Speciality Chemicals Magazine SEP / OCT 2024 | Page 20

PHARMACEUTICALS

giving us reliable data to work with and extensive knowledge in the safe handling of the reagent .

Engineers then used the information to design the necessary plant equipment that could handle the chemical process safely , within the prescribed limits from the research . The diazomethane gas would be generated by reacting 4- ( N-nitroso-Nmethylamino ) -4-methylpentan-2-one ( NMK ) with potassium hydroxide and piped directly into the reactor vessel diluted with nitrogen for the chemical transformation . 4

However , the use of NMK as a precursor to diazomethane also has a number of safety implications : it is thermally unstable , decomposing violently from 120 ° C , and reacts with alkalis ( including concrete ) to generate diazomethane ; as well as evolving gas on standing .

Reaction calorimetry during the diazomethane generation indicated that reagents were potentially being accumulated , and with the reagents being immiscible , a phase transfer catalyst was necessary in the mixture , as well as consistent , monitored mixing and temperature control . The gas generation was to be controlled carefully so that it was not generated faster than it could be consumed by the chemical reaction , avoiding the build-up of any large concentration .

Further assessment of the diazomethane was conducted to determine the consequences of an ignition , and the effect on plant equipment and personnel . This confirmed that an ignition inside the equipment would be a detonation rather than deflagration . The operating parameters of the reaction were therefore designed to dilute the reaction environment with nitrogen at 25 % of the LFL in air and the concentration of diazomethane would never be greater than 2 %.

This was thus set to be below the LFL , providing a comfortable margin of safety either within or outside the reaction equipment . Even were there to be an ignition source present , the point of potential exclusivity would never be reached , and these parameters allowed for a large margin of safety , including errors in measurement of the LFL , plant measurement capabilities and any small deviations within the processing steps .

A robust and reliable control system was developed to ensure the reaction and gas concentration remained within the desired operating parameters , ensuring that the critical services of power and nitrogen were provided , and incorporating a reliable emergency shutdown system . The plant was also designed with T6 temperature classification , meaning that the maximum surface temperature generated by the equipment would be 85 ° C , to address any concerns of the auto ignition temperature and risks of flammability . To protect personnel and minimise the risk of toxic exposure , all work was to be conducted in a dedicated building with remote operations . Ventilation systems and pipework were located outside the building to avoid any build-up of diazomethane within the plant , and the building ’ s ventilation stacks were monitored to ensure the environment and local community were not exposed to any contamination through emissions .

A third hazard study was then undertaken to test the design in terms of the potential for over-concentration of the reaction , any release of toxic gas from the scrubbers , and any leak of the system . The consequences of these were modelled to recognise the potential extent of an explosion or gas leak , to identify event frequency and identify any available improvements .

Further refinements to the design were then made . Additional safety integrity level trips were added around the reactors to maintain the excess dilution of the gas with nitrogen and multiple scrubbers were implemented with redundancy in the circulation pumps , alongside auto-changeover systems within the exhaust system .

Results

The outcome of the project was successful : the end product was delivered to the customer and Sterling had no safety incidents , allowing it to define an operational procedure for conducting diazomethane reactions at scale . To date , the company has used over 500 kg of diazomethane generated in situ for manufacturing campaigns .

Implementing early hazard identification studies was shown to be beneficial and provided Sterling with reliable safety data , with which it could perform safe , efficient chemical reactions in the hundreds of kilogram scale , with multiple containment and risk-mitigation strategies . By spending time to understand and evaluate the specific hazards , a material that would be widely viewed as incompatible with large-scale manufacture could be handled safely and with reproducible results across multiple batches . ●

Sam Brogan

HEAD OF R & D

20 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981