Accurate temperature control achieving big results, on a small scale

Development chemists at Johnson Matthey (JM) spotted subtle, yet statistically meaningful, differences in impurity profiles when studying the key processing parameters in the production of active pharmaceutical ingredients. They realised the root cause was the lack of consistency of temperature profiling provided by the parallel reactor they were using.

‘Without accuracy of temperature, you cannot conduct a successful design of experiment (DoE) exercise,’ says Timothy Davies, senior development chemist at JM.

Johnson Matthey’s impurity profiles fixed by Mya 4

Despite consistently setting the temperature to 55.0°C, the development team’s prior setup would show reaction temperature variations between 51.2 – 55.3°C over eight identical experiments. This led to an unwanted impurity content (at the end of the reaction) of between 1.98 – 3.23%.

Performing the same experiments in Mya 4, the reaction temperature was controlled accurately at 55⁰C across four repeats, which led to a lower and much more consistent impurity content profile at 1.84 ± 0.07%. With temperature being the most significant variable to affect impurity profiles in JM’s experimental studies, it had proven difficult to quantify the effect of other variables – such as stirrer speed and reagent stoichiometry. ‘The precision of temperature control provided by the Mya 4 has been essential to understanding key processing parameters of temperature sensitive experiments. It is allowing us to improve our understanding of current manufacturing processes,’ adds Davies.

Bridging the gap: R&D and mass production

Since installing their Mya 4 Reaction Station, the JM development team has obtained reproducible, reliable and meaningful results thanks to accurate and consistent temperature control. This upgrade in equipment is also allowing the development chemists at JM to carry out DoE exercises on a smaller scale, which was not previously achievable.

The link between process R&D and manufacturing is crucial, whether the process chemist is working on small-scale processes which will be applied on a manufacturing scale or studying existing manufacturing processes in the lab to better understand key reaction parameters. Achieving similar conditions, on small to large scale, is vital.

‘If we can get better experimental data and identify a key parameter to improve on a small scale – such as better temperature control – which will have an impact on manufacturing scale – such as a 5% increase in yield, this also helps justify capital expenditure in the production facility,’ says Davies.

‘Mya 4 fulfils the need of a multipurpose small-scale reactor system that is not over-specified. The fact that the unit is so versatile is a strong advantage,’ says Gilbert. ‘On previous systems I’ve looked at, flask sizes were limited to one or two options. I would have loved one two years ago so I could have used it as the workhorse for most of the project.’

Within a few weeks of being installed, Mya 4 was already making a huge difference in Purolite’s lab. Used daily for R&D work, Mya 4 supports critical projects including a multi-stage activation reaction at 40°C, with an exotherm which lasts about 10h. Mya 4 is also being used in an application to immobilise a protein on the surface of a resin at 30°C. With its limited temperature window to avoid denaturation and proximity to ambient temperature, it proved a difficult application before Mya 4. With experiments now directly scalable to pilot plant scale but also performed in smaller batches, this results in lower cost and less waste for Purolite.

Mya 4 is a four-zone reaction station that offers precise heating, active cooling, software control and data logging for 24/7 unattended chemistry.

This innovative reaction station provides ultimate flexibility: independent control over four zones with temperatures ranging from -30°C to +180°C, a wide choice of vessels from 2ml to 400ml and the option of magnetic or overhead stirring.