safety considerations.
Efficient Scale-up & Process Control in the Chemical Industry
The earlier that non-scalable conditions are recognized, the more easily a process can be modified with improvements for safety. A webinar presented by Lubrizol focuses on how to improve process development and scale-up by leveraging calorimetry and in situ process analysis. Lubrizol redefined traditional process development to reduce the time and complexity of scale-up/scale-down.
A chemical reaction is affected by multiple parameters, such as concentration, addition rate, temperature, the solvent, catalyst and pH. Further, reactions may also be affected by the stirrer type or speed which impact the mass transfer and further influence the result of the experiment. Rather than adopting a "trial-and-error" approach, where each parameter is examined individually and interactions between them cannot easily be detected, scientists apply the DoE methodology in the synthetic organic chemistry lab.
Case studies from the Zurich University of Applied Sciences (ZHAW) and Lonza SA apply the Design of Experiments (DoE) methodology to:
- Identify the Impact of Reaction Parameters
- Reduce Process Variability
- Shorten Chemical Development Cycles
- Support the Quality-by-Design (QbD) Approach
Rapid Decision Making Enabled Through Chemical Process Intensification
Within chemical process development, program timing often dictates making informed decisions with limited process understanding, especially in the early clinical delivery space. To facilitate this, Merck & Co Pharmaceutical Process Development Intensification Laboratory presents how to acquire deeper, more fundamental process understanding in a resource-sparing manner.
Process development and scale-up workstations, such as OptiMax HFCal, RC1e with HFCal and RTCal, provide scientists with thermodynamic data in real time. Combined with in situ FTIR spectroscopy for real time reaction kinetics measurements, scientists and engineers can understand and model chemical reactions allowing the rapid scaling of a process from lab to plant.
Applications
Chemical Process Development and Scale-up Applications
How Heat Transport in Agitated Vessels Affects Process Scale-up
Scaling-up a chemical process from lab to manufacturing gives useful results only with accurate heat transfer coefficients. Measuring the jacket and reactor temperature (during the release of a well-defined amount of heat) allows researchers to accurately compute the thermal resistance which is used to model the heat transfer and make critical predictions for reactors at larger scale. Reaction calorimetry is essential to determine parameters that impact the heat transfer and the heat transfer coefficients to develop models to maximize the bandwidth of a manufacturing plant.
Mixing in a Chemical Reactor and the Effect on Reaction Kinetics and Scale-up
Mixing is the reduction or elimination of inhomogeneity of phases that are either miscible or immiscible. Process scale-up and optimization require that the impact of mixing on the reaction rate be quantified. Automated, controlled experiments can be run in parallel in a laboratory reactor system to establish a mass transfer correlation, and provide a means to quickly adjust the gas/ liquid interface area and reactor volume. This achieves the desired conditions required for the scale-up or scale-down of a process.
Screen and Optimize Catalysis, Hydrogenation, Polymer Synthesis and Other Reactive Chemical Syntheses
Chemists working in chemical synthesis discover and develop innovative chemical reactions and processes.
Optimize Crystal Size, Yield and Purity
Optimization and scale-up of crystallization and precipitation to produce a product that consistently meets purity, yield, form and particle size specifications can be one of the biggest challenges of process development.
Study Chemical Reaction Rates and Measure Kinetics Inline
In situ chemical reaction kinetics studies provide an improved understanding of reaction mechanism and pathway by providing concentration dependences of reacting components in real-time. Continuous data over the course of a reaction allows for the calculation of rate laws with fewer experiments due to the comprehensive nature of the data. Reaction Progression Kinetics Analysis (RPKA) uses in situ data under synthetically relevant concentrations and captures information throughout the whole experiment ensuring that the complete reaction behavior can be accurately described.
