Just because a drug has made it to the market does not mean there is no room for improvement in its synthesis. If the originator company is to alter its process, then there are the additional costs involved of changing the approved manufacturing process with the regulator, but if the savings are substantial then this can be well worth doing. Generics companies are not constrained in this way, and if they are to bring out their own versions on patent expiry, finding the cheapest possible way to make it will be advantageous to their bottom line in this very margin-driven sector of the market.
One example is the manufacturing process developed by Indian company Unichem to make tofacitinib, the small molecule rheumatoid arthritis treatment developed by Pfizer, and marketed as Xeljanz.1 The company focused on the synthesis of the key intermediate (3R,4R)-(1-benzyl-4-methlypiperidin-3-yl)methylamine, and its subsequent conversion to the citrate salt of the API. The authors state that the manufacture of this intermediate is the most costly part of the process, as it is both tedious and requires an expensive reagent, and while alternative syntheses have been published, these have numerous drawbacks, including complexity and poor chiral purity.
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