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Sound Waves Shake Pharmaceuticals Into Cocrystals

Chemical Engineering: Resonant acoustic mixing provides a green, scalable way to cocrystallize compounds

by Sarah Webb
February 6, 2014 | APPEARED IN VOLUME 92, ISSUE 6

Credit: Resodyn
Combining pharmaceutical compounds in a resonant acoustic mixer like this one forms cocrystals in multigram quantities.
Credit: Resodyn
Combining pharmaceutical compounds in a resonant acoustic mixer like this one forms cocrystals in multigram quantities.

Ideally, the active ingredient of an oral medication should readily form crystals, dissolve quickly in the digestive tract, and be rapidly absorbed in the body. If a compound can’t do those things on its own, scientists can help it by crystallizing the compound with one or more other compounds, forming cocrystals with the desired properties.

Now, researchers report that vigorously combining compounds using intense sound waves—a technique known as resonant acoustic mixing—could provide a green and scalable way to produce pharmaceutical cocrystals (Org. Process Res. Dev. 2014, DOI: 10.1021/op4003399).

Traditionally, chemists have produced cocrystals either by crystallizing the compounds together out of a solution or by grinding the chemicals together mechanically with a mortar and pestle or a ball mill. Mechanical methods limit the use of solvents and are therefore more environmentally friendly. But they are also difficult to carry out on the multikilogram scales needed in the pharmaceutical industry.

Jerry S. Salan, CEO of Nalas Engineering Services, in Centerbrook, Conn., thought of a way around this roadblock. He knew that resonant acoustic mixing produces enough force to combine and coat powders, so he wondered whether that force also could produce cocrystals. Acoustic mixers use high-intensity sound waves to transfer mechanical energy to the materials being mingled. The waves vibrate the materials inside a sample vial with forces 10 to 100 times that of gravity.

As a proof of concept, researchers at Nalas placed the anticonvulsant drug carbamazepine and the coformer compound nicotinamide along with a small amount of solvent into a resonant acoustic mixer. After one hour, the combination readily formed cocrystals that matched the quality of those formed by other methods. The researchers successfully produced cocrystals on a variety of scales, using 100 mg, 1.5 g, and 22 g of the solid starting materials.

Resonant acoustic mixing provides a way of screening cocrystallization conditions with various compounds and doesn’t need a lot of solvent, says Nalas’s David J. am Ende. Commercially available resonant acoustic mixers come in capacities up to 200 L, which should be sufficient for pharmaceutical-scale operations, the researchers say.

Over the past decade, pharmaceutical companies have realized that cocrystallization could offer a way to make better medicines, says Mike Zaworotko of the University of Limerick, in Ireland. “This paper addresses one of the major hurdles of how to make cocrystals on a larger scale,” he says. Further research will be needed to confirm that the process will scale up and to determine if this technique will apply to a range of compounds, he adds.

Nalas has filed a provisional patent for the cocrystallization process. It is seeking a commercial partner to help carry out additional studies needed to scale up the method.



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Harry Smith (February 9, 2014 9:22 AM)
This article does not present anything novel in it's approach. There is plenty of precedence in the literature regarding the use of ultrasound otherwise termed as acoustic mixers in this article and its application to co-crystallization. Ultrasound is only ideally capable of accelerating the nucleation rate of molecules from solution during crystallization and at a localized level enhancing solubility. Ultrasound is not responsible for shaking pharmaceuticals into co-crystals. On a molecular level these two compounds have to be compatible with each other from a bonding perspective Co-crystallization is very difficult even by mechanical and not possible with many other molecules. Ultrasound will not overcome physics unfortunately.

The example of carbamazepine and nicotinamide represents a very simple model system. Co-crystallization from solution without the need for ultrasound is very much feasible ,scalable and more importantly has already been demonstrated for the system discussed (Hammond and Roberts, University of Leeds). There is so much prior art out there its no longer worth investing in patents in my opinion as there really isn't an inventive step to defend.
David J. am Ende (February 18, 2014 3:22 PM)
It does not appear that Harry Smith has in fact read our article in OPRD (Org. Process Res. Dev. 2014, DOI: 10.1021/op4003399) because he mistakenly assumes we are claiming the use of ultrasonics for cocrystallization. This is not the case. Ultrasonics operate at a frequency above 20 kHz. We are in fact claiming the use of resonant acoustic mixing (RAM) wherein the entire vessel and contents are vibrated at a resonating frequency of about 60 Hz which is well below ultrasonic frequencies. Low frequency acoustic waves are efficiently propagated through solids. In addition, the resonance force exerted on the materials during RAM is 80 to 100 times the force of gravity and is uniformly distributed throughout the material. The demonstration that cocrystallization is facilitated by resonance acoustic mixing is new and was successfully demonstrated on several compounds beyond carbamazepine-nicotinamide. These include carbamazepine-4-aminobenzoic acid, carbamazepine-saccharin as well as CL20-HMX and other energetic cocrystals. We also claim that process conditions can be developed faster by this approach than by traditional solution phase crystallization. Scale-up of cocrystals is thus made amenable by maintaining the resonant g-forces across scales and thus fills a niche for scaling up cocrystallizations in general.

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