(344a) Manufacturing of Low Fill Weight Capsules Using a Nozzle Dosator Capsule Filling Machine

Introduction

Capsule filling using
nozzle dosators (ND) has been widely investigated (Jones, 2001; Newton, 2012) and
it is one of the main technologies used by pharmaceutical industry today. Nozzles
come in sizes that match the diameter of capsules (from 00 to 5), and deliver a
specific volume of powder into capsules. However, the amount of powder that the
smallest nozzle (size 5) can handle is in the range of 40 mg-80 mg (depending
on the density of the powder formulation).

Some new and prospective pharmaceutical
products require the handling of even smaller powder quantities: 5mg-20 mg. A
straightforward solution is to extend the use of nozzle dosators (by reducing
the diameter of nozzles) and take advantage of the features already available
for this technology: large output, highly automated, check weight for quality
control of every single capsule. However, this requires understanding the
design space for nozzles of smaller diameter and to revisit the effects of process
parameters and powder properties on capsule quality. It is expected that
miniaturizing the nozzles will affect the process performance and capsule
quality.

In the current research, Design
of Experiments (DOE) as part Quality by Design approach is used to study the
effects of process parameters and material properties for three small nozzles
on fill weight and weight variability. A capsule filling machine (Labby, MG2)
with a single ND is used.

Materials and Methods

The DOE (D-Optimal with
Design statistics G-Efficiency) includes four process parameters of the capsule
filling machine (Labby, MG2): 1- Diameter of the nozzle (3 different nozzles),
2- Size of dosing chamber (three sizes), 3- Depth of powder bed in the bowl (3
values), and 4- Speed of capsule filling (3 values). The DOE also considers two
interactions between process parameters: 1- Size of dosing chamber and powder
layer depth; and 2- Diameter of the nozzle and size of dosing chamber. The DOE
has two constraints for the ratio between size of dosing chamber and layer
(interaction 1): never smaller than 1:2 and never larger than 1:5 (which are
typical values found in capsule filling machine set-up).

The materials are four
different grades of lactose: Respitose ML001, ML006, SV010, and SV003 (DFE). The
following material attributes are characterized (in triplicates): particle size
and shape; bulk and tapped density; compressibility; 3 flow indexes (Carr
index, Basic flowability energy (measured with FT4), and ffc (measured with
FT4)); cohesion (measured with FT4), wall friction, and air permeability
(measured with FT4).

In order to precisely
assess capsule fill weight, and hence guarantee the validity of the conclusions
of the current study, we follow the following procedure:

1. Weighing of empty capsules: The powder is filled into size 3 gelatin capsules, which are approximately 48 mg ± 3 mg. The empty body of capsules is much heavier than the powder fill itself. The variability in the weight of the empty capsules (± 3 mg) is almost as large as the low-dose content (5 mg). Therefore, the weight of the empty body must be known before filling capsules. Empty capsules are weighed and numbered for identification before filling.
2. Use a high precision scale in our experiments: DENVER SI-234A (Readability: 0.0001 g; Reproducibility: 0.1 mg).

For each run in the DOE, capsule
filling is performed with MG2 equipment (Labby) and the method is as follows:

1. Fix the size of the dosing chamber with the aid of adjustment gauges (2.5mm, 3.75mm, and 5mm).
2. Fill capsules for 5 minutes to reach steady state of the operation.
3. Collection and weighing of the first group of 20 numbered capsules.
4. Continuously run the machine for 5 minutes.
5. Collection and weighing of the second group of 20 numbered capsules.
6. Compare the net weight of the two groups of capsules.
7. If the fill weight of the two groups of capsule does not differ by more than 10%, then the data is combined in a single group (a batch of 40 capsules).

Results

First, the effects of four
process parameters and two of their interactions on fill weight and weight
variability for four powders is discussed. The lines in Table 1 corresponds to
each run in the DOE and show the values for each of the four process parameters,
and the fill weight and weight variability for each of the four powders tested.
At the bottom of the columns named weight and weight variability for each
powder, we indicate the parameters that significantly correlate with each of
these two capsule attributes. For instance, fill weight always correlate with the
diameter (dia) of the nozzle and the size of the dosing chamber (cha). Hence,
filling is performed on volumetric basis.

At the bottom of the columns for
weight variability, the parameters that affect fill weight variability are indicated.
These parameters depend on the type of lactose tested and nozzle diameter (dia)
is always one of them. The interactions between process parameters do not
significantly affect either fill weight or weight variability.

Table 1: Effect of process parameters on fill
weight and weight variability for four different grades of lactose (Respitose
ML001, ML006, SV010, and SV003).

Then, the effects of material
attributes (for the group of four powders) on fill weight and weight
variability is discussed. Figures 1 and 2 show the material attributes that
have a statistically significant correlation with fill weight and weight
variability respectively. Bulk and tapped density have the largest correlation
with fill weight. Many material attributes affect weight variability, however
their effect is rather small (see small coefficients on y axis of Figure 2). Particle
size shows the largest correlation with weight variability.  

Figure 1: Material attributes that affect fill weight. Bulk and tapped density show
the strongest correlation with fill weight.

Figure 2: Material attributes that affect fill weight variability. Many parameters
have a small effect but still statistically significant. Particle size has the
largest effect on weight variability.

Conclusions

            The current study uses
QbD principles to understand the effect of process parameters of a nozzle
dosator capsule filling machine and material attributes on fill weight and
weight variability of capsules with low fill content. This study is focused on
low fill weight (5mg-45mg). In order to fill these amounts of powder, nozzles
with smaller diameters than the traditional nozzles (sizes 0 to 5) are required.

For the powders tested, fill
weight is affected by the diameter of the nozzle and the size of the dosing
chamber. Diameter and size of the chamber are the two parameters that define
the volume of the dosing chamber (the R² of models is at least 90%).
Hence, filling is performed on volumetric basis.

            The material attributes
that have the largest effect on fill weight are bulk and tapped density. Many
material attributes affect weight variability, even though their effect is
rather small.

Acknowledgments

To MG2 and GSK for their financial
and scientific support

References

Jones, B.E. (2001). The filling
of powders into two-piece hard capsules. International Journal of Pharmaceutics
227, 5-26.

Newton, J.M. (2012). Filling hard
gelatin capsules by the dosator nozzle system - Is it possible to predict where
the powder goes?. International Journal of Pharmaceutics 425, 73-74.