Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen

Abstract

Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issues such as waste container overpressurization or fire. In this study, multiple module calorimeter (MMC) testing along with micro-GC tests of small scale (1−2 mL) representative lab samples were performed to detect and predict the potential safety hazards associated with the scale-up of an ATH process. Due to the safety concern discovered in the early safety screening tests, methanesulfonic acid (MSA) quench was implemented at the end of the ATH reaction to suppress hydrogen generation, avoiding possible overpressurizing the waste drum and the need to use special hydrogenrated equipment at pilot-and production-scale. A safety assessment was performed to ensure that the subsequent vacuum distillation poses no risk of hydrogen combustion caused by using a standard pump/system. The process improvements and rigorous safety assessments enable the ATH reaction to be scaled-up using standard pilot plant equipment without the need for special handling and monitoring requirements for hydrogen gas. This study provides useful guidance and recommendations for safer scaling-up of similar organic synthetic reactions which may also generate flammable gas.

Performing Hazard Analyses and Setting Triggers for Reevaluation in Lab-Scale Chemical Reactions

“…Additionally, flow rates may change and the larger volumes of gas may increase the pressure beyond safe limits. 16,17 The Molecular Foundry focuses on exploratory research and not full-scale production, which is also the case in academic laboratories. Within our facility, revising the ISM form and holding safety discussions are required for scale-up.…”

Selective reduction of carboxylic esters enabled by a coaxial double-tube continuous-flow reactor with on-the-fly H2 degassing

“…18,22,23,27 As the lightest gas (14 times lighter than air), hydrogen gas represents a great hazard and risk owing to its wide flammability limits, low ignition energy and high deflagration index. 28 The rapid evolution of hydrogen gas in a batch stirred reactor during the reaction process can create a highly flammable and potentially explosive atmosphere. This might present a serious safety concern in practical operations, particularly on large scales.…”