(T1530-09-60) Impact of Vacuum Drum Filling Parameters on Dry Powder Inhaler Performance

Purpose: Dry powder inhalers (DPI) are becoming increasingly popular due to growing interest in pulmonary drug delivery. The performance of lactose-based DPI drug product is the net result of a series of manufacturing unit operations including micronization of active pharmaceutical ingredients (API), powder blending, and low dose powder filling. The DPI formulations are developed with a focus on performance characteristics of the bulk powder; however, manufacturing, specifically powder filling can also influence the final product performance. In this study, the process parameters of a Harro Höfliger vacuum drum filling system (typically used for DPI filling) has been evaluated to understand the impact on manufacturing variability and DPI performance for a model albuterol sulfate/lactose blend.

Methods: For this study, formulation consisting of inhalation grade lactose and micronized drug was prepared. Inhalac 230 was selected as the carrier lactose and Albuterol Sulfate, micronized using Air Jet mill was used as the model drug (Table I). The Albuterol sulfate (1.48%) and Inhalac 230 blend was prepared using Turbula T2F mixer at different blending times and blending speeds and blend with acceptable blend uniformity was used to fill size 3 inhalation grade HPMC capsules. The capsules were filled using Harro Hofliger’s DrumLab at different vacuum pressures using bore size 13.5 mm³ drum, and net fill weight of each capsule was recorded to evaluate the average fill weight and fill weight variation (%RSD). The filled capsules were later evaluated for delivered dose uniformity and Aerosol performance using Next Generation Impactor. A medium resistance RS01 device was used for the dose actuation at a flow rate of about 52 L/min to achieve a pressure drop of 4.0 kPa. Additionally, the influence of stirrer geometry on capsule filling performance and DPI performance was also evaluated.

Results: A linear relationship was observed between fill weight and filling vacuum pressure (Table II). The % RSD of the fill weight was less than 2% for all the filling conditions for n=75 capsules. However, lower %RSD was observed at higher vacuum levels and asymmetric stirrer which could be attributed to the additional compression caused by the paddle-shaped geometry of the stirrer. The aerodynamic performance was evaluated using NGI and as shown in Figure 1, the capsules filled at 600 mbar vacuum levels led to statistically significant (p < 0.05) higher Albuterol deposition in stages 2- 7 compared to the capsules filled at 200 mbar. The higher deposition could be the result of more fine particles being pulled into the drum bore when the vacuum is applied. However, this needs further investigation.

Conclusion: This study explored the impact of vacuum drum filling process parameters such as vacuum pressure and stirrer geometry on the Dry Powder Inhaler performance. It was concluded that higher vacuum demonstrated better filling performance with higher fill weight and lower % RSD. However, the capsules filled at a higher vacuum using a standard stirrer led to better aerosol performance. The studies related to the impact of hopper fill level, stir duration and drum bore size on filling and aerosol performance are ongoing.

Table I: Material attributes of selected formulation components

Table II: Fill weight and %RSD for the capsules filled on Drum Lab at different filling parameters

Figure 1: Drug deposition at a) Each stage of NGI; b) all NGI stages and device components for capsules filled at different vacuum levels and using standard stirrer.