Our recent webinar, The Perfect Particle — Why Size Matters, was a deep-dive into the world of particle size. Particle size is one of the first physical properties that needs to be considered in an active pharmaceutical ingredient (API).
During the webinar, Zohar De-Valenca, our Senior Manager of Manufacturing Sciences & Technology, spoke to our listeners about why particle size is so crucial and what top technologies exist for the milling of APIs. Enrico Bettitini, Subject Matter Expert in Solid State, then answered questions from the audience.
If you missed the live event, here are the highlights!
What is Particle Size?
Particles come in many shapes and forms, some are easy to characterize and some are difficult, depending on the morphology and the shape of particle.
In order to measure the particle, we need to convert each particle into a sphere, theoretically. The sphere is equal to the particle it represents. By converting the particle into a sphere, we get one dimension with which to measure the particle – the diameter. The conversion itself is done by volume or mass or any other property, depending on what we want to measure.
This conversion into a sphere is relevant for a single particle.
Particle Size Distribution (PSD)
A bulk however, isn’t comprised of a single particle, but is a statistical population. It usually behaves in a normal distribution. When we measure the particle size, we don’t measure a single particle but the entire population. Doing this gives us the particle size distribution, PSD. The PSD is a statistical characteristic.
While we measure all the particles in the sample, to describe a distribution we usually note three percentiles: D90 – the larger particles in the sample, D50 – the medium-sized particles, and D10 – the small particles. Once we know the sizes, we know how to deal with the bulk.
Our results are as good as our methods. We need to consider two things when choosing our measuring technology. The first is how accurate the method is, and the second is how repeatable the results are using this method.
There are 3 main methods for analyzing particle size.
- Laser diffraction – we use a device that lights a laser beam through a suspension of the sample. A detector senses the way the laser diffracts within the suspension and can therefore determine the size of the particles within the suspension. This method converts the particle to a sphere through volume. It is the most common method
- Sifters – we measure the weight of the sample and how much weight is left on each sifter. This is a relatively old method but is straightforward and effective.
- Image analysis – we take a small sample from our batch and take microscopic pictures of it and measure particles by hand, using measuring software.
Bulk and Tapped Density
Bulk and tapped density are two important properties to understand. Bulk density is the density of the powder at rest. There are some small particles, some large particles, and a lot of air between them. This gives us a certain amount of product per volume which is the bulk density.
Tapped density is what happens to the particle after you’ve tapped the sample. The small particles realign and fill the gaps between the large particles, which means the volume of the entire bulk reduce, which increases the density. We use a tapping device to do this.
Why Mill APIs
By controlling the particle size of the API we can control the dissolution profile and have the desired results for the final dosage form. This is extremely important.
Another thing we can control with the particle size is flowability and handling. Usually large particles tend to flow better and be less sticky than small particles. The one we want depends on what result we’re trying to achieve.
Another thing to consider is compatibility with the formulation. Particle size differs for different formulations, such as tablets, capsules or inhalation products.
Lastly, we need to make sure the API is a smooth flowing powder without any aggregates. We mill them in order to achieve this consistency.
3 Top Milling Technologies
At Teva api, we use multiple types of milling technologies. The three most common ones are:
- Cone Mill
This is the least aggressive one. It is meant for large particles, ranging from 100-1000 microns. It’s a conical screen with a rotating impeller in the middle. Once the impellor is rotated, the particles are first impacted and then sheared by the screen.
It’s made of two milling chambers. The first milling is done on the top and it’s very similar to the cone mill. The second chamber provides a secondary impact for the particles that breaks them into an even finer dust. This mill heats up so it has a cooling jacket so that the chemical properties won’t be affected by the heat.
- Spiral Jet Mill (Micronizer)
This uses only compressed air without any moving parts. A strong stream of jet using air or nitrogen pushes the particles into the micronizer chamber. The chamber is round so the particles move in a circular motion. The particles collide with one another and result in them breaking into fine dust. The fine particles leave the chamber through the middle, while the large ones stay in the chamber and can only “leave” once they’re small enough.