Combinational Approach for Advanced Understanding of a Low-Dose Capsule Filling Process for Inhalation Application

Eva Faulhammer¹, Sandra Stranzinger^1,3, Vittorio Calzolari², Stefano Biserni², Peter Loidolt³, Amrit Paudel^1,3, Johannes Khinast^1,3

¹Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, Graz, 8010, Austria

²MG2, Via del Savena 18, Pianoro BO, 40065, Italy

³Technical University Graz – Institute of Process and Particle Engineering, Inffeldgasse 13, Graz, 8010 Austria

The precise filling of capsules with doses in the milligram-range needed for inhalation application relies on a well understood filling process. This study aims to understand the complex relationship between material attributes and process parameters and their influence on critical quality attributes (fill weight and fill weight variability) of a low-dose dosator capsule filling process. The used combinational approach comprises an in-depth analysis of the process based on experimental and in silico simulation studies.

For experimental studies, three grades of lactose excipients were filled into size 3 capsules using a conventional dosator nozzle capsule filling machine (Labby, MG2, Bologna, Italy) and a combination of various instrumental settings. The fill weight and the weight variability of Lactohale 100 (155 µm) remained almost the same, regardless of the process parameters throughout the process time. Lactohale 220 (13.40 µm)) delivered entirely different results. After a certain run time, depending on instrumental settings, a ‘steady-state’ with constant fill weights and low weight variability was achieved. Moreover, a dosing chamber length of 2.5 mm and a powder bed height of 10 mm resulted in significantly lower fill weight variability. In silico studies clearly confirmed the “challenging” behavior of the powder with the smallest particle size. It could be demonstrated that the dosator nozzle is not completely filled up with powder at the end of the dipping step. Remaining unfilled spots significantly influenced the weight variability.

This study presents a further step towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling.