Generally, in oral polymer-based
drug delivery systems an amphiphilic polymer is utilized as the carrier matrix
for an active pharmaceutical ingredient (API) with low water solubility. The
homogenous distribution of the API within the polymer matrix enhances its water
solubility. Regarding the API’s physical state in such systems, this can be
simply dispersed within the polymeric matrix forming a solid dispersion, or it
can be dissolved forming a solid solution. During my Ph.D. the latter case was
dealt with. In addition, I have exploited a model drug delivery system, where
Soluplus® (BASF SE) was used as the polymer matrix and fenofibrate as the API.
The injection moulding of polymer-based
drug delivery systems is a technology whose development is still at academic
level. Up-to-date, commercialized state-of-the-art polymer-based drug delivery
systems are produced using hot melt extrusion.
Over 1 year has now gone since
I finished my PhD at JKU. And now I have
a clearer view of how the knowledge and experience which I have acquired during
my Ph.D. can be applied to different areas of the plastics industry.
Below follow my
favorite top 5 takeaways [1]:
Takeaway number #1: Powder
processing on the plasticizing unit of an industrial injection moulding machine
- “compounding on a single screw”
In order to process/mould the
aforementioned polymer-API system (in pre-specified compositions) into the
targeted tablet shaped drug delivery system two approaches were followed:
1) Conventional approach: Twin-screw
compounding followed by injection moulding
Since both components of the
drug delivery system were powders, a twin screw compounding process was at
first used to obtain pellets in which the API was well dissolved within the
polymer (first step). Following, these pellets were successfully
processed into tablets using a 50 ton ENGEL e-mac all-electric injection
moulding machine with an 18 mm three section, reciprocating screw (second step).
Such double-step procedure is conventionally chosen to deal with the joint
processing of different powders.
2) 100% injection moulding
In an attempt to simplify the conventional
approach, herein the above-described injection moulding machine was used to
directly process both powders. To accomplish this, the common hopper was
replaced by a combined hopper and gravimetric dosing unit where the (manually
premixed) powders were placed.
The first challenge of this
approach was to avoid undesirable agglomeration of the powders in the hopper
due to the temperature gradients established at the start of the plasticizing
process. In order to minimize this phenomenon,
the first section of the plasticizer unit (right after the hopper) was additionally
air cooled. This step permitted a stable
plasticizing process.
The second challenge of this
approach was to effectively mix and melt both powders during the plasticizing
step utilizing the standard three section screw. The latter provided
insufficient mixing capability for the processing of the studied system. As a
result, solid powder could still be observed in the final tablets. To improve
the powder mixing during the plasticizing process, the utilization of screws
with additional mixing elements (e.g. pineapple mixer) was helpful.
To sum up,
elimination of the compounding step in powders processing may be feasible upon
small adjustments in equipment, i.e. specific hopper and screw design. The
first allowed sufficient powder transport into the feeding section without
agglomeration, while the second facilitated melting and mixing of the different
components.
Takeaway number #2: Design of
the injection mould for drug delivery systems - “how to hit the 200k tablets
per hour?”
The traditional tablets
manufacturing process utilizes a tablet pressing machine capable of producing
200k tablets per hour in its small configuration. Nevertheless, the inherent
processing of powders in such technology involves several steps, such as
sizing, blending, drying, compression, etc. [2]. This results in increased
overhead costs and lack of process flexibility.
The utilization of the
injection moulding technique may allow the production of tablets with enhanced
water solubility by one-step procedure. While such process may introduce added
value in the tablet manufacturing industry, can it reach the benchmark productivity
of 200k tablets per hour achieved by the well-established manufacturing process?
Within the project time two mould
concepts based on 6 cavities (1 injection cycle produces 6 tablets) were tested:
I) Central cold runner sprue (40 mm),
star distributor and side gating; II) Central
hot-runner with open nozzle, star distribution and side gating with shorter
distribution arms for more efficient ejection (see Figure 1 below).
Figure
1:
Moulded
parts of the two investigated mould concepts.
These prototype mould concepts permitted the
assessment of the feasibility of using injection moulding for the fabrication
of useful tablets, i.e. where the drug is well dispersed within the polymer
matrix. However, in a large-scale scenario moulds with a higher number of
cavities and shorter flowing ways (to minimize unused material) would be
obviously required.
