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.

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.

Picking up good vibrations: Exploration of the intensified vibratory mill via a modern design of experiments.

The aim of this work was to strengthen the understanding of the intensified vibratory mill by unravelling the milling process in terms of the particle size reduction and heat generation via a modern design of experiments approach. Hence, the influence of five process parameters (acceleration, breaks during milling, bead size, milling time and bead-suspension ratio) was investigated via an I-optimal design. Particle size was measured via laser diffraction and the temperature of the sample after milling was computed. To advance our understanding, a mechanistic model for the set-up of wet-stirred media milling processes was applied on the observed milling trends. A generic approach for the optimisation of the milling process was retrieved and included the optimisation of the bead size and intermittent pausing for effective cooling. To finetune the remaining process parameters, the present work provides contour plots and strong predictive models. With these models, the particle size and the temperature after milling of suspensions manufactured with the intensified vibratory mill could be forecasted for the first time.

Exploration of the heat generation within the intensified vibratory mill.

Recently, the intensified vibratory milling (IVM) has emerged as a viable milling technology known for its nanosizing and high-throughput potential. The extent of the heat generation is ambiguously discussed within the literature. For this reason, the impact of formulation and process parameters for both particle size reduction and heat generation, needs further investigation to develop robust processes using the IVM technology. For this reason, the impact on particle size and heat generation of three different process parameters: - bead-suspension ratio; milling time; and acceleration - as well as one formulation parameter - API concentration - was investigated by a one-variable-at-a-time approach. Further the effect of additional fixtures on the heat generation was noted. The data obtained in this work showed that if the impact on heat generation was taken into account, the process parameters could be fine-tuned to optimize the nano-sizing potential while containing a continuous milling process. A longer milling time and production of highly concentrated formulations were proposed as gentle optimisation steps for the herein presented comminution process.

Size Analysis of Small Particles in Wet Dispersions by Laser Diffractometry: A Guidance to Quality Data.

In the present work, the question how to obtain high-quality laser diffraction (LD) results is discussed by investigating various hurdles that can be encountered during particle size measurements in wet dispersions and the associated data interpretation. Following this an effective troubleshooting is discussed based on theoretical insight into the LD measurement. As an important element in the Mie theory, the refractive indices of the model compounds, bedaquiline and cinnarizine, were quantified using the LD software, the Becke line technique, and the single solvent technique, as described by Saveyn et al. [Saveyn H, et al. Part Part Syst Char. 2001;19:426-432]. The influence of parameters such as obscuration level, background quality, and fitting of data were investigated and a summative flow chart has been provided. Through this analysis the present work emphasizes the need for a systematic approach when conducting LD measurements, including standard performance of an obscuration titration and an extended method optimization, to reach high-quality LD results.