Solid
dose tablet manufacturing processes often lack reliability and
robustness as a result of errors in production and a shortfall in
process control. Facing unprecedented economic pressures, pharmaceutical
manufacturing companies are continuously looking to improve on the
quality of their products and the productivity of their processes.
Multi-physics numerical simulation is emerging as game-changing
technology to help step up efficiency, enhance quality, and shorten
time-to-market through virtual prototyping and optimization.
Challenges of Solid Dose Tablet Manufacturing Tableting
(compression from a powder into a solid dose tablet) and tablet coating
are two vitally important steps in the tablet manufacturing process
that ultimately determine the weight, thickness, density, hardness and
coating of the final solid dosage form. Variability in any of these
attributes not only negatively impacts the release profile and
therapeutic efficacy of the medicine, it alters the disintegration and
dissolution properties of the tablet, leads to tablet defects and causes
breakage during bulk packaging and transport.
With the adoption of novel manufacturing processes such as non-stop
end-to-end processing, and the push to build quality and efficiency into
production, solid dose tablet manufacturers have a challenging road
ahead of them because they must pinpoint the key factors and
requirements that will lead to robust and repeatable processes,
resulting in superior products.
Why Numerical Simulations? Multi-physics
Computational Fluid Dynamics (CFD) is a numerical method for predicting
the coupled behavior of fluid, gas and particulate flows including heat
and mass transport. A significant advantage of using numerical
simulations is that it allows for the validation of a design or process
before physical tests need to be carried out. For example, the
development of a new tablet shape or coating material calls for
performing an extensive number of costly and time-consuming experiments
to avoid unexpected variations, identify unpredictable process
parameters and address scale-up problems. Studying these effects through
numerical simulations can greatly reduce time, material and development
costs. In addition, numerical visualization tools offer a wealth of
detailed information, not always readily available from experimental
tests. This not only results in an increased level of insight into the
details of what is going on inside the processes, it enables innovation.
A Solution With its automated polyhedral
meshing technology and comprehensive range of physics models, STAR-CCM+
is a complete multi-disciplinary simulation toolkit to tackle a wide
range of applications in the pharmaceutical industry. One capability in
STAR-CCM+ that is particularly well-suited for the simulation of tablet
manufacturing processes is Discrete Element Modeling (DEM), fully
coupled with numerical flow simulations and delivered in a single
software environment.
Tableting and coating involve a large number of discrete particles
that interact with each other and the fluids surrounding them. DEM
accurately tracks these interactions and models contact forces and
energy transfer due to collision and heat transfer between particles and
fluids. The DEM capability in STAR-CCM+ can predict dense particle
flows with more than one million particles in a reasonable time, making
it practical for analyzing real-world tablet manufacturing processes
such as filling, compressing/compacting, coating and drying.
Figure 1 shows the results obtained from a STAR-CCM+ simulation of
pre-compression in a tablet press to determine how to overcome common
tablet defects such as capping (splitting of the tablet’s upper cap)
that often occur as a result of entrapment of air and migration of fine
particles during the compression process. DEM is used to track the
interaction of the particles with each other and with the die as they
are re-arranged and move into the empty spaces during pre-compression.
This simulation offers a detailed look at the uniformity of the granule
distribution and can help determine the optimal pre-compression force
and dwell time required to ensure that fine particles will be locked in
place before compression starts, greatly reducing the risk of incurring
common tablet defects during production.
DEM
simulations with particle-fluid interactions also provide realistic
solutions to assess uniformity of film coating thickness, a critical
parameter for tablet quality. Figure 2 depicts a simulation performed
with STAR-CCM+ for the coating process in a fluidized bed where DEM is
used to analyze the random movement of particles as their trajectories
change while layers of coating are applied. Parameters such as particle
velocities, residence time and coating thickness are monitored during
the simulation. These can be fed as objective functions into Optimate, a
module in STAR-CCM+ that enables intelligent design, to help identify
the important factors for equipment design (e.g. nozzle spacing) and to
determine optimal equipment operating conditions.
In future releases, STAR-CCM+ will also have a novel Lagrangian
passive scalar capability, enabling the user to easily monitor the
coating thickness and other features of tablets. Figure 3 illustrates a
case where 70,000+ tablets are tumbled in industrial coater. The goal of
the study is to improve on inter-particle coating uniformity by
determining optimal spraying equipment settings in the tumbler. Two
Lagrangian passive scalars representing coating thickness are defined:
one with source volume confined to one cone above surface, another with
source volume confined to two cone volumes and with an effective spray
area identical as for the first passive scalar. Using this approach, a
single simulation allows for a comparison of the inter-particle coating
uniformity for two different spray zones and the result indicates that
the two sprays configuration provides a more uniform coating
distribution.
Conclusion In today’s competitive climate,
manufacturing of solid dose tablets must have a focus on building
quality and efficiency into processes and multi-physics CFD simulations
offer a cost-effective way to achieve this through rapid prototyping and
optimization. The complex flow-fields associated with tableting and
coating can be addressed with ease by using the high-end physics models
delivered by STAR-CCM+, including the powerful DEM and novel passive
scalar capabilities. Users in the pharmaceutical industry are fully
leveraging these state-of-the art technologies as it opens the door to
explore innovative ways to improve quality, reduce cost and shorten
time-to-market.
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