The control of crystal particle size of active pharmaceutical ingredients (APIs) is necessary where the final product performance is reliant upon having well defined and engineered mesoscopic particles. The size of the particle and the crystal form of the active ingredient can influence behaviour, such as rate of dissolution. This is of particular importance given that over 40% of new molecules being developed are poorly water soluble.

There is need for developing technologies that can tailor particles for a variety of applications. For many new drugs, the need for improved and efficient drug delivery systems has become apparent, especially when administered in a particulate form. In respiratory drug delivery, effective deep lung deposition is achieved with particles of one to five microns in size.

Size reduction –or ‘top-down’ destructive -methods for mesoscopic particles, such as fluid energy milling (or micronizing), are capable of achieving the target size range, but the high energy required for such processes often damages the crystal surface, leading to highly charged and cohesive particles which results in the chemical and physical instability of the drug. We may also see undesirable surface polymorphological transformation and amorphous structure. Micronization can also lead to generation of considerable heat which may be incompatible with the material of interest.

SAX^TM particle engineering technology for the production of microcrystalline particles with narrow size distribution now shows great promise in applications for preparing particulate pharmaceuticals with defined physicochemical properties. SAX involves the formation of a drug substance solution followed by its atomization, controlled evaporation of the solvent, collection of the pre-concentrated viscous droplets in a vessel containing non-solvent and crystallization via nucleation with power ultrasound. The product slurry is then transferred to solid isolation, preferably by spray-drying or supercritical carbon dioxide drying. Our proprietary screening methods for SAX and related techniques involve Design of Experiments taking account of: Solvent and solubility, Atomizer and atomization, Productivity and flow rate, Temperature, and Ultrasound and non-solvent - see process flow-chart.

SAX and related techniques for the preparation of micro and nano-crystalline particles for drug delivery take things to a different level in terms of crystallinity and morphology control. To achieve optimal drug delivery to the lung it is important to ensure that the drug is formulated into particles of the appropriate aerodynamic size, shape and density. With SAX techniques we have manufactured particles for asthma and COPD as well as inhaled antibiotics.

SAX is a scalable, economic and generally ambient temperature and pressure technology, and is used to produce micron and submicron crystalline particles for drug delivery. Importantly the technology is eminently scalable and is undergoing rapid engineering and chemistry development.

This ‘solution to particle’ methodology avoids many of the issues apparent with the various methods available to date. Importantly, the use of SAX also allows the production of uniform and often spherical drug particles with unique nanotopology and superior aerodynamic properties. SAX has been applied to many compounds to date including the steroidal asthma drugs Budesonide and Fluticasone, long acting beta-agonists (LABAs) Salmeterol and Formoterol, antibiotics for inhalation, and many new chemical entities (NCEs) under development.

It also provides the platform for a novel particle engineering solution whereby a single droplet containing the two or more APIs in an exact ratio can be converted to a combination particle containing the very same drug substances as separate crystalline entities. In combination therapies for asthma and COPD the APIs often have synergistic action at molecular and cellular level (such as inhaled steroids and long-acting beta agonists) and need to be delivered in an exact ratio to the site of action in the lung. Indeed triple therapy has now also become possible with SAX technology and the scale-up concepts as illustrated left..

We believe SAX and other sonocrystallization technologies are set to revolutionize the manufacturing inhaled medicaments. SAX is now available for partnering and evaluation.

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