| TECHNOLOGY |
Sonocrystallization--or crystal formation through ultrasound--has been around for a long time in the lab. The problem has been in scaling up systems based on metal probes sticking into crystallizers. "That doesn't work because you tend to get hot spots," she says. "The ultrasound is thrown just a couple of centimeters from the probe tip instead of throughout the reactor. Plus, the probe erodes, giving all kinds of contamination problems." In the Co.'s design, ultrasound is delivered through transducers bonded onto the outside walls of a flow cell. The flow cell may be configured with the crystallizer in two ways. In a batch mode, it is connected through a tube through the crystallizer lid. When the crystallizer contents are ready for seeding, an aliquot is sent up to the flow cell by vacuum or pressure and treated for the period required to form the desired crystal seeds. Then the seeds are dropped back to the bulk. This setup is used when the goal is to use ultrasound to produce seed crystals only.
In a continuous mode, the flow cell is connected to the crystallizer in a loop. Material from the bulk enters the loop, is treated in the flow cell, and then circulates back to the crystallizer. This setup is used when the bulk needs to be treated with ultrasound to control size distribution. McCausland says both modes have been scaled up to 4,500 L. there is evidence that use of ultrasound to nucleate potentially polymorphic systems likely forms either the ground-state polymorph or one near the ground state. Where this can be very useful is when a drug candidate has been screened for polymorphs and a potential ground state has been identified. "We can run tests with ultrasound and see if we can get a more stable polymorph. "You can never prove that any technique produces the ground state. In a lot of development projects, you don't know what the ground state is."
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