The Leeds team, working with Ana Kwokal of pharmaceuticals maker PLIVA, Zagreb, Croatia, has produced via batch crystallization the desired form of an active pharmaceutical ingredient called Entacapone, which has six polymorphs. A self-adsorbed layer of Entacapone on a gold substrate promoted the crystallization and controlled the form produced (Figure 1). More details appear in Crystal Growth & Design.
“If you imagine the way that oil sits on top of water, that’s similar to how the monolayer works, says Kevin Roberts, a professor in the Faculty of Engineering. “We’ve shown that we can produce a well-defined crystal structure using a self-assembled monolayer bound onto a metal substrate within a regular reactor… Because this is a really simple solution to ensuring consistent crystallization, it has huge potential commercially. Our next steps are to make sure it’s just as efficient on an industrial scale,” he adds.
“More research is planned but the timetable is not yet clear — probably it will involve the development of scale-up technology at Leeds,” notes Roberts.
“I think the technology is generic but Entacapone is favorable given the strong bonding of this particular molecule through its cyano group to gold,” he says. One prospective application is for materials that are hard to crystallize due to their conformational molecular flexibility. “SAMs can potentially enable easier growth, enabling us to achieve better quality crystals,” Roberts explains.
He also points to another driver for the use of the technique: “Scale-up of crystallization is always problematic due to mixing variation with scale and to the increasing volume/surface area with reactor size. SAMs can potentially be designed to provide better scale-up technology.”
One possible downside, though, is that by lowering the barrier to nucleation the technique tends to produce larger crystals, which may impact purity.
While gold particles serve as the SAM substrate for Entacapone, the team also has used the approach with cheaper substrates.
The key challenge for making the technique commercially viable is finding a robust crystallization catalyst support suitable for use at large scale that can be separated easily at the process end, Roberts says.
The Leeds development builds upon work done in the “Chemicals Behaving Badly II” initiative, a program of the U.K.’s Engineering and Physical Sciences Research Council.