Sonocrystallization Applications

What is Sonocrystallization?

Sonocrystallization is the application of ultrasound energy to control the nucleation of a crystallization process.

Applying Ultrasound to crystallization results in:

  • Nucleation at the lowest level of supersaturation where the crystallization overcomes the tendency of the compound to re-dissolve in the solution
  • Narrowing of the metastable zone width
  • Narrow particle size distribution
  • Decrease in the level of undercooling necessary to achieve crystallization (hence avoiding crash crystallization)
  • Highly repeatable and predictable crystallization
  • Polymorph control

Crystallization consists of two major events:

Nucleation: Solute molecules gather into clusters and reach a critical size to constitute nuclei

Crystal growth: Subsequent growth of the nuclei

An image demonstrating the sonocrystallisation process
The sonocrystallisation process

Depending on conditions, either nucleation or growth may be predominant over the other this results in crystals with different shapes and sizes.

Classically, Nucleation is random, and resultant crystallization processes are uncontrolled, leading to poorly performing API, and drug formulations

How does sonocrystallization work?

The ultrasound energy creates sequential compression then expansion. Over several cycles, a bubble forms and grows then collapses. The collapse of the bubble provides energy to encourage the nucleation process at the earliest possible point in time. This results in highly repeatable and predictable crystallization.

An image showing the sonocrystallisation bubble collapse process
The sonocrystallisation bubble collapse process

Particle Size Control

It is possible to control the size and number of particles produced by the timing of the application of the ultrasound to the supersaturated solution. Three examples are given below:

 1. Continuous ultrasound produces many nuclei resulting in small crystals  
 2. Initial ultrasound only produces finite nuclei which can be grown into large crystals  
 3. Pulsed ultrasound gives tailored crystal size  
Polymorph Control

Ultrasound can induce crystallization over a range of supersaturation conditions and therefore potentially access a range of different physical forms.

Low supersaturation: Tends to yield thermodynamic polymorph (most likely to produce a single polymorph)

High supersaturation: Tends to yield kinetic polymorph (if a stable kinetic polymorph is accessible)

The key advantage to polymorph studies using Sonocrystallization is reproducibility.

Polymorph control example:

  • L-glutamic acid has two polymorphic forms: alpha & beta
  • Meta-stable alpha-form: produced under kinetic control
  • The metastable alpha form is difficult to obtain
  • Use power ultrasound to reproducibly prepare the alpha or beta form
An image demonstrating sonocrystallisation reproducibility
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Category: Applications