Published in the April-May issue of PharmaChem, 2002
Written by Viktoria Cassersten, Market Communications Officer
Edited for the web site.

Cambrex Pharma supports the Pharmaceutical Industry by providing premium development and manufacturing services. Thanks to advanced and dedicated process safety work, performed in-house in different scales, the company handles hazardous processes many others refuse to undertake.

When handling high energetic processes, process safety is vitally important. Cambrex Karlskoga AB, one of Cambrex Corporation’s subsidiaries, dates back to the 19th century and the work of Alfred Nobel, the legacy of whom is synonymous with major scientific achievements and cutting edge technology.
When Alfred Nobel started to work with nitroglycerine during the 1850’s it was considered to be too dangerous to be of any practical use. The young Italian chemist Ascanio Sobrero invented nitroglycerine in 1846 by mixing glycerine with sulphuric and nitric acid. Nitroglycerine is extremely sensitive to physical impact and at that time, when impure nitroglycerine was used it was very difficult to predict under which conditions the liquid would explode. Alfred Nobel wanted to find a safer explosive and studied these problems in detail. He succeeded in creating a controlled detonation of nitroglycerine. His first major invention was a blasting cap (igniter), a wooden plug filled with black gunpowder, which could be detonated by lighting a fuse. This in turn, caused an explosion of the surrounding nitroglycerine.
   Alfred Nobel worked hard to improve nitroglycerine as an explosive that could be used in rock blasting and in mining. One of his most important discoveries was when he found that by mixing nitroglycerine with silica, the mixture could be turned into a paste. The paste could be kneaded and shaped into rods suitable for insertion into drilling holes. He called his paste dynamite and went on develop a blasting cap, which could be used to detonate dynamite under controlled conditions. The dynamite became the groundwork in Alfred Nobel’s world empire. Over the years, he founded factories and laboratories in some 90 different places in more than 20 countries.
   Towards the end of his life, Alfred Nobel acquired the company AB Bofors in Karlskoga. He decided to build a laboratory that became the basis of the more scientific developing work within Bofors. Alfred Nobel died in 1896 and at that time the company mainly developed and produced explosives. Nitration with nitric acid was the key technology to produce explosives and gunpowder.

Alfred Nobel (1833-1896). Cambrex Karlskoga AB, one of Cambrex Corporation’s subsidiaries, dates back to the 19th century and the work of Alfred Nobel.

Hazardous processes

During the 1930’s the company started to use the known technologies for producing other chemical products with civil applications. In 1941 the company produced its first active pharmaceutical ingredient and still it was the chemistry of nitric acid that was the base, i.e. nitration and oxidation. Also for these civil applications, these nitration reactions were hazardous and if not well understood and controlled might give di- or trinitro compounds or an auto oxidation of the material involved. 
  

Roland Ohlsson, Process Safety Engineer, preparing an experiment with the CPA.

Reaction calorimeter

 In the middle of the 1980’s the company needed to find out more in detail about chemical reactions heat-outputs and thermal stability profiles. Thus it would be possible to optimize the processes and get them more cost-efficient without compromising with safety aspects. Lars Stenmark, Research & Development Manager at the time, began to study the literature and do market research to find out what kind of techniques and instruments were available. He found that the Swiss chemical industry had a good method with a systematic approach using a reaction calorimeter. Data from experiments with the reaction calorimeter enabled a total control of the reaction and to study whatever synthesis desired. This technique also permits the monitoring of consequences if something goes wrong and thereby to determine the safety margins.
But the reaction calorimeter the Swiss’ used did not match Mr Stenmark's expectations completely. Mr Stenmark came into contact with the founders of ChemiSens: a small Swedish company specifically developing reaction calorimeters. Mr Stenmark immediately understood this version would be more suitable for the company needs (Nobel Chemicals at that time). The reaction calorimeter, a Chemical Process Analyzer (CPA), used a different measuring principle than traditional calorimeters. The reaction power was measured by independent heat flow sensors giving on-line a direct value of heat output regardless of heat transfer properties, agitation etc.

