458431 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

Friday, November 18, 2016: 4:15 PM
Continental 5 (Hilton San Francisco Union Square)
Eva Faulhammer1, Sandra Stranzinger1, Peter Loidolt2, Vittorio Calzolari3, Stefano Biserni3, Stanko Srčič4, Rok Dreu4, Amrit Paudel1 and Johannes G. Khinast5, (1)Research Center Pharmaceutical Engineering (RCPE), Graz, Austria, (2)Process and Particle Engineering, Technical University Graz, Graz, Austria, (3)MG2, Bologna, Italy, (4)Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, (5)Institute of Process and Particle Engineering, Graz University of Technology, Graz, Austria


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 process.


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 Modeling

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.

Conclusion 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.


[1]         B. E. Jones, “The filling of powders into two-piece har+d capsules,” Int. J. Pharm., vol. 227, no. 1, pp. 5–26, 2001.

[2]         M. Llusa, E. Faulhammer, S. Biserni, V. Calzolari, S. Lawrence, M. Bresciani, and J. Khinast, “The effect of capsule-filling machine vibrations on average fill weight,” Int. J. Pharm., vol. 454, no. 1, pp. 381–387, 2013.

[3]         M. Llusa, E. Faulhammer, S. Biserni, V. Calzolari, S. Lawrence, M. Bresciani, and J. Khinast, “The effects of powder compressibility, speed of capsule filling and pre-compression on plug densification,” Int. J. Pharm., vol. 471, no. 1, pp. 182–188, 2014.

[4]         S. B. Tan and J. M. Newton, “Powder flowability as an indication of capsule filling performance,” Int. J. Pharm., vol. 61, no. 1, pp. 145–155, 1990.

[5]         R. Patel and F. Podczeck, “Investigation of the effect of type and source of microcrystalline cellulose on capsule filling,” Int. J. Pharm., vol. 128, no. 1–2, pp. 123–127, 1996.

[6]         F. Podczeck and J. M. Newton, “Powder and capsule filling properties of lubricated granulated cellulose powder,” Eur. J. Pharm. Biopharm., vol. 50, no. 3, pp. 373–377, 2000.

[7]         E. Faulhammer, M. Llusa, C. Radeke, O. Scheibelhofer, S. Lawrence, S. Biserni, V. Calzolari, and J. G. Khinast, “The effects of material attributes on capsule fill weight and weight variability in dosator nozzle machines,” Int. J. Pharm., vol. 471, no. 1–2, pp. 332–338, 2014.

[8]         E. Faulhammer, M. Fink, M. Llusa, S. M. Lawrence, S. Biserni, V. Calzolari, and J. G. Khinast, “Low-dose capsule filling of inhalation products: Critical material attributes and process parameters,” Int. J. Pharm., vol. 473, no. 1–2, pp. 617–626, 2014.


Extended Abstract: File Not Uploaded