Used for producing pasta, plastics, and more, extrusion is a widely used technique to combine and shape materials. Now, researchers report using twin-screw extrusion–where two solid reactants mix via a pair of interlocking screws and are ground together before being extruded–to synthesize biologically active pharmaceutical ingredients for the first time (ACS Sustainable Chem. Eng. 2020 DOI: 10.1021/acssuschemeng.0c03816). Because twin-screw extrusion operates continuously and without solvents, this process could potentially reduce the costs and environmental footprint of pharmaceutical manufacturing.
Pharmaceutical synthesis is notoriously inefficient. Producing the active ingredients in medications often requires a series of solution-based batch reactions that need steps to remove unreacted materials and by-products in between batches. Continuous flow reactions save time and reduce waste, but they still require solvents. Medicinal mechanochemistry, which blends solid compounds mechanically without solvents, has emerged as an alternative to further reduce waste. “I think it’s very inspiring,” says Evelina Colacino, an organic chemist at the University of Montpellier.
Previously, Colacino, who also leads a European initiative called Mechanochemistry for Sustainable Industry, used laboratory-scale ball-milling, a batch process in which metal balls grind materials together, to prepare dantrolene and nitrofurantoin, a muscle relaxant and an antibiotic commonly prescribed for urinary tract infections, respectively. Both compounds share a hydrazone functional group, which can be prepared by a condensation reaction. Using mechanochemistry for that step avoids solvents, heating, or adjusting pH, Colacino notes.
To perform this mechanochemical synthesis continuously, Colacino teamed up with Deborah Crawford, an organic chemist at University of Bradford, who has used twin-screw extrusion to prepare metal-organic frameworks and perylene dyes at large scales.
The researchers used a standard screw configuration that transports each reactant to a kneading chamber, where the two screws interlock, press the solids together and force them to react. After adjusting the chamber’s temperature and the rotational speed of the screws, the extruder generated 0.23 grams of nitrofurantoin per minute, with complete conversion to the desired E isomer and no additional purification steps.
The twin-screw extrusion technique could be very powerful, says Matthew Bio, who leads Snapdragon Chemistry, a company that designs flow processes for chemical manufacturing, including pharmaceuticals. More foundational knowledge will be needed before this can become mainstream, he says.
“There’s a lack of understanding, sort of like where continuous manufacturing was maybe 10 years ago or 15 years ago,” Bio says. Ensuring that the solid ingredients mix properly, especially if they have very different flow properties like sugar and flour, also adds to the process complexity, he says.
Crawford notes that some of this groundwork has already been laid (ACS Sustainable Chem. Eng. 2018 DOI: 10.1021/acssuschemeng.7b02202). “This area of research could progress rapidly,” she says. Large extruders operating at kilogram scales for other processes already exist. Pharmaceutical companies have also been using extruders for preparing co-crystals or formulations, so extrusion is not a completely foreign technique, Crawford notes.
Since pharmaceutical compounds can crystallize in different forms with varying physical and biochemical properties, a larger obstacle is the lack of information on whether crystals prepared by twin-screw extrusion are identical to their solution-based counterparts so that they can be substituted in drug formulations. To that end, Crawford is examining biological properties of active pharmaceutical ingredients prepared via extrusion. “We need to prove that we get the same materials that either work the same, or work better,” she says.