(198v) Cryo Jet Milling for Micronization Enhancement of Inhalation Particles

Pulmonary drug delivery is one of the most used routes of drug administration, especially for the treatment of pulmonary diseases that affect a significant part of the population, such as chronic obstructive pulmonary disease and asthma [1]. As main benefits, inhaled drug products offer high bioavailability, rapid and local action, and minimal adverse side effects [2,3]. One of the most common strategies for delivering drugs to the lung is through dry powder inhalers (DPIs), as they are propellant free, portable, relatively inexpensive, and do not require hand-breath coordination [4,5]. DPIs are traditionally combined with carrier-based formulations, in which the active pharmaceutical ingredient (API) is physically mixed with a coarse carrier, which is responsible to support the aerosolization and delivery of the former. However, to achieve an appropriate distribution and penetration throughout the deep lung, API particles must be in the size range of 1-5 μm, which can only be typically achieved through micronization [6].

Jet milling is one of the most used techniques in the pharmaceutical industry to achieve particles within the inhalation size range [7]. This technology achieves particle size reduction through high velocity compressed gas jets in a confined chamber, promoting highly energetic particle-to-particle collisions [8]. Despite its many advantages, jet milling can induce the formation of thermodynamically unstable amorphous content on the processed particles and negatively impact the performance and stability of the micronized API [7,9]. Towards minimizing the risk of amorphization and degradation during the process, cryo jet milling has been proposed as an alternative technique for micronizing more sensible APIs. By promoting lower temperatures within the chamber, cryo jet milling should be able to minimize the temperature of the particles during the exothermal breakage process and hinder amorphization [10,11]. However, other variables may also come into play and the existence of conflicting findings in the literature indicates that the impact of lower gas temperatures in micronization may not be straightforward. Within the limited number of studies on cryo-milling, some have indeed shown greater reduction of particle size and lower amorphization for some APIs through lower process temperatures, while others observed an opposite behaviour. Therefore, the intrinsic API physical properties are likely to play a role in the way temperature impacts their micronization in jet milling [12].

The goal of this study was to evaluate the cryo jet milling (CJM) impact on the micronization of APIs for inhalation drug delivery. First, the effect of gas temperatures, i.e. room temperature (RT), -10ºC and -30ºC, in particle size distribution (PSD), amorphous content (AC) and yield was assessed with four different APIs. The micronization trials were performed in a lab-scale spiral jet mill, at constant process conditions (). Then, the API which presented higher improvements with CJM was selected for further micronization trials, to explore the effect of gas temperature at different grinding pressures and evaluate their impact on aerodynamic performance. Selected micronized trials were therefore formulated with a lactose monohydrate blend (4% API, 10% LH230, 86% SV003) and blended through a low shear mixer (Turbula® T2F). The final blends were filled in HPMC size 3 capsules and actuated in a PowdAir® device for performance evaluation, through fast screening impactor (FSI).

The particle size distribution (PSD), amorphous content (AC), and process yield of the four API micronized at different temperatures were characterized. For both APIs 1 and 2, a reduction of the micronization temperature led to progressively lower PSD, AC and higher yield recovery. In contrast, for APIs 3 and 4, no significant improvement was obtained with the use of lower temperatures and even a slight particle size increase was reported. From all quantified outputs, it is possible to state that these results are in-line with the contradictory literature on CJM, as the effectiveness of the technology may depend not only on the process conditions used but also on the intrinsic properties of the input material.

Towards deconvoluting process- and material-related changes promoted by using CJM, an assessment of the impact of temperature on the micronization energy can be performed. According with Midoux et al. [13], lower micronization temperatures should in fact lead to a slight reduction of the specific energy of the process (ESP) and consequently result in a lower particle reduction capability of the process, for the same P_grinding and F_feed. That trend is apparently observed for APIs 3 and 4 in which slightly higher particle sizes are reported for increasingly lower temperatures. However, for APIs 1 and 2, an opposite trend is observed with an PSD reduction being obtained as the micronization temperature was reduced. Such divergent behavior is most likely a consequence of a change in the physical behavior of the micronized material at lower temperatures.

One of the potential changes in API properties can be related with the AC reported after the micronization step. The presence of AC is commonly associated with the more “stickier” material and, consequently, lower process yields. The most sounding case is observed in API 2, in which the lower temperatures led not only to a reduction of the AC but a considerable increase in the recovered product. Moreover, having “stickier” material can also hinder particle size reduction which could explain the divergent trend observed between PSD and ESP for APIs 1 and 2. The impact of temperature may also impact other material properties such as brittleness, tensile strength, and hardness. Although challenging to quantify, especially for inhalation-sized particles, future work should aim to characterize the impact of lower temperatures on the main particle breakage-related material properties.

Overall, from this initial screening, API 2 was the one presenting higher benefit from CJM, by achieving combined reductions in both PSD and AC, as well as an increase in process yield. Therefore, API 2 was selected to undergo a more extensive set of trials to explore the impact of CJM at different grinding pressures (= and ). Based on the results. it is possible to conclude that the effect of lower micronization temperatures is comparable from low to high grinding pressures, as a slight tendency of smaller PSD and a consistently lower AC were observed for reducing milling temperatures.

However, it was confirmed that to achieve inhalation size range particles with API 2, two micronization passages were required in each trial. Therefore, three additional trials were performed, with two passages each, at different micronization temperatures and a constant = . Results indicate that the effect of lower temperatures in AC is even sounder after two micronization passages, as performing two passages at -30ºC represents a reduction of approximately 43% when comparing with the process at RT. This improvement was backed by a ~32% increase in yield, which is most likely a direct consequence of the lower AC as previously discussed. Despite these improvements, results indicate that after two passages the PSD results are comparable across the different temperatures, indicating that no additional comminution efficiency is observed in the inhalation particle size range. This conclusion was also confirmed with PSD measurements performed after seven days from the last micronization passage (after full recrystallization), where no considerable differences being reported among trials. Overall, although not improving particle size reduction, CJM presents great potential in reducing the AC and increasing the yield, which has evident value for improving and sometimes even enabling micronization processes of amorphization-prone APIs.

Finally, the micronized powders from these last three trials were formulated and their aerodynamic performance characterized. The FSI results (Figure 1) indicate a positive trend on performance with reduced micronization temperatures, as the -10 °C and -30 °C trials respectively presented an increase of 10% and 33% of fine particle fraction of the emitted dose (FPF_ED), in comparison with RT. As PSD is identical across trials and the density of the micronized powders is unlikely to be changed by the micronization process, these improvements most likely come from changes in the interaction forces with the lactose carrier and the detachment mechanisms during DPI actuation. These can be affected by the morphology, surface area and surface energy of the micronized particles. Additional characterization (SEM, BET and iGC) is ongoing to assess differences in the properties of the micronized powders that can explain the improvements obtained in the FSI.

Overall, these preliminary results indicate that CJM can provide benefits to the micronization process of APIs, when compared with the standard jet milling process performed at RT. The most sounding differences were observed for AC and process yield, while minor differences were reported for PSD. However, the effects of CJM were found to be highly API-specific, leading to property changes in the final micronized powder in two out of the four APIs tested. For the selected API for an extended testing protocol, lower micronization temperatures resulted in similar improvements across a wide operational range and even higher differences to standard jet milling in case of multiple micronization passages. Finally, the material micronized at lower temperatures also presented better aerodynamic performance, which are thought to be caused by changes in the particle morphology and surface properties with CJM.