Chemical Recovery, an important factor in manufacturing strategy
By Dr. Niteen A. Vaidya, Founder and CTO, ChiroSolve
Concerted steps are being made, within the chemical industry, to reduce the amount of waste product produced. Known as green chemistry, the chief aim of this movement is to reduce the cost, environmental impact and health hazards associated with chemical processes on a large scale through a systematic re-evaluation of the entire industrial process. Rather than focus on safe waste disposal, which is an end-stage process and does nothing to cut down on the amount of waste produced, green chemistry focuses on designing synthetic procedures using cheap, minimally harmful solvents, the lowest possible amount of reactants, that produce little to no waste product.
With the introduction of cap-and-trade legislation and the need for carbon economy within the chemical industry, a vital step in designing a green process is the recovery step, which involves isolation of solvents and reagents, after completion of the reaction. If the recovery process allows re-use of the starting material, it will also reduce the development cost. Normally, valuable catalysts or intermediates are difficult to recover, because recovery is often a tedious process, sometimes taking months at a time. It wastes the time of valuable scientists and the complete recovery of the valuable reagents is of course never certain. “Recovery is still a big challenge,” says Dr. Ashwin Krishnan, a synthetic organic chemist who has worked in asymmetric synthesis as well as chiral resolution for chemical and biotech companies. “It depends on the complexity of the molecule, and it can go for weeks or months. You cannot predict what will work and what will not.” Therefore thinking about the recovery strategy early on (rather than as an afterthought) during method development can save lot of efforts at the later stage. The need, then, is to design reactions that use least toxic chemicals, less volatile solvents, and recoverable material; so that you end up with overall green process.
Chemical recovery and recycling is specially a sensitive topic during the production of Enantiomerically pure compounds. This is because the most often used Chiral Resolution Techniques start with a racemic mixture, which is made up of two or more chiral isomers with different chemical, functional and biological properties. For drug molecules, in many cases, one isomer may have the desired therapeutic properties, while the other(s) may cause side-effects. As a result, US-FDA now requires the companies to develop chirally pure or enantiomerically pure drugs where possible. As a result, only small percentage (50% or less) of the racemate may be converted to the desired enantiomer, while the rest may become waste.
Standard separation procedures for recovery of most compounds, namely distillation, crystallization and chromatography are difficult and often expensive, but are the most viable for recovery efforts on an industrial scale. Of these techniques, resolution via diastereomeric crystallization remains the most widely used technique for recovery of chiral compounds.
When the diastereomeric crystallization process incorporates re-racemisation of the undesired isomer, a very high yield of the preferred enantiomer can be obtained at a much lower cost than is typically possible with other resolution or synthetic/biologic procedures.
In the racemisation process, the unwanted isomer is recycled through a chemical reaction step that causes its conversion back to racemic form; so that the process can be repeated again by re-using the newly obtained racemate. This process is repeated multiple times, with each subsequent pass yielding additional good product. In theory, a yield of 100% can be obtained with this method.
Whether racemization is incorporated in the process or not, diastereomeric crystallization is a useful method for identifying the optimum chiral resolution process for large scale manufacturing. Examples of commercially available drugs produced using this enantiomeric separation method include Paroxetine, offered by Novo Nordisk subsidiary Ferrosan, and Clopodogrel/Plavix, marketed by Sanofi-Aventis and Bristol-Myers Squibb (BMS).