Determine the Safety of Chemical Processes Prior to Scale-up
How can I be sure that my chemical process is safe? It is critical to understand the risks inherent in moving a chemical process to a larger scale before manufacturing begins. The use of reaction calorimetry is an essential part of process development studies, providing detailed information about the rate of heat production. This allows researchers to optimize the temperature and dosing profiles to maximize process safety at all times, and reduce to a minimum the risks involved.
Scaling-Up Agitation, Dosing, and Crystallization
Changing the scale or mixing conditions in a crystallizer can directly impact the kinetics of the crystallization process and the final crystal size. Heat and mass transfer effects are important to consider for cooling and antisolvent systems respectively, where temperature or concentration gradients can produce inhomogeneity in the prevailing level of supersaturation.
Scaling-up a chemical process from lab to manufacturing gives useful results only with accurate heat transfer coefficients. Measuring the jacket and reactor temperature (during the release of a well-defined amount of heat) allows researchers to accurately compute the thermal resistance which is used to model the heat transfer and make critical predictions for reactors at larger scale. Reaction calorimetry is essential to determine parameters that impact the heat transfer and the heat transfer coefficients to develop models to maximize the bandwidth of a manufacturing plant.
Mixing is the reduction or elimination of inhomogeneity of phases that are either miscible or immiscible. Process scale-up and optimization require that the impact of mixing on the reaction rate be quantified. Automated, controlled experiments can be run in parallel in a laboratory reactor system to establish a mass transfer correlation, and provide a means to quickly adjust the gas/ liquid interface area and reactor volume. This achieves the desired conditions required for the scale-up or scale-down of a process.
Chemists working in chemical synthesis discover and develop innovative chemical reactions and processes.
Optimization and scale-up of crystallization and precipitation to produce a product that consistently meets purity, yield, form and particle size specifications can be one of the biggest challenges of process development.
In situ chemical reaction kinetics studies provide an improved understanding of reaction mechanism and pathway by providing concentration dependences of reacting components in real-time. Continuous data over the course of a reaction allows for the calculation of rate laws with fewer experiments due to the comprehensive nature of the data. Reaction Progression Kinetics Analysis (RPKA) uses in situ data under synthetically relevant concentrations and captures information throughout the whole experiment ensuring that the complete reaction behavior can be accurately described.
How can I be sure that my chemical process is safe? It is critical to understand the risks inherent in moving a chemical process to a larger scale before manufacturing begins. The use of reaction calorimetry is an essential part of process development studies, providing detailed information about the rate of heat production. This allows researchers to optimize the temperature and dosing profiles to maximize process safety at all times, and reduce to a minimum the risks involved.
Changing the scale or mixing conditions in a crystallizer can directly impact the kinetics of the crystallization process and the final crystal size. Heat and mass transfer effects are important to consider for cooling and antisolvent systems respectively, where temperature or concentration gradients can produce inhomogeneity in the prevailing level of supersaturation.
Publications
Publications Related to Chemical Process Development and Scale-up
White Papers and Guides
In chemical process scale-up, understanding temperature change and the associated heat that is accumulated by the reaction are critical to process saf...
This paper describes the Design of Experiments (DoE) approach and how it is used to identify the relationship between parameters, defining optimal set...
Grünenthal Process R&D safely automates dosing and runs highly exothermic reactions unattended to increase productivity without additional staff.
Advances in organic chemistry allow researchers to expand R&D of molecules and optimize process conditions. A new white paper presents 4 case studies...
Reaction Calorimetry provides an understanding of a chemical process and is a source of safety and scale-up information. Reaction calorimeters determi...
Citations
Continuous measurements from infrared spectroscopy are widely used for obtaining reaction profiles, which are used to calculate reaction rates. This...
Related Products
Products For Process Development and Scale-up
Reaction Calorimeters
Reaction Calorimetry For Screening, Process Development, and Process Safety Studies
FTIR Spectrometers
Fourier Transform Infrared (FTIR) Spectrometers For Real-Time Monitoring Of Chemical Reactions