The CPA was improved out of the company’s experiences and demands

The CPA developed by ChemiSens was a prototype, which needed further development. Nobel Chemicals bought a CPA in 1988 and started to cooperate with ChemiSens to improve the reaction calorimeter technically as well as its performance. For the first time, the CPA was used in industrial applications. During the evaluation project, which lasted for three years, Nobel Chemicals tested several regular processes like nitrations, catalytic hydrogenations, diazotations etc. ChemiSens improved the CPA out of Nobel Chemicals' experiences and requirements.
   Thanks to the reaction calorimeter, the company was able to get an almost complete set of data for all kinds of reactions. To be able to get a complete set, Mr Stenmark also purchased a Differential Scanning Calorimeter, DSC, based on the power compensation principle.

 
The small stainless steel reactor is very similar in function to the full-scale ones. It is for example equipped with similar type of stirrers, pressure relief valve, emergency cooling, and inlets for liquids as well as solids.

   The more experience and knowledge the personnel gathered working with the CPA/DSC, the more convinced they were that they had chosen the right instruments. The CPA showed a very high technical excellence in performance. It is mainly used for isothermal measurements of the heat that will develop within the desirable reaction. From the data, it is also possible to determine the important degree of accumulation of energy at any stage of the reaction. The reaction calorimeter includes two different types of reactors, one in stainless steel and one in tantalum for more corrosive environments. Together they can handle almost every reaction the company has, from –50°C up to 150°C and also at elevated pressures up to 20 bars. The reactor is put in a thermostating unit bath that absorbs the heat withdrawn and also serves as a thermal surrounding for the reactor, which is essential for precise calorimetric measurements. The reactors are also very similar in function to the full-scale ones. They are for example equipped with similar type of stirrers, pressure relief valve, emergency cooling, and inlets for liquids as well as solids.
   The DSC is used as a screening test instrument to identify thermal hazard potential of substances, such as undesirable reactions like exothermic decompositions. A sample is heated from room temperature to 400°C and eventual heat output is measured. This is a fast technique requiring only a few hours for a complete scanning experiment and only a few milligrams of sample. The small sample size also permits testing of very energetic substances. To prevent sample evaporation, sealed high pressure crucibles of stainless steel or gold plated steel are used. Combined with isothermal (at constant temperature) experiments the kinetics of decompositions may be examined and thereby give an indication of the decomposition behavior. The isothermal mode is often used to estimate induction time (time to maximum decomposition rate) for reaction systems with autocatalytic behavior.

Data from CPA and DSC are vital when scaling up

The combination of CPA and DSC has become an extremely useful and powerful tool to provide data of hazard potentials for chemical substances and reaction mixtures. Today adiabatic and micro calorimetry for relevant substances and mixtures are added to the testing programmer when scaling up to full scale. For substances with structural groups which confer instability (nitro, nitramine, azide, diazo, peroxide etc) extra attention is always applied and these are still subjected to explosivity testing (impact, friction and heat). The data gathered is important input to safety review sessions prior to pilot and full-scale runs.

 
The DSC-technique only requires a sample of a few milligrams. The crucible material is stainless steel or gold plated, depending on the substance tested.

To summarize, the company has built substantial advantages in the process safety field. These consist of significant experience with difficult processes in different scales (kilo scale to production scale), remote control capabilities and broad availability of testing techniques. Dedicated risk analyses and assessments on advanced chemistry, based on chemical reactivity and thermal data as well as other chemical properties, have become a competitive edge for the company.  

REFERENCES

• www.nobel.se (Nobel e-museum)
• Rolf Berntson, retired Technical Director
• Lars Stenmark, Director, Development & Supercritical Fluid Technologies Department at Chematur.
• Roland Ohlsson, Process Safety Engineer at Cambrex Karlskoga AB