Particle Sizing for Pharmaceutical Drug Development

You’ve got a splitting headache, so you reach into the medicine cabinet to grab a couple of paracetamols.  Or maybe you’re suffering from heartburn, so turn to a well-known indigestion liquid.  Or perhaps a cold is your ailment, so you grab a cold remedy to alleviate your symptoms.  How can we be sure that these medications will work, and soothe your head, calm your stomach and relieve your flu-like symptoms?

Fortunately, of course, pharmaceutical companies have to demonstrate that the drug products they are developing are reproducibly effective and efficient, meeting their desired Quality Target Product Profile (QTPP).  Critical Quality Attributes (CQAs) for the drug product, such as bioavailability, product stability and content uniformity, are identified, and associated Critical Material Attributes (CMAs) selected to assess, monitor and control the CQAs.

As a critical material attribute (CMA) for all solid dosage forms and liquid suspensions of pharmaceuticals, measuring the particle size distribution is an essential element of the materials characterization toolkit for pharmaceutical development and manufacture.

Particle size distribution of paracetamol

Taking paracetamol as an example: the particle size distribution of the active ingredient (API) is critical to its bioavailability.  The larger the surface area of a particle, the greater its solubility and dissolution rate, leading to increased bioavailability and a faster-acting drug release.  The particle surface area is a function of particle size, so the smaller the particle size, the greater the dissolution rate and bioavailability of the drug (all other factors being equal).

Particle size distribution of indigestion liquid

Turning to the indigestion liquid: the finer the particle size, the more cohesive the material is, the more prone it is to aggregation over time, and the poorer its colloidal stability.  This in turn will affect the bioavailability of the drug, as the particle size distribution has now become larger over time, making the product less efficient.

Particle size distribution of cold remedy tablets

The content uniformity of the cold remedy tablets is also dependent on the particle size distribution of its constituents.  With a larger particle size, some unit doses may not meet potency specifications.  Furthermore, the excipient blend selection is also based on particle size.  The packing density of powders is dependent on their particle size distribution, with a mix of fine and coarse material leading to a higher packing density, and a lower permeability – leading to a slower disintegration of the tablet.

So, whether optimizing the particle size of the API and excipients during formulation development, checking the particle size of the raw materials from suppliers or conducting quality control at different stages of the manufacturing process, the measurement of particle size and particle size distribution is essential in pharmaceutical development and within the manufacture of pharmaceutical products.

Laser diffraction is the go-to technique for particle size analysis, and the Mastersizer 3000 is the world leader in this technology.  Variously described as “a must-have instrument in the pharmaceutical industry”, an “excellent instrument to have in a pharmaceutical laboratory” and “one of the essential characterization techniques in our lab” by our customers on Select Science, the Mastersizer 3000 is considered the gold standard for particle size analysis in pharmaceutical development and manufacturing/QC.

In the second and third blogs in this series, we will look at why this is the case…