It is a function of the particle’s size, shape and density, with a ‘sweet spot’ of 1–5 µm for the particle to reach the deep lung. Larger, and it may well hit the back of the throat and be swallowed; smaller, and it’s likely to be exhaled before it reaches the target tissue deep in the lungs.

Aerodynamic diameter is not the only factor that affects the dose delivered to the lung, however. To be delivered to the lung, the dose first needs to be successfully emitted from the device. This emitted dose can also depend on particle size, but also moisture content, excipient choice, and active loading of the formulation. Both physical and chemical stability can play a role as well.

Particles for inhalation are routinely made via spray drying, and careful process design is critical if target properties are to be achieved. The API and any excipients are first dissolved together in a suitable solvent; for a small molecule this is often a mixture of an alcohol and water, while it is normally an aqueous buffer for a biotherapeutic.

The solution is pumped through an atomizer, which breaks it up into small droplets that are sprayed into a drying chamber containing a heated drying gas. The droplets start to shrink as they come into contact with the hot gas, with the outside initially forming a skin before fully solidifying. Finally, the particles are separated from the gas, and collected using a cyclone. The particles can have a range of morphologies; they might be reasonably spherical, for example, or could be more irregular and ‘raisin’-like.

Many variables can pose problems when scaling up. At the start of the process, the solution needs to be carefully prepared, which can be particularly challenging when working with a biologic, and may require another operation such as tangential flow filtration before the spray drying can begin.

Regardless of whether the API is a small molecule or a biologic, atomization is key to obtaining the optimal sized particles, and controlling this can get more difficult as the scale increases. Similarly, the collection of the small inhalation particles in the cyclone can prove challenging. But before this, drying kinetics, including changes in relative humidity, can have an effect on the aerodynamic diameter of the particles that form.

Of course, there is a complex interplay between the different parameters in a spray drying process, regardless of the type of material that is being dried. While sufficient drying gas is essential, too much would be wasteful.

The nature of the material will inform the choice of outlet temperature limit; for an amorphous formulation, this will often be led by the glass transition temperature. If, as is the case for a biotherapeutic, temperature sensitivity is an issue, its thermal stability must be taken into account. Inlet temperature is also important; if it is too high, material can accumulate towards the top of the equipment.  And then there is relative saturation (or humidity for water). The conditions need to be sufficiently dry to ensure the material produced is not too wet or tacky.

These limits can all be used to aid in setting appropriate process conditions that strike a balance and lead to the powder having the appropriate properties. Fundamentally, the atomization process is critical, as is the impact of drying kinetics on particle density and morphology. As the scale goes up, these parameters necessarily become more difficult to predict and control. But, with care, it is possible to create a process that reliably and consistently produces powders whose aerodynamic diameter is ideal for delivery to the deep lung.

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