Antisolvent precipitation is an indispensable tool for the process chemist: Often crystallisation can be achieved by mixing a solution of the drug substance to be crystallised with an antisolvent, so that after mixing the solution is supersaturated and crystallisation occurs. Usually it is precipitation – or ‘crashing out of solution’- of 
amorphous and ultrafine particles due to extremes of supersaturation. Molecule-to-Particle techniques using power ultrasound such as anti-solvent precipitation take advantage of the excellent dispersive and crystal nucleation properties of transient cavitation. The precipitation conditions must be chosen to maximise crystal nucleation at the expense of growth.
We can take advantage of these effects by mixing in the presence of an ultrasonic field. The two streams can be mixed either in continuous mode or in a recirculation process loop using ultrasonic devices shown. In recirculation mode the antisolvent stream is recirculated rapidly through the flow-cell whilst the optional feed API solution is fed slowly into the flow cell whereby flow rates are often over 100:1. This leads to rapid dispersion and crystallization of micron and sub-micron sized particles which can then be isolated by spray drying for example. This ‘reverse’ antisolvent process (most often chemists would add antisolvent - Feed is antisolvent - to API solution) is essential so as to avoid growth of particles in a ‘normal’ antisolvent process. At Prosonix we have a range of dispersive technologies using ultrasound appropriately named Dispersive Crystallization with Ultrasound: DISCUSTM.
We have produced a number of microcrystalline steroids by this ‘reverse’ process and see this as an effective means of preparing mesoscopic crystalline particles at truly industrial scale. The options are quite diverse: The non-solvent –solvent system may be miscible, such as an ethanol solution dispersed into heptane, or immiscible where we might typically use dichloromethane or toluene dispersed into water, with continuous removal of the more volatile solvent. One can feed in a melt of the API (so long as the melting point is not unreasonably high). All these methods can be used for preparing aqueous nanosuspensions often with the use of stabilisers.
DISCUS Sonocrystallization can be applied to the preparation of aqueous nanosuspensions, or sub-micron colloidal dispersions of pure drug, being ideal formulations to improve bioavailability. Nanosizing is the size reduction of the API down to sub-micron range in an aqueous media; typically down to 100-200 nm size and stabilised with surfactants or polymers. The nanosuspensions can be dried using conventional techniques such as spray-drying or lyophilization.
This ultrasound mediated emulsion crystallization, developed by Prosonix, is a novel particle engineering technique, to facilitate formation of submicron to micron-sized particles in order to improve therapeutic efficiency. This technique is beneficial for poorly water-soluble drug candidates.
In a typical process, a drug is dissolved in organic solvent which is immiscible with the non-solvent of choice. Ultrasound is applied in order to achieve a stable emulsion. Each emulsified droplet can be subjected to heat or mass transfer effects so as to achieve either evaporation, cooling or diffusion in order to bring about the required degree of supersaturation and crystal nucleation. The application of ultrasound assists in the dispersion and stabilization of the drug particles in non-solvent.
We believe DISCUS and other sonocrystallization technologies are set to revolutionize the manufacturing inhaled medicaments. DISCUS is now available for partnering and evaluation.
