Ozonolysis in Flow

Going the Extra Mile for a Greener and Safer R&D 

The TAPI R&D team developed an innovative ozonolysis in flow synthesis process that offers a selective and environmentally friendly solution to a challenging, synthetic step in our route of synthesis. A prototype of an in-house developed flow ozonator was created and subsequently applied to the design of reaction equipment, enabling larger scale synthesis.  

In this blog, you’ll see how this approach resulted in minimizing the environmental impact, improving product quality, and ensuring high process safety.    

Background    

The oxidative C=C bond has been identified as a critical chemical transformation in the manufacturing process of the API Voclosporin. Traditionally, heavy metal-based catalysts are employed for this type of reaction. However, these catalysts often lead to over-oxidation and impurity formation.   

The use of heavy metals presents several challenges in terms of:   

• Product contamination, as heavy metals can contaminate the final product, affecting its purity.    

• Environmental impact, as catalyst leakage into the environment poses risks to ecosystems.    

• Waste disposal and recycling, as proper disposal of heavy metal-containing waste is complex and costly.   

The Advantage of Ozonolysis   

Although various oxidative reactions can be considered for this purpose, only a limited number of transformations are compatible with the sensitive molecular scaffold of Cyclosporine, requiring high selectivity and process robustness. One such reaction meeting these criteria is ozonolysis.   

Ozonolysis offers a selective and clean alternative to heavy-metal based oxidative double bond cleavage. In ozonolysis, side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Moreover, using proper equipment design, any excess ozone is catalytically decomposed back into oxygen.   

The Ozonolysis Challenge  

However, ozonolysis has significant drawbacks from an environmental, health and safety (EHS) perspective. There is an inherent toxicity and potential explosion hazard associated with the ozone, especially when mixed with flammable solvents, so precautionary measures are critical during the process design.   

 Large-scale batch ozonolysis is considered too hazardous, prompting the exploration of an alternative flow approach.   

The Flow Ozonator   

We set about to build an industrial flow reactor for ozonolysis, starting with a simple prototype based on 3D printing technology. This conceptual shift of reactor design aims to enhance safety while maintaining the desired reaction selectivity, product quality and process robustness. It also represents a unique solution since flow ozonator systems are not commercially available and therefore need to be designed as tailor made systems.   

A prototype of the flow ozonator was developed in-house in our R&D department. The first proof-of-concept system was 3D printed to verify basic functionality and perform feasibility lab studies. 3D printing technology was also used to improve the design of a larger scale, nGMP prototype that allowed us to overcome several technological challenges.    

The final design was subsequently applied to the production equipment, which met all Atex requirements of a production environment.   

The industrial equipment enabled successful production of GMP validation batches and will enable sufficient capacity. Notably, this approach minimizes environmental impact, improves product quality, and ensures high process safety.    

Side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Additionally, any excess ozone is catalytically decomposed back into oxygen, minimizing any EHS risk.   

9 Key features, functionalities, and unique properties of TAPI’s flow ozonator are as follows:   

• Ozone is produced and consumed in the same close reactor zone.   

• Excess ozone is continuously decomposed to oxygen in the same close reactor zone via an implemented catalytic ozone destructor.  

• Low amount of ozone at any point in the reaction – less than 100 mg.   

• High level of operator protection.    

• Low amount of flammable methanol actively mixed with ozone in the air – less than 50 mL.  

• Very short residence time – less than 10 s therefore overoxidation / formation of by-products suppressed.   

• Low reaction temperature used – reduced solvent vapour well below the flash point of methanol in air.   

• Very low accumulation of reactive intermediates.    

• Since synthetic process in production is continuous and there are no interruptions or delays, predicting and managing production times and costs becomes easier for businesses.   

The implementation of this creative in-house ozonolysis flow technology significantly enhances process safety, robustness and mitigates the environmental footprint associated with chemical processes and optimizes product purity profile and quality.   

It also represents a remarkable example of the benefit of continuous manufacturing applied to a challenging transformation of a complex API.   

For the avoidance of doubt, TAPI is not offering Voclosporin and will not sell Voclosporin, if such offer or sale infringes valid patents, unless in accordance with conditions permissible under applicable law.