Of course quite often some co-crystals are very easy to deal with and simple cooling crystallization can be straightforward - they simply fall out of solution -but more often than not they can be awkward to deal with, and avoidance of fractional crystallization of the API or the co-crystal former needs to be addressed. Whilst grinding is a tried and tested screening method, ultrasound assisted approaches can be excellent - see patents on sonic slurry by Scott Childs. We are finding we get fantastic results for co-crystal preparation by avoiding API + co-crystal former slurries and using ultrasonic cavitation as a powerful nucleation tool for: (i) solution based work [cooling cryst, antisolvent variants], (ii) atomization / spray drying techniques whereby we can treat an API+cocrystal former (or individually depending upon solubility) to obtain nearly dry material lacking in structure / amorphous / partly amorphous and then use ultrasound to obtain co-crystals quite effectively (so called UMAX technique) then isolate crystals (often microcrystalline), and (iii) continuous techniques yet to be published but again using ultrasound. Type (ii) methods can also be seen as a continuous processing or in the very least batch continuous - just think spray-drying. The key is to have efficient use of 20-40 kHz ultrasound, and importantly have the ability to scale-up to commercial production with viable industrial sonocrystallization devices. Large scale sonocrystallization approaches to 'difficult' co-crystals are not too far away, if not already available via our methods.

Can ultrasound be used for continuous crystallisation manufacturing techniques ensure consistent crystal properties (size, distribution and morphology) and better filtration rates in the production of fine chemicals and pharmaceuticals?

The scientific fraternity is still uncertain whether we really need a liquid assisted grinding or solvent recrystallization for co-crystal synthesis.

There are interesting instances where one or the other has not yielded co-crystal. There are instances where mechanisms mediated by a eutectic are found to be pre-requisite and solution crystallization could not yield co-crystals. Sonocrystallization could very well provide a useful tool for co-crystals.

There appears to be a number of people looking into ways to up-scale co-crystals (from the bench) by conventional batch crystallisation. Having had discussions on continuous crystallisation as an alternative to batch processes, it seemed there could be some mileage in applying this approach to co-crystals. I think ultrasound might help.

I would be interested to hear if other people or Prosonix have explored this option or whether they see continuous crystallisation as a way forward for up-scaling co-crystals.

Many thanks.

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