(720f) Optimization of a Low-Dose Dosator Capsule Filling Process for Dry Powder Inhalation (DPI) Applications Using in-Line PAT Approaches

Introduction

Delivery of
medicinal products through the lungs has been the focus of a series of research
projects in the last few years. Especially Dry Powder Inhaler (DPI) devices
that utilize capsules as the dose-holding system represent one of the most
rapidly expanding fields in pulmonary drug delivery in recent years (Islam and
Gladki, 2008).
Among the several low-dose capsule filling systems currently available, the
dosator principle plays an important role in the filling of capsules for DPI
application. One of the greatest challenges for successfully manufacturing
high-quality low-dose inhalation products is dose uniformity (Islam and
Cleary, 2012).
In previous studies, the effect of critical material attributes and process
parameters on a low-dose dosator capsule filling process was assessed (Faulhammer et al., 2014; Stranzinger et al., 2017). However, little work has
been performed in understanding the filling process of powder blends (e.g.,
powder containing API and excipient) on the filling performance. For powder
mixtures, it can be assumed that the machine vibration present at the powder drum
(on all kind of capsule filling machines (dosator nozzle, dosing drum or tampin
pin systems)) induces particle movement of the contained material, and thus, on
the long time segregation can occur (Metzger et al., 2011; Rosato et al., 2002).

Thus, the objective of
this study was (1) to get a deeper understanding of the behavior of powder mixtures
during a low-dose capsule filling process by in-line monitoring of the powder
layer and (2) to evaluate optimization strategies to reduce segregation. The gained
knowledge will help improving the filling performance of challenging powders
for DPI applications.

Materials
and Methods

The carrier substance, i.e.,
α-lactose monohydrate (Lactohale 100), was supplied by DFE Pharma (Goch,
Germany) and was used as received. Salbutamol sulphate USP (SS) was purchased
from Selectchemie (Zurich, Switzerland) and used as the model API. In order to
generate inhalable sized particles (1 µm – 5 µm), air-jet milling
(micronization) was performed (Spiral Jet Mill 50 AS, Hosokawa Alpine AG,
Augsburg, Germany). An injection pressure of 6 bar and a milling pressure
of 3 bar were set and powder was fed manually at an estimated rate of 30 g/h.

Blend preparation and
characterization

Adhesive mixtures of 5 wt%
and 10 wt% API content were prepared. For the 5 wt% blend 285 g Lactohale
100 and 15 g SS were weighed in a plastic vessel, and for the 10 wt%
blend 270 g of carrier and 30 g of API were used. In both cases, the
sandwich method was used. More precisely, the carrier was first layered in the
vessel followed by a layer of API in the middle and topped with a layer of the
carrier. The powders were mixed in a Turbula® blender T2F (Willy A. Bachofen
Maschinenfabrik, Muttenz, Switzerland) and for 60 min at 68 rpm.

The blend uniformity was
assessed by analyzing the drug content in several aliquots of blends with reversed
phase high performance liquid chromatography (HPLC) (Faulhammer et
al., 2015).
Furthermore, powder characteristics (such as particle size, friction
angles, bulk and flowability properties) were determined for pure
carrier, API and blends.

Capsule filling

The powder blends were
filled into hard gelatin capsules of size 3 (provided by Capsugel, Bornem,
Belgium) with a lab-scale dosator nozzle capsule filler with special
adjustments for low powder dosing (Labby, MG2, Bologna, Italy). A combination
of the following process parameters was used: A dosing chamber length (dcl) of
5 mm, a dosator diameter (dia) of 1.9 mm a filling speed of 3000
capsules per hour (cph) and two powder bed heights (pbh) of 5 mm and 10 mm.
For reconditioning the powder bed, an additional scraper made of steel was
mounted (see Figure 1). The weight of filled and empty capsules was measured
with a Denver SI-234A (Denver Instrument, Bohemia, NY, USA) scale.

In-line API Monitoring
using RAMAN spectroscopy

For the purpose
of monitoring possible segregation during the process, RAMAN spectroscopy was
applied. The in-line sampling system was a filtered fiber-optic probe with
uniform global illumination (PhAT probe, Kaiser Optical Systems, Lyon, France).
The PhAT probe can generate a 6 mm diameter spot. The position of the
probe, which is a few centimeters above the powder layer and precisely horizontally
centered allows a representative sampling of the region of interest, i.e., the
position where the dosator dips into the powder bed.

Results
and Discussion

Performance evaluation of
the ‘Modified Scraper’

The segregation emerging
during the regular set-up, now detectable in-line, was compared to a modified
geometry including an additional scraper (a solution that MG2 already adopts to
improve the capsule filling mass uniformity), with the intention of reducing
segregation.

Figure 1 illustrates the
installed ‘Modified Scraper’. A visual inspection of the powder layer revealed
a mixing of the blend inside the rotary container, which is expected to lessen segregation
of the API to the bottom. Figure 2a presents a RAMAN spectrum of the blend
which demonstrates that peaks of SS and LH100 are clearly distinguishable and
can therefore be used to monitor changes in the SS concentration during the
process. Figure 2b shows a capsule filling process without using the ‘Modified
Scraper’, showing clearly the signature of segregation. Figure 2c demonstrates
that the ‘Modified Scraper’ can reduce the segregation tendency which results
in a more homogeneous powder bed.

Conclusion
and Outlook

The findings of this study
suggest that for low-dose dosator capsule filling, it is strongly recommended
to continuously control the powder layer to ensure high-quality products.
Furthermore, the in-line Raman analysis proved to be valuable towards process
optimization strategies and for improving the existing capsule filler set-up.

References

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