Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations.

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of repose tester to the experimentally observed response. A simulation of the 25-minute bin blending process predicted inhomogeneous API distributions along the rotation axis of the blending container. These concentration differences were confirmed experimentally in a production-scale mixing trial using high-performance liquid chromatography analysis of samples from various locations in the bin. Several strategies to improve the blend homogeneity were then studied using DEM simulations. Reversing the direction of rotation of the blender every minute was found to negligibly improve the blending performance. Introducing a baffle into the lid at a 45° angle to the rotation axis sped up the axial mixing and resulted in a better final blend uniformity. Alternatively, rotating the blending container 90° around the vertical axis five minutes prior to the process end was predicted to reduce axial segregation tendencies.

Carrier particle emission and dispersion in transient CFD-DEM simulations of a capsule-based DPI.

The dispersion of carrier-based formulations in capsule-based dry powder inhalers depends on several factors, including the patient's inhalation profile and the motion of capsule within the device. In the present study, coupled computational fluid dynamics and discrete element method simulations of a polydisperse cohesive lactose carrier in an Aerolizer® inhaler were conducted at a constant flow rate of 100 L/min and considering an inhalation profile of asthmatic children between 5 and 17 years approximated from literature data. In relevant high-speed photography experiments, it was observed that the powder was distributed to both capsule ends before being ejected from the capsule. Several methods of ensuring similar behavior in the simulations were presented. Both the constant flow rate simulation and the profile simulations showed a high powder retention in the capsule (7.37-19.00%). Although the inhaler retention was negligible in the constant flow rate simulation due to consistently high air velocities in the device, it reached values of around 7% in most of the profile simulations. In all simulations, some of the carrier powder was ejected from the capsule as particle clusters. These clusters were larger in the profile simulation than in the constant flow rate simulation. Of the powder discharged from the capsule, a high percentage was bound in clusters in the profile simulation in the beginning and at the end of the inhalation profile while no more than 10% of the powder ejected from the capsule in the 100 L/min constant flow rate simulation were in clusters at any time. The powder emission from the capsule was studied, indicating a strong dependency of the powder mass flow from the capsule on the angular capsule position. When the capsule holes face the inhaler's air inlets, the air flow into the capsule restricts the powder discharge. The presented results provide a detailed view of some aspects of the powder flow and dispersion of a cohesive carrier in a capsule-based inhaler device. Furthermore, the importance of considering inhalation profiles in addition to conventional constant flow rate simulations was confirmed.

Estimating inter-patient variability of dispersion in dry powder inhalers using CFD-DEM simulations.

Drug delivery from a capsule-based dry powder inhaler depends on the inhaler's design, the drug's formulation, and the inhalation maneuver. The latter affects both the air flow and the capsule motion in the inhaler. It is well known that patient-to-patient variability is a major challenge in the design of new inhaler types. Modeling and simulation are important tools for understanding such systems, yet quite complex. Simulation studies of capsule-based dry powder inhalers have disregarded the transient nature of the inhalation process, adopting a constant flow rate through the inhaler instead. In addition, either no capsules, a capsule in a fixed position, or a capsule rotating at a constant rate have been considered. In this work, literature data for three inhalation flow profiles were incorporated into coupled simulations of the air flow and carrier particle motion through an Aerolizer® dry powder inhaler with a rotating capsule and compared to simulations at constant air flow rates. The results for the profile simulations indicated that the carrier powder experienced larger velocity fluctuations. Acceleration events were tracked as a measure of collision- and flow-induced dispersion. The majority of fast particle accelerations occurred when the particles collided with the swirl chamber walls. Of the two common particle dispersion metrics, only the peak particle force distribution appeared to be sensitive to the inhalation profiles, while the effect of the profiles on the cumulative impulse was small.

Understanding the motion of hard-shell capsules in dry powder inhalers.

The delivery of small drug particles from a dry powder inhaler (DPI) into the patient's peripheral airways requires the dispersion of the powder. In DPIs that contain a rotating pierced capsule, the capsule's motion is paramount to powder dispersion. Previous studies have simplified the capsule motion in an Aerolizer® inhaler as a constant rotation around a fixed center. The present work examines deviations from this simplified motion and describes the capsule collisions with the surrounding inhaler walls. High-speed photography was employed to analyze the motion of a size 3 capsule in an Aerolizer® inhaler at various flow rates ranging from 30 to 100 L/min. Frequent collisions of the capsule with the surrounding inhaler walls were observed. Computational fluid dynamics (CFD) simulations indicated that the air flow through the capsule governs the behavior of small drug particles, while inertial forces are the dominant influence on large carrier particles in the capsule. Discrete element method (DEM) simulations were employed to study the effect of the capsule-inhaler collisions on the powder discharge from a rotating capsule. The collisions vastly improved the discharge of a polydisperse model carrier powder from the capsule over a wide range of cohesiveness.