The benefits of cryogenically generating microparticles pre-freeze drying

Robert Bullich, Telstar, discusses the generation and freeze drying of microparticles.

Freeze drying (lyophilisation) is a drying process whereby a product solution is first frozen and subsequently dried by solvent sublimation in primary drying and by desorption in secondary drying. Sublimation is the change of phase of the solvent from solid to gas without passing through an intermediate liquid phase.

In freeze drying applications, product is typically dosed in containers, vials or ampoules or in trays for bulk production. Conventionally, the product undergoes initial freezing inside the freeze dryer with product loaded onto a series of shelves inside a vacuum chamber. A heat transfer circuit cools down the shelves, freezes the product and removes the freezing latent heat. The same circuit can provide energy to the product to promote sublimation during primary drying and desorption during secondary drying.

Limitations of conventional FD

Freezing is a non-homogenous process. Product in containers freezes at different temperatures and at different points in time; the result is a crystalline structure which differs from one container to the next.

During sublimation heat must be transferred through the ice and little-by-little the solvent is sublimated.

Generating and drying microparticles avoids these problems and provides frozen product as microspheres that have been generated by a homogenous process. Microparticles have an enormous surface area compared to the block of ice present in conventional FD. When heat is transferred to the microspheres, sublimation takes place over the entire surface and thereby sublimation speed is increased.

Cryogenic generation of microparticles

Microparticles can be generated using various methods:

Spraying into liquid nitrogen: The microparticles are formed by atomisation of an aqueous feed solution containing the API beneath the surface of a cryogenic liquid (eg, liquid nitrogen). The aqueous solution is sprayed directly into liquid nitrogen through a capillary nozzle under high pressure to form frozen microparticles.

Dual-fluid nozzle: Product is atomised via a dual-fluid nozzle in a chamber. Atomizing N₂ gas and liquid are pressure-driven to the nozzle assembly. Liquid is fed to the nozzle cap and external atomisation is achieved by the exiting N₂ gas. Liquid droplets are frozen with liquid N₂ that is sprayed by pressure through nozzles.

Ultrasonic nozzle: The spray freezing is performed by atomisation of liquid solution into a separation funnel filled with liquid nitrogen using an ultrasonic nozzle.

Spraying into a cooling gas stream: Frozen microspheres are generated by dispersing the substrate liquid using high precision nozzles into single droplets, which by gravity pass through a cooling zone with a current of N₂ gas at low temperature, producing frozen particles.

Vacuum freezing: Liquid solution is sprayed as droplets into the top of a column under vacuum. As water evaporates from the particles the latent heat is removed and the droplets freezes to form particles.

Freeze drying process

After generation, frozen microparticles can be loaded into a freeze dryer in appropriate containers; vials or trays. Water is sublimated in the primary drying and desorbed in secondary drying as in conventional freeze drying processes.

Freeze drying conditions can be more aggressive than in the conventional process; due to the enormous surface area of the particles the sublimation rate is much higher and the duration of the drying process is substantially reduced. The reduction in drying time depends on the product, its concentration and particle size.

Advantages of microparticle freeze drying

The main advantages of this process compared to the conventional process are:

• Microparticles are frozen in an ultra-rapid process;
• Particles are spherical with a uniform size distribution;
• Droplets are frozen instantaneously into a homogeneously structure so there is no dispersion of concentrations. Crystal structure is homogenous from particle to particle. In conventional freeze drying the product undergoes concentration of components and the resulting dry product is not homogenous;
• Microparticles are dried very rapidly because the high surface area and cycle duration is consequently reduced;
• The dried product is in a convenient powder form and it doesn’t require a crushing process in order to be readily manipulated;
• Microparticles are porous and have good solubility.

Challenges

One problem is to increase the sublimation rate as much as possible while minimising product loss. At high sublimation rate, sublimating vapour exits the particle surface at high velocity in all directions, resulting in particle floatation. As a consequence of this mechanism, microparticles can be transported from the drying chamber to the condenser, where they are readily retained in the ice surface and lost upon defrosting.

To properly control the microparticle size is another challenge. Size depends on the nozzle diameter and the spray pressure. The various generation methods affect the size and uniformity.

Particle generation and freeze drying must be carried out under sterile conditions for aseptic parenteral products. All fluids and components of the system must be clean and sterile and sterility must be maintained during the process and during unloading of the dry product.

In all cases containment will be required to eliminate the risk of aerosols causing environmental contamination. 

Conclusions

Microparticles have new and exciting properties and lend themselves to a broad range of process applications. In the shorter term, the main opportunities are in non-sterile production: tablets, APIs, ingredients for inhalation, etc. Outside of medical products, there are also applications for food and general fine powder materials.