• Isothermal reaction calorimetry is usually employed to provide thermodynamic and kinetic data for the desired reaction.
• What is the rate of gas or vapor generation during the desired process?
• Gas evolution rate and volume measurements should be incorporated (if necessary) as part of the isothermal process characterization stage.
• “Tempered” reactions (generating vapors) are more-easily controlled than “gassy” reactions (generating non-condensable gases).
From the thermal screening tests and isothermal reaction calorimetry, safe operating conditions can be determined. There are some specific issues relating to scale-up which can cause problems. Generally these relate to:
• Changes in heat-transfer rate as compared with small-scale equipment (reactor surface-to-volume ratio).
• Changes in mass transfer (power-to-volume ratio). Agitation is a critical function for safe chemical production since it impacts on the rate at which process materials come together and the rate at which heat is dissipated from the bulk of the mixture to the vessel wall or internal coils (where heat exchange occurs).
In addition to the factors outlined previously, other effects of scale-up may be equally as critical in ensuring safe manufacture. For example, the following factors should be considered:
• Changes in the purity of process materials.
• Changes in the materials of vessel construction.
Up to this point, the characteristics of the desired reaction only have been considered. In most cases, a process can be conducted safely if the normal procedure is followed. However, the potential for deviations from the normal procedure — as a result of human error or equipment malfunction — must be evaluated. Hazard assessment techniques (such as hazard and operability [HAZOP] studies) should be conducted to provide a formal strategy for the identification (and eventual correction) of potential deviations. It is then necessary to ask: What are the consequences of conceivable process deviations on the thermal safety of the process?
The structured hazard-identification approach should be supported by the examination of the consequences of the identified process deviations (either theoretically or, more usually, through further experimentation).
Once the hazard-identification stage has been completed, one or more bases of safety for the production-scale facility should be implemented and documented. Any safety measure that is applied should conform to the appropriate corporate engineering design codes. This applies to process control instrumentation or protective safety measures such as emergency relief venting, containment systems, etc.
The impact of each basis of safety on the other hazards presented by the process (e.g., flammability, explosibility, toxicity, environmental impact, etc.) must be considered.
The use of a “prescribed” method for assessing scale-up hazards is not considered to be a good approach. In applying such an approach, free thinking is not encouraged, and a “check-list mentality” ensues. By doing this, important issues that may be specific to individual processes may not be considered.
Broad guidelines, which describe the engineering and administrative activities to be conducted, provide latitude for free thinking during the scale-up safety review. At various stages during the scale-up review, adherence of the study to these guidelines should be ensured.
The team as a whole should verify that — at the end of each stage of the scale-up process — the relevant data have been compiled and that there is agreement concerning the elimination or adequate control of safety hazards. Evaluation of performance should be conducted after startup of each scale-up stage. In cases where unexpected events occur during scale-up, the cause of the event should be identified, and then the scale-up review should be examined to determine the root cause of the deficiency.
Safe scale-up of chemical processes can be achieved in a cost-effective and efficient manner. The utilization of the skills of many different disciplines within the research and development, engineering and production departments, allied to an efficient assessment strategy will achieve this. The selection of the most appropriate experimental technique required to generate the necessary data, combined with its interpretation in the context of the process lifecycle, is pivotal. The approach presented above will achieve safe scale-up in a cost-effective manner with little or no influence on the time to market.
ABOUT THE AUTHOR
Swati Umbrajkar, Ph.D., is the manager of the Chemical Process Evaluation Group at Chilworth Technology. Dr. Umbrajkar received her Doctorate from the New Jersey Institute of Technology. She consults with clients on process safety issues including high-pressure DSC cell tests, adiabatic calorimetry (ARC and ADC), reaction calorimetry (RC-1), all of which allow for the safe scale-up of batch and semi-batch processes. She has expertise in determining self-acceleration decomposition temperature (SADT) and time to maximum rate (TMR). She has authored several articles on the subject of chemical process safety. Contact: Swati Umbrajkar, Ph.D., Tel: 609-799-4449,