Predictive Milling of Active Pharmaceutical Ingredients and Excipients

Spiral jet milling is a size reduction process used in various industries, ranging from paints to food and pharmaceuticals. It has great benefit in the pharmaceutical industry due to its ability to reduce particulate solids to micron sizes and narrow size distributions. Despite its heavy usage, the underlying size reduction mechanism of the mill is not well understood. However it is generally known that the milling behaviour is dependent on the grinding conditions of the mill, as well as the materials physical and mechanical properties. The system is also very energy inefficient.
In this work the milling behaviour of active pharmaceutical ingredients and excipients in the spiral jet mill has been analysed based on their mechanical properties, as established from the Ghadiri and Zhang semi-brittle breakage model. Using the Single Particle Impact Test Rig, the breakability index (αH/KC2) of three pharmaceutical materials (paracetamol, aspirin, and α-lactose monohydrate) is determined. It is shown that the order of breakability is paracetamol > aspirin > α-lactose monohydrate.
For milling studies the Hosokawa Alpine Aeroplex Spiral Jet Mill 50AS is used. The change in specific surface area (ΔSSA) due to milling is quantified by size analysis and related to the breakability indices. The order of ΔSSA is α-lactose monohydrate > paracetamol > aspirin at high grinding pressure conditions. The loading of particles in the grinding chamber of the mill is found to be an important characteristic for the classification of milled materials in addition to the effects of centrifugal and drag forces.
Numerical simulations have been carried out and used to analyse the behaviour of the spiral jet mill. Using Computational Fluid Dynamics, the mechanics of internal particle classification by size of the 50AS has been analysed. Particles of 2 µm and less are shown to be classified. The Discrete Element Method is coupled with Computational Fluid Dynamics to investigate the effect of grinding conditions and particle properties on the particle motion and fluid-particle energy transfer, including gas pressure, the number of particles and the particle size distribution. A very small amount of energy is transferred to the particles from the fluid, highlighting the energy inefficiency of the system. Interparticle interactions are found to have a greater amount of dissipated energy compared to particle-wall interactions, which suggests interparticle collisions are the primary source of particle breakage. The majority of the stress exerted on the particles is close to the wall of the mill, with the normal stress being greater than the shear stress. A very low proportion of particles are found to be in contact at a given time, indicating particle breakage occurs from instantaneous collisions rather than particles shearing against each other.
Finally the potential for scale-up of the spiral jet mill is investigated based on the fluid power input to the system. There is a good comparison of the ΔSSA of α-lactose monohydrate milled in four different mills at similar fluid power input conditions. Two of the mills are the 50AS and the Hosokawa Alpine Piconizer (33 AS), and the other two are of different design but with internal diameters of 2 inches and 4 inches, i.e. roughly similar size to the Hosokawa mills. The latter two mills had a greater fluid power as the grinding nozzle diameters are larger than the Hosokawa mills.