Sota Kurita of KNC Laboratories Co Ltd explores the pros and cons of using ozonolysis in pharmaceutical process development.
Oxidation is an important reaction in organic synthesis and there are a number of methods available. Ozonolysis in particular has some unique advantages, including cleanliness and selectivity, and is frequently used by laboratory chemists. Ozonolysis has a number of advantages over conventional oxidation, including:
- Relatively quick reaction with good yields
- Relatively clean reaction and even less side reaction
- Easier purification through gaseous oxidants
- Lower production costs (especially with large-scale campaigns)
However, a number of shortcomings are also apparent:
- Oxidative/reductive work-up
- Low-temperature reaction
- The unstable nature of the ozonide intermediate
- The flammability of oxygen as an ozone precursor
- The need for purpose-designed equipment
Even taking these into account, ozonolysis is still an attractive option for a pharmaceutical process chemist, especially at the later stage of a multi-step synthesis. Ozonolysis offers significant advantages over conventional oxidation in terms of yield, selectivity and product purity, and this has an immediate effect on total production costs.
Refining production
The major concern surrounding ozonolysis in large-scale synthesis is process safety. Ozonide, the intermediate of ozonolysis, is by nature unstable, and many accidents have been reported. Generally, however, the stability of the ozonide increases with the size of the molecule, so the risk of an unstable ozonide will be significantly lower with a complex pharmaceutical intermediate.
In spite of these advantages, there is a major obstacle for pharmaceutical process chemists who opt for ozonolysis in drug development projects. Process development and validation of a pharmaceutical campaign is accomplished through a series of clinical trials, so process chemists also need to provide multi-kilogram-scale GMP material for these trials.
There are several precedents for commercial-scale ozonolysis, but few for pilot-scale production. This will be crucial in making ozonolysis a practical choice for process chemistry.
The process can be developed during clinical trials, and when the project faces possible scale-up to commercial volumes the process will be re-evaluated and modified to suit commercial production. In this situation, there are three options: scale-up; increasing the number of batches; or a continuous reaction.
Scale-up, the most common approach in conventional chemistry, is not the preferred choice for ozonolysis. Because of the unstable nature of ozonide and relatively high exothermic reaction, simple scale-up always runs the risk of runaway reaction, and it is almost impossible to control when it happens. Increasing the batch numbers may be safer and more practical, but scale-up has an immediate impact on the production cost.
Ozonolysis is particularly well suited to continuous reaction, which offers distinct advantages in terms of cost, flexibility and safety. Micro-reactor technology offers process chemists a powerful tool, delivering cost- and time-efficient process development.
Conversely, safety evaluation is vital to process development and successful scale-up. The stability of ozonide is clearly an area that requires further investigation. However, as has been seen, stability usually increases with the size of molecules, and can sometimes be safely isolated and purified by conventional flash chromatography. Ozone is a very strong oxidiser and highly toxic, and both ozonide and ozone have strong catalytic decomposition characteristics. The reactor system should therefore be carefully designed to minimise such risks.
The other major issue is oxygen; the concentration of ozone gas, which is generated by silent or corona discharge in pure oxygen, is usually up to 10 per cent, so flammability is a vital consideration, especially when using flammable solvent.
Recently developed thermodynamic analytical equipment, such as RC-1, ARC and TG-DTA, and in situ spectrometry, has made detailed process safety data readily available. Supported by a comprehensive assessment of process safety and a purpose-designed pilot plant, ozonolysis can potentially be a vital tool for pharmaceutical process chemists.
Company profile
KNC Laboratories Co Ltd specialises in the contract research and manufacturing of organic chemicals.