Monday, 3 October 2016

Injection moulding of oral polymer-based drug delivery systems - 5 takeaways of my Ph.D.



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.






No comments:

Post a comment