FAQ about Hazardous Chemistry

Hazardous Chemistry is usually defined as a process involving the use of highly energetic reactions and/or hazardous chemicals. Its use is well established for the commercial synthesis of APIs and intermediates and is offered by specialist CDMOs (Contract Development and Manufacturing Organizations).

Hazardous Chemistry is a key technology in the API process development toolbox, with potential to improve process cycle time, purity and yield, reducing both operational costs and environmental impact.
The use of Hazardous Chemistry can contribute to streamline API synthetic routes. The amount of impurities and by-product generated may also be limited, leading to cost-effective syntheses affording the targeted compound in high yields. 
Hazardous Chemistry can also lead to design new chemical structures with interesting bio-active properties, offering the means to improve overall product quality (e.g. Tetrazoles).

No, Hazardous Chemistry is run in similar equipment to classical chemistry and in the case of Novasep sometimes the same. Manufacturing equipment at Novasep Leverkusen is especially designed for running azide chemistry in order that such reactions can be scaled up to 3m³, 6m³ or 12m³ batch size as required. Nevertheless, the safety investigations before transferring and scaling-up Hazardous Chemistry need to be more elaborate than for simple chemistry. But as these tests are performed in-house and within the Process Development department, they are not a great cost contributor.

In case of explosive substances handling, a special permit from the authorities is required. Novasep’s Leverkusen site has such a permit. Azide chemistry is common at Novasep and therefore all production equipment on our site is especially designed for handling sodium azide.
One of the major threats is the formation of highly explosive heavy metal azides. To avoid that, all equipment is set up free of copper and its alloys. This is certainly a significant barrier for starting azide chemistry from scratch. Safety precautions for other Hazardous Chemistry reactions may be implemented on a case-by-case basis.

Our Leverkusen site was originally an explosives manufacturing site, and this continued until 1999. 
There are many bunkers on site: most of them are historic legacy but some are still being used for storage, manufacturing (e.g. nitroglycerin), or testing of explosives and high energy compounds (e.g. Koenen test).
Inside the plants, one will find typical reactors, equipped similarly to classical chemistry plants.
The differences are much less obvious and will probably only be noticed if one knows what to look for (e.g. no copper, see Q4).

There are chemical structures that are not easily synthesized without Hazardous Chemistry, such as the group of sartans which typically contain a tetrazole moiety. These are made in one step from a nitrile and an azide, typically sodium azide. For a non-hazardous route, a much longer synthesis would be required and the product itself would still contain the tetrazole which is a critical structure element with high energy content.

The handling of high energy compounds poses the risk of fast decompositions with a release of much energy, which can cause an explosion or a runaway reaction. An explosion of sensitive compounds may be triggered by rather little stimuli like impact or friction. The sensitiveness is tested in experiments defined by the UN-manual for tests and criteria and are being performed with all compounds with critical structure elements. Only if the results confirm the absence of an explosion risk, larger quantities of such compounds may be prepared. One counter measure for handling explosive substances may be a phlegmatization which would be developed at Novasep.

Under continuous conditions, the total volume of solution reacting at any given time can be
significantly reduced thus decreasing the associated hazards. In addition, flow reactors, have
increased heat exchange capabilities allowing to control more efficiently reaction exotherms than
their batch counterpart. 

But when looking at hazardous chemistry, handling of the raw materials, isolation of the final
product, drying… are multiple aspects that one should consider. Hazardous chemistry, whether
performed under batch or continuous conditions, requires a deep comprehension of the risks
associated with energetic chemistry and the expertise to handle such compounds.

