Shedding a light on the physical stability of suspensions micronised with intensified vibratory milling; A trend observed with decreasing particle size as a function of time

Abstract

Intensified vibratory milling is a nanonisation and micronisation technology which can be used to enable the oral bioavailability of poorly soluble compounds. The generated nano- and microsuspensions entail a large surface area which enhances the compounds dissolution rate, yet this large surface area is thermodynamically unfavourable and hence spontaneous destabilisation may occur, i.e. physical instability. Stability studies on suspensions manufactured via intensified vibratory milling have, to the best of our knowledge, not been reported in the literature before. An extended stability study was, therefore, executed with 30 bedaquiline suspensions milled with the intensified vibratory mill under various process settings. The particle size distribution was measured immediately after production, after four weeks of storage at 5 °C and after eleven weeks of storage at 5 °C with laser diffraction and scanning electron microscopy. In addition, a caking test was applied to scrutinise the redispersibility of the prevailing sediments. One sample whose sediment proved to be redisperible, demonstrated a peculiar trend during storage where a narrowing of the particle size distribution and a general particle size reduction was detected which opposed the conventional stability tendencies, i.e. stability or Ostwald ripening. This enigmatic trend was further explored via a repetitive analysis with laser diffraction and in a further phase, with an orthogonal particle sizing technique. Still, no matter the frequency nor technique, a narrowing particle size distribution was observed. To the best of our knowledge, this article, for the first time in the pharmaceutical literature, reports a narrowing particle size distribution of a micronised suspension containing an organic compound. Inevitably, this trend might shed a fundamental new light on the stability trends, exposed by suspensions post-micronisation by high energy milling.