A starting point for an upscale of this process would be, for example,
assessing the possibility of utilizing a “Mini Hot-Runner System” (Günther-Heiβkanaltechnik GmbH). Here a top gating replaces the side gating and a mould with a
greater number of cavities can be achieved with minimal material losses. In a feasible production scenario, an
injection mould with 128 cavities could be utilized on a barless all-electric
injection moulding machine having a low clamping force (e.g. 1900 kN). For an
estimated production cycle time of 8 seconds 57,600 tablets per hour could be
obtained. In this scenario, 4 injection moulding machines would be necessary to
compete with a small tablet pressing machine in terms of productivity.
Takeaway number #3: Numerical
simulations of the drug distribution - “know where your drug will end up in the
cavity”
Where is your API during the injection moulding
process and finally in the ejected tablet? The use of numerical CFD simulations
can help you to visualize the API along the process chain.
During my Ph.D., I utilized OpenFOAM simulations based on tailor-made particle tracking models
to better understand the mixing in the metering section. Furthermore, I also
utilized the injection moulding software Sigmasoft
(Sigma Engineering GmbH) with the tracer function (coloured velocity vectors)
for a straight-forward (virtual) visualization of the API distribution during
the filling of the part holding the 6 cavities as well as in a single cavity.
Important to note is
that a simulation is a simplification of the reality and, thus, additional
experiments must also be performed to test its accuracy. For instances, I have
performed colouring experiments that helped to make visible the velocity
gradients during the filling process. These were then compared to the gradient
estimated by the aforementioned simulations and an optical accordance could be
found.
Takeaway
number #4: Understanding the pharmaceutical industry markets - “get to know
which markets grow the most”
My Ph.D. topic focused on
poorly water-soluble drugs. Nevertheless, other type of drugs, such as
psychotropic drugs, respectively antidepressants exhibit poor lipid solubility
[5], which is also necessary for drugs to be absorbed by the human body.
According to Scientific American
[5] the consumption of
antidepressants among adults in USA was found to be four times higher in the
late 2000’s compared to the early 1990’s. Researchers estimated that 8 to 10%
of the USA population takes an antidepressant type.
The development of novel
polymer-based systems capable of efficiently delivering such drugs orally will certainly
be objective of research in days to come. In this regard, utilization of
injection moulding as a manufacturing technique of tablets may be of equal
interest.
Takeaway number #5: Ideas for future
application development - “polymer processing techniques wake up traditional
pharmaceutical processing”
Promising innovations can
simply arise from transferring established processes from one industry to
another, even when these seem so unlikely to be combined, such as it happens
with the plastics and pharmaceutical industries.
While Soluplus® and
other related polymers (e.g. Kollidon®, Eudragit®, etc.) were purposefully
designed to fulfill the requirements of the pharmaceutical industry in terms of
drug delivery abilities, the utilization of suitable standard thermoplastics
may be capable of totally disrupt such markets. For instances, it has been
recently shown that thermoplastic polyurethanes (e.g. Tecophilic™
grades ) can be used as matrix excipients for the production of similar
drug delivery systems (oral dosage forms) [3, 4]. The latter were produced by combining hot melt
extrusion with injection moulding. Inherent advantages included formulations
with high drug loads (65 %wt) and controlled release in vitro and in
vivo.
I
hope that these takeaways demonstrated that the use of an implemented polymer
processing technique, such as injection moulding applied to a different industry
(in this case, the pharmaceutical industry) can open up new problem solving
capabilities which add value to our societies.
Till
next time!
Greetings,
Herwig
Literature:
[1] Juster H., Numerical Simulation
and Experimental Validation of Polymer Based Drug Delivery Systems Produced
with Injection Moulding, PhD-thesis, 2015
[2]
Fischer D., Breitenbach J., Die Pharmaindustrie: Einblick, Durchblick,
Perspektiven, Spektrum Akademischer Verlag, 2009
[3] Claeys B. et al., Thermoplastic
polyurethanes for the manufacturing of highly dosed oral sustained release
matrices via hot melt extrusion and injection molding, European Journal of
Pharmaceutics and Biopharmaceutics, Volume 90, February 2015, Pages 44-52
[4] Verstraete G., et al., Hydrophilic
thermoplastic polyurethanes for the manufacturing of highly dosed oral
sustained release matrices via hot melt extrusion and injection molding, Int J
Pharm. 2016 Jun 15;506(1-2):214-21. doi: 10.1016/j.ijpharm.2016.04.057.
