(788d) Decoupling of a Low-Dose Dosator Capsule Filling Process in Dynamic and Static Mode Tests to Understand the Extend of the Effect of Powder and Process Parameters on Capsule Quality Attributes | AIChE

(788d) Decoupling of a Low-Dose Dosator Capsule Filling Process in Dynamic and Static Mode Tests to Understand the Extend of the Effect of Powder and Process Parameters on Capsule Quality Attributes


Faulhammer, E. - Presenter, Research Center Pharmaceutical Engineering (RCPE)
Stranzinger, S., Graz University of Technology
Loidolt, P., Technical University Graz
Paudel, A., European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM)
Khinast, J. G., Graz University of Technology


The precise filling of capsules with small powder
quantities is essential for a broad range of industrial operations and a number
of low-dose capsule filling machines are currently available. Filling
principles can be categorized in either volumetric (e.g., the dosator nozzles,
vacuum drum filler, vacuum dosator and tamp filler) or gravimetric (e.g.,
micro-dosing) methods. Capsule filling using the nozzle dosator technique has
been widely investigated and is an important technology applied in the pharmaceutical
industry today especially for the filling of capsules for inhalation, as the
doses need a controlled degree of compaction to ensure an efficient dose
delivery [1] [2] [3]. It is known that a large
number of powder and processing parameters affect the quality of filled
capsules [4] [5] [6] [7] [8]. However, the precise
dosing of small powder quantities still poses significant problems. Thus, the
objective of this study is to decouple the dosing event, which consists of
multiple steps in order to identify and understand in-depth the complex
relationship between material attributes and process parameters and their
influence on critical quality attributes (fill weight and fill weight
variability). Supported by in silico simulation, we will link those
material properties to process performance and develop a mechanistic
understanding in order to optimize the low-dose dosator capsule filling


Materials and Methods

Three different grades of alpha lactose
monohydrate (Lactohale100, 200, 220 – DFE Pharma) specially designed for
inhalation application were used as received. The following material attributes
were characterized in triplicate: particle size (Qicpic OASIS/L dry dispersing
system Sympatec, Germany), bulk (BD) and tapped density (TD) (Pharmatest
PT-TD200), true density (AccuPyc II 1340, Micromeritics, Norcross, USA). The
compressibility (CPL), air permeability (PD), flow function coefficient (FFc),
cohesion (C), angle of internal friction (AIF), basic flowability energy (BFE),
wall friction angle (WFA) were measured with the FT4 powder rheometer (Freeman
Technology, Malvern, United Kingdom). Results are displayed in table 1.

Table 1: Inhalation carrier characterization


Lactohale 100

Lactohale 200

Lactohale 220

Particle size and friction properties

Volumetric mean diameter [µm]

       160.02   ±0.62

       83.63  ±n.a.

    16.38   ±n.a.

Angle of internal friction (AIF) [°]

         18.43   ±0.49

       21.24  ±0.53

    25.73   ±2.66

Wall friction angle (WFA 3 kPa 0.2 Ra) [°]

           7.70   ±0.02

       11.46  ±0.82

    19.97   ±3.82

Bulk powder properties

Bulk density (BD) [g/ml]

0.6972 ±0.0036

     0.6223  ±0.0031

0.3996 ±0.0067

Tapped density (TD) [g/ml]

0.8275 ±0.013

     0.9962  ±0.0017

0.7847 ±0.0066

True density [g/ml]

1.5385 ±0.0028

     1.5426  ±0.0024

1.5466 ±0.0042

Compressibility (CPL) at 8 kPa (ratio ρcompBD) [%]

           1.05   ±0.00

       12.66  ±0.29

    36.95   ±0.16

Air permeability (PD) at 8kPa [mbar]

           1.05   ±0.02

         7.00  ±0.10

    12.04   ±0.55

Flow properties

Basic flowability energy (BFE) [mJ]

910.67 ±43.00

   1722.85  ±27.00

   667.32   ±10.80

Flow function coefficient (FFc)

           6.58   ±0.01

         4.04  ±0.01

      1.65   ±0.01

Cohesion (C) [kPa]

           0.24   ±0.02

         0.39  ±0.01

      1.05   ±0.13


Dynamic capsule filling: The powders were filled into hard gelatin capsules
of size 3 (supplied by Capsugel) with a lab scale capsule filling machine
(Labby, MG2, Bologna) adopted with a special low dose equipment. Two volumes of dosing
chamber (2.5, 5 mm), two different dosator sizes (1.9, 3.4 mm), two different
powder bed heights (5, 10 mm) and two different filling speeds (500, 3000 cph)
were used for the experiments. The study was performed under humidity controlled conditions
(45-55 % relative humidity). To create an initial powder bed without
densification, the layer was adjusted manually. After setting all machine
parameters, capsules were collected at time point 0, after 25, 50, 75, 100
rotations for a total run time of 30 minutes in order to sample from the same
position inside the rotating container. Powder feeding was adjusted according
to the amount of powder collected during capsule filling. Subsequently, the
weight of filled and empty capsules was measured with a Denver (SI-234A) scale.

Figure 2: Capsule fill weight of Lactohale220 at different
combinations of process settings


Static capsule filling: The static mode capsule
filling experiments were conducted under the same combination of process
settings and environmental conditions as the dynamic mode tests. The difference
here is that the powder is picked up from a static powder bed not a rotating
drum in order to study the effect of powder layer homogeneity on capsule
quality attributes and to get a mechanistic understanding about the powder
compaction behavior inside the dosing chamber.

Simulation and

In addition to the
experiments, DEM simulations of the static capsule filling experiments are
performed. Therefore, a model of the dosator is implemented in the DEM software
LIGGGHTS® and different particle contact properties are used to describe the
filling behavior of different powders. The simulations show the evolution of
the powder mass inside the nozzle during filling and therefore help to
understand the dosator process in more detail.

and Outlook

In this research, various material attributes of
different grades of lactose were determined and their performance during
capsule filling using a lab scale low dose dosator nozzle system was
investigated in dynamic mode. Obtained results will be correlated with
experiments conducted with the static stand-alone device and the simulation work to understand the influence of particular process
parameters on the filling performance, which will furthermore lead to an
improved filling process.


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