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.

[5] URL: http://www.scientificamerican.com/article/the-rise-of-all-purpose-antidepressants/

Jack Welch and his uprise in GE Plastics (incl. Infographic)

"We were scared to death but filled with dreams - and just nuts enough to try anything to get the plastic to work" were Jack Welch words when he found out the issues around the - back at the time- new plastic named NORYL. Find out how Jack Welch and his team tackled this problem as well as his career path at GE Plastics.

My top 5 favorite apps for polymer engineering operations (incl. video)

Our mobile phones became an essential tool of our daily lives. This is true for polymer engineering operations as well. Selection of the right polymer for a certain application, troubleshooting in injection moulding, or simple polymer engineering calculations can nowadays be effectively supported by existing mobile phone apps.

This post will give you an overview of the apps I currently use on a daily business basis. I made a video, which supports this post in a more dynamic manner.

Following are my top 5 favorite apps:

1. ENGEL e-calc: for all kind of calculations in injection moulding >> link to app
   
   
2. WIBA Assist: good troubleshooting, material and calculations in injection moulding >> link to app
   
   
3. PSG – Plastics Service Group: injection moulding problems and possible remedies
    >> link to app
4. Kunststoff Institute Lüdenscheid: surface defect guide >> link to app
   
   
5. FIMMTech: good for design of experiments >> link to app
   
   

All five are linked to the Google play store.

Let’s check out the video:

Do you know another great App for plastics processors?

 Please let me know!

Thanks & Greetings,

Herwig

Polymer injection moulding & reciprocating screws: successful since ever, but what will happen in the future?

Figure 1: cross-sectional design of Willert's plasticizing unit.

Recently, PTonline posted an article about the invention birthday of the reciprocating screw and the injection moulding apparatus patented by William H. Willert (Clinton). This was what triggered me to have a look at the current plasticizing systems and related future concepts:


In Figure 1 the cross-sectional design of the plasticizing system of Willert’s patent can be seen. It is composed of three main elements, i.e. the reciprocating screw, the barrel and the material delivering part. If we compare the plasticizing unit of the figure to those implemented in our nowadays injection moulding machines, we won’t find much of a difference.

Before we think about implementing new plasticizing systems, a basic question arises: Do we already know (after 60 years) everything about the melting process during plasticizing, respectively the temperature of the melt in the antechamber?

There are analytical models such as the melting model of Tadmor [1], which describe how a solid bed of polymer pellets are melted in the plasticizing unit by the heat transferred from the hot barrel and the shear heat, also known as viscous dissipation, generated by the rotation of the reciprocating screw.  In injection moulding processes, the screw reciprocates until the necessary amount of polymer is melted.  In the best case scenario, a homogenous temperature distribution of the melt in the antechamber is attained. In this case, all the melt components, e.g. polymer, colors and additives are equally distributed throughout and we can say that “the screw has done a good job”.

However, how can we analyze the distribution profile of the melt temperature?

Formerly, the melt would be separately injected into a thermally isolated cup and a thermocouple would be inserted into it to record the temperature (offline measurement). This would simply show whether the temperature profile set on the barrel was reached.

Just very recently and yet at university level, an innovative inline measuring method has been proposed [2].  This utilizes an ultrasound sensor-based system which determines the axial profile of the melt temperature in the screw chamber and channels via reflection. Such inline measuring capabilities will allow us to further develop and improve the plasticizing process with the aim to decrease temperature gradients within the injection unit. The inline accessed data will be crucial to set up and validate more accurate CFD simulations of the plasticizing process. Therefore, simulating the plasticizing process utilizing different mixing elements in a reciprocating screw set up will lead to more assertive conclusions regarding the best design to enhance the melt homogeneity. Consequently, though the principle of the reciprocating screw will remain, new screw designs may finally arise in a near future to meet the requirements of processing ultra and high performance plastics, such as PI, PEEKs, PAEKs, etc.

Besides reciprocating screws, which other plasticizing systems can be found in injection moulding?

• Ultrasonic Injection Moulding

In the field of replication of micro parts (parts containing micro features whose weight is below 1g) the development of new plasticizing solutions starts to be noticed. Current micro injection moulding machines use two stage systems, which allow a separation of the plasticizing phase via extrusion and the injection phase via a stamper. For precise injection of few grams of melt for moulding micro parts, plasticizing by means of ultrasonic energy emerges as a new alternative [3]. Ultrasonic injection moulding machines utilize ultrasound energy to enable the transition from granule to melt in a homogenous manner throughout the plasticizing unit. Thus, the residence time of the melt is reduced to a minimum, which is advantageous when working with materials prone to degradation by the process temperature and/or shear. Overall, this is a totally new concept of injection moulding, which requires new strategies for process control as well. Let’s see how this technology develops, but it looks certainly promising in businesses, such as healthcare and watch manufacturing for instances.

• Inverse screw injection moulding

Finally, plasticizing small melt amounts can also be realized by a new concept based on an inverse screw system (see Figure 2 below) [4]. The main difference to current injection moulding reciprocating screws can be found in the internal structure of the inverse screw: the screw flights for conveying the polymer pellets into melt are part of the cylinder. Using this internal structure sufficient space for processing standard pellets in the feeding section can be accomplished. Furthermore, the diameter of the plunger is reduced. This plunger is placed coaxially within the cylinder. The main advantage of this design is to have the melting benefits of a reciprocating screw combined with the precision of a plunger during injection. This system was already tested for several commodities and engineering thermoplastics. Benefits include shorter residence times and precise repeatability, which makes this system also a promising development partner in the manufacture of high precision parts.



Figure 2: Schematic representation of the inverse screw unit [4].



The above mentioned systems are the pioneers who set foot on the ground of new injection moulding innovations and they will be niche players. In the field of microreplication more and faster movements can be seen in terms of completely new developments that totally disrupt well-known plasticizing systems. Let’s see what will be presented at the K show this year in Düsseldorf.
Greetings and until soon!

Herwig

Literature:

[1] Z. Tadmor: Fundamentals of plasticating extrusion. I. A theoretical model for melting; Polymer Engineering& Science, Vol. 6, 1966

[2] B. Praher et al.: Non-invasive Ultrasound Based Temperature Measurements at Reciprocating Screw Plastication Units: Methodology and Applications, PPS-30, 2014

[3] Ultrasion S.L.  (http://ultrasion.eu/)

[4] Ch. Hopmann et al.: New plasticizing process for increased precision and reduced residence times in injection moulding of micro parts, CIRP Journal of Manufacturing Science and Technology, 2015