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The Challenges of Increased Complexity in API Development and Manufacture

There is no getting away from it: the small molecule drugs now entering and travelling through the clinical pipeline are becoming more complex. This increasing complexity poses a variety of challenges that pharmaceutical and biotech companies will need to overcome. First, there is the molecule itself. It may be that, as an integral part of the way it is designed to hit the target, it includes features and moieties that are difficult to make. Chiral molecules, for example, nowadays are unlikely to be progressed unless they are single enantiomers, and this requires chirally selective chemistry or separation processes to make them. The more chiral centres it contains, the greater the complexity of the synthesis is likely to be. Complexity in the chemical structure might also result from functional groups that are difficult to handle or insert, or perhaps the molecule has one or more quaternary centres, which can be particularly challenging. Moreover, if the final molecule or intermediates are highly potent, their development and manufacture will require special handling procedures, including dedicated equipment with high containment, and trained personnel.

The chemistry required to make it might also be complex. While skilled process chemists will do their best to find alternatives, there are times when it is unavoidable. Some reactions require very low temperatures or high pressure. Or they might involve reagents that are particularly hazardous, perhaps because they are extremely toxic, or even explosive. As an example, a client engaged us to make an API for Phase 1 studies where the synthesis involved an unstable intermediate within the synthetic route. This intermediate required very low temperatures to prevent degradation, and new equipment would be needed. The installation and qualification of this equipment had a long lead time and added to the cost. Moreover, the workup and purification of the molecule were particularly laborious. The low stability of the intermediate and the related low purity (about 80%) had a knock-on effect on the subsequent step, which gave a yield of just 58%. The crude API also had low purity, which therefore also required a tedious purification.

An obvious change to make seemed to be to try switching to a different, more stable intermediate. This was successful, and the increased stability of the new intermediate meant that 97% purity could be achieved with a simple aqueous work-up followed by crystallisation. This increased purity improved the subsequent step, too, with an improved yield of 77%. A re-slurrying was all that was required to achieve the desired purity of the final API.