(402e) Development of a Tablet Manufacturing Line Via Hot-Melt Extrusion and Strand Pelletization

Development of a tablet manufacturing line via hot-melt extrusion and strand
pelletization

T.R. Hörmann^1,4, O.
Scheibelhofer², J. Rehrl^2,4, A. Funke³, A.
Paudel^2,4, J.G. Khinast^1,2,4

²
Research Center Pharmaceutical Engineering, Graz,
Austria

³ Bayer AG, Chemical and
Pharmaceutical Development, Germany

⁴ European Consortium on Continuous Pharmaceutical Manufacturing
(ECCPM), 8010 Graz, Austria

ABSTRACT

Hot-melt
extrusion (HME) is a versatile, inherently continuous process for making
amorphous solid dispersions (ASD) with improved bioavailability of poorly
soluble active pharmaceutical ingredients (APIs)¹. Pellets
can be made via cold or hot-strand cutting of the extrudate and offer excellent
flowability and handling properties. However, the production of tablets from
hot-melt extruded pellets is challenging, since the pellets are dense,
non-porous particles with lower surface-to-volume ratio, thus not facilitating
inter-particle bonding in comparison to powders. Moreover, many polymers
exhibit elastic deformation upon compression. In our work we addressed the
corresponding challenges to develop an effective formulation and a robust
process.

The investigated line is shown in Figure 1. The aim of the HME formulation
development was the generation of a stable ASD from a poorly soluble API yielding
immediate API release from HME pellets. Five extrudable polymers were screened
for ASD stability, miscibility and processability. The screening resulted in a
ternary formulation with 10 % (w/w) in two polymers, i.e., Eudragit®E and HPMC
E5 (Methocel®E5). The composition ratio of these polymers was optimized using
small scale techniques to identify the best trade-off between processabiliy in
HME and pelletization, and ASD performance (stability and dissolution profile).
Molecular interactions and miscibility were characterized extensively in order
to gain a detailed product understanding. Process development for the HME and
pelletization process was done in two steps: i) a process parameter screening
and ii) a robustness study of process and product performance upon small
deviations from the optimal settings. Subsequently, a design space was
established for the process, which was experimentally validated.

Tableting formulation development consisted of an initial
small-scale screening step using several binders and disintegrants on a compaction
simulator, followed by formulation optimization with Avicel PH102 and Kollidon
CL on a rotary tablet press. It was possible to identify a formulation with 40%
(w/w) of HME pellets, yielding mechanically stable tablets with desired API
release profile. Next, downstream process development was performed with the
selected formulation.

Powder blending was optimized in terms of mass flow rates aligned to
the HME-pelletization step and the residence time distribution (RTD) was characterized.
Since RTD was not equal for pellet and powder components in the process unit,
the RTDs of the two materials were determined separately. This facilitates
accurate material tracking through the continuous process line setup. This
approach was also used to evaluate pellet and powder RTDs in semi-continuous
tableting runs. The combination of findings from tablet formulation development
and downstream process characteristics allows a performance prediction of the
complete continuous processing line. This can be deployed for example, to
develop advanced process control strategies.

Process development studies for the continuous HME-pelletization
process could be performed in a very efficient way by investigating a number of
process parameter (DoE) set points in short sequence without process
interruptions. A comparison of the effort needed showed a potential to reduce process
development time by approx. 50% compared to traditional batch-wise fluidized
bed granulation. The API demand during the process development phase could be
reduced by approx. 30%. This demonstrates the ability to develop continuous
processes more efficiently.

REFERENCES

1.   J.
Breitenbach, Melt extrusion: from process to drug delivery technology, Eur. J.
Pharm. Biopharm. 54 (2002) 107–117