Learn more about regulations for the handling of hazardous substances at Novasep:

In order to standardize the transport of hazardous substances, the United Nations are providing various recommendations:
“Since 1956, the United Nations Committee of Experts on the Transport of Dangerous Goods has compiled, maintained and updated what are known as UN Recommendations on the Transport of Dangerous Goods (UN Model Regulations Rev. 12, 2001).
These official recommendations include suggested standards on categorization, labelling, and harmonized numbering of DG items for quick reference. 
However, these official recommendations are not binding: local regulations can choose to adopt, enhance or exclude regulations.”
(Source: https://log.logcluster.org/display/LOG/Dangerous+Goods)

Source: https://log.logcluster.org/display/LOG/Dangerous+Goods

Storage depends on the hazard class and should be aligned with national authority permits (e.g. explosive substances may require a bunker for storage).

Discover the regulatory requirements on Novasep's Leverkusen site:

To find out the answer:

To find out the answer:

Hazardous Chemistry is certainly suitable for API synthesis and Novasep is indeed producing APIs under cGMP conditions with azide or other hazardous reactions on the very last step.
Novasep does not discriminate between hazardous and non-hazardous chemistry in this respect.

The valsartan case has raised the attention to a risk of nitrosamine contaminations in APIs. A nitrosamine risk assessment is standard at Novasep for all cGMP production. Azide chemistry needs special attention as sodium nitrite can be used to decompose residual azide but poses the risk of nitrosamine formation with secondary amines.
Novasep is establishing workup procedures without nitrite treatment in presence of the API or an intermediate. The azide decomposition will be performed either separately with azide containing phases or they will be incinerated directly on site in an incineration plant for liquid waste streams.

The development time for Hazardous Chemistry is only marginally longer than for non-hazardous chemistry as additional safety tests need to be performed.

Learn more about hazards assessment during process development:

Azide chemistry involves products that may have a high energy content and could be explosive. More significantly, sodium azide (and other hydrolysable azides) releases hydrazoic acid when acidified. Hydrazoic acid is low boiling and extremely shock sensitive (like nitroglycerin) but also highly toxic. It needs to be avoided under all circumstances to condense neat hadrazoic acid.
We recommend performing azide reactions under alkaline conditions or in non-protic media. If acidic conditions are required, conditions and the gas phase concentration of hydrazoic acid need to be carefully monitored.

Learn more about Novasep's assets for Hazardous Chemistry:

Learn more about Novasep's capabilities for Hazardous Chemistry reactions:

A safety test facility in-house is useful for performing Hazardous Chemistry as no compounds need to be transported outside the site and results are quickly available. Direct access to the safety specialists allows us to react quickly to problematic results and adjust processes accordingly.
Production equipment needs to be designed specifically for running azide chemistry safely. Other Hazardous Chemistry reactions may involve specific equipment.

With 2 sites in Europe able to handle hazardous reactions, Novasep has a proven track-record in developing and manufacturing APIs using Hazardous Chemistry:
- Our Leverkusen site, located in Germany, has more than 150 years of experience in energetic reactions.
- Our Chasse-sur-Rhône site, located in France, has more than 10 years of experience in Ozonolysis.

Novasep is experienced with a wide range of Hazardous Chemistry reactions such as Azide chemistry, Hydrazine reactions, Nitroalkane chemistry, Ozonolysis, Carbonylation, Cyclopropanation.

Our expertise also includes Alkyllithium handling, Hydroxylamine chemistry, Sodium metal handling, Hydrides handling, Highly exothermic reactions, the handling of explosive compounds, the handling of highly toxic materials and thermally/mechanically unstable.

Learn more about Hazardous Chemistry training at Novasep:

Novasep is used to handling explosives, but also to find modifications to such compounds so that they are no longer explosive. This is called phlegmatization. Typically, as much of an inert compound would be added to the explosive material as is needed to dilute it enough to lose this property. The nature of possible phlegmatizing agents will always be assessed together with the customer. Such agent could be a formulation additive for the API or a solvent used on the next step of the downstream chemistry of an intermediate.

Novasep is still producing well known nitroglycerin under cGMP conditions for medical purposes (e.g. treatment of angina pectoris).

Novasep is producing some compounds that are sold as standard products. Quite often they are either based on sodium azide or their manufacturing involves Hazardous Chemistry.

Find out more in our products catalog!