(M1130-08-44) Bioavailability Improvement through Particle Engineering

Purpose: Nowadays, more and more active pharmaceutical ingredients (API) exhibit poor solubility behavior (eg. Class 2 and/or Class 4) from the BCS classification. As such, particle engineering may be a powerful tool to overcome the bioavailability issue by improving the dissolution rate. It is known that the dissolution rate is driven by the equation of Noyes-Whitney and as such a particle size reduction will lead to increase in surface area as well as decrease in thickness and in fine to an improvement of the bioavailability.

Methods: An innovative Active Pharmaceutical Ingredients presented too slow kinetics of dissolution and to answer this challenge, different approaches were investigated. As first, micronization technique (jet mill, as of now, the reference technique on to the market) has been assessed. As expected, the particle size was significantly reduced and powder characterized by laser diffraction techniques however, results exhibited similar kinetics of dissolution to that of the unmilled/unmicronized material. In-depth investigation demonstrated the tendency of the API to re-agglomerate below a critical particle size (by electrostatic phenomenon). As an alternative, it was then envisaged to assess the milling technique. Although less efficient than the micronization to strongly reduce particle size, it will still produce lower PSD, better flow properties and possibly minimize the electrostatic behavior of that particular material.

Results: Hammer technique was employed at a laboratory scale (50-100g scale) to produce various PSD grades in between the unmilled material and the micronized material. Analysis by laser diffraction confirmed the different PSD grades and kinetics of dissolution of each grade were determined using an automated platform (only a few mg of solids required). Results demonstrated that the milling approach was suitable to not only reduce the PSD but also to avoid the electrostatic behavior and improve the kinetics of dissolution when compared to that of the unmilled material as requested by the Client.

Conclusion: This new developed physical treatment was then successfully scaled-up to a multi-kg scale (50kg) with satisfactory results in terms of PSD and kinetics of dissolution data. The requirement of improving bioavailability was demonstrated through particle engineering approach. This method could be applied to many APIs belonging to Class 2 compound where micronization may not be suitable (either electrostatic behavior and/or amorphization).