Transcript - R&D of Mini-tablets on STYL'One Evo

minitableting webinar visual

Feature article


Jan. 7, 2021

On December 9th Ard Lura, PhD student from Heinrich Heine University (Düsseldorf) presented his work on “Research and Development of mini-tablets on a STYL’One Evo”. Bruno Leclercq, MEDELPHARM’S Science Lab head and business developer also presented innovations from MEDELPHARM that are valuable for mini-tableting. The session ended with a Q&A. 

For those who could not join us, you can freely access the transcript below.

Note that members registered to MySTYL'One can access the full video of the webinar HERE.

#webinar #mini-tablets #transcript #mini-tableting

Transcript- R&D of Mini-tablets on STYL’One Evo

minitableting webinar visual

Full webinar available

Read below the webinar’s full transcript

[Quentin Boulay, MEDELPHARM] – Introducing the webinar

Good morning, good afternoon, or good evening to all of you. And welcome to this first My’STYLOne Live Session.

These sessions are a set of events where users of STYL’One compaction simulators have the opportunity to share their expertise with you during a 30-minute live presentation. My name is Quentin Boulay, I'm product marketing manager at MEDELPHARM and I will guide you through this webinar today.

But before we get started just a few words on this station and how you can interact with us. You'll notice this webinar is browser based. So if you disconnect for any reason just click on the link that you received by email to rejoin the platform. In order to ask questions, you can send them via the question widget on the right side of your screen. Just type them into the box and click on submit. You’ll have until the end of the session to address any questions or thoughts you may have. We will select the questions for a Q&A session at the end of the webinar.

This session will be divided into two parts. First, I will start with a brief introduction of MEDELPHARM and MySTYL’One. Then Ard Lura from the University of Düsseldorf will introduce his work on Mini-tableting.
After, Bruno Leclercq, our Science Lab head and business developer will present some innovations from MEDELPHARM that are useful for Mini-tableting. We will end this session with a Q&A.

[Quentin Boulay, MEDELPHARM] – Presenting MEDELPHARM & MySTYL’One

So, MEDELPHARM is a global leader in compaction simulators, with more than 35 years of experience in tablet compression technology and more than 150 compaction simulators in operation worldwide. We are specialized in the design, development and manufacture of tableting solutions for R&D, scale-up and production support. Our first breakthrough solution that we got to the market and that some of you are still using was the STYLCAM, the fully mechanical compaction simulator.

And since then, we’ve continued offering innovative and disruptive solutions to the market with the STYL’One series which has been well accepted by the market and widely used. Last summer, we moved to a new building that you can see on the background of this slide in order to support our growth and to host MEDELPHARM activities including: our Innovation Center (for the design and development of STYL’One solutions and associated softwares), our production workshop where we manufacture STYL'One Nano and STYL’One Evo and where we offer after sales service, and our Science Lab where we perform customer studies, machine demos and internal testing to support the design and development team.


Medelpharm New Building

Innovative Technologies and Services for Powder Processing

One short word on MySTYLOne before we start the presentation on Mini-tableting. is the website you've all registered on. The website is built for users of STYL’One and STYLCAM equipments. So if you are a user of your machine do not hesitate to create your MySTYLOne account. You'll get access to additional exclusive resources linked to your machine for example documentation backup, calibration files or software updates. You'll be able to exchange with all the other users of STYL’One equipment around the globe with a Forum. And you'll find a comprehensive library of STYL’One content, regular events like this one, and fresh compaction news

So just remember one single address

Enough talk from me! So, today we are honored to launch this series with one of our beloved partners: Heinrich Heine University in Dusseldorf, Germany.

So please welcome, Ard Lura, PhD student at this university, who will present his works on “R&D mini-tablets on the STYL’One Evo compaction simulator”.

Please Ard, take over.

Part 1 - Ard Lura presenting his work R&D of mini-tablets on STYL'One Evo

[Edit] - MySTYL'One members, remember you can access the full video replay HERE

Thank you very much for the kind introduction. I will just share my screen with you.

So hello everybody and good afternoon. Thank you very much for the kind introduction and welcome to my talk about parts of my PhD thesis where I conducted experiments with the STYL’One Evolution on Mini-tablets. My name is Ard Lura and I'm in the working group of Professor. Dr. Breitkreutz in The Institute of pharmaceutics and biopharmaceutics and I'm happy to share parts of my work now with you.

But before we start we have first to make some definitions about mini tablets or what are actually mini-tablets.

What is the state of the art?

When we have a look in the pharmacopoeias, you actually do not find any definition for mini-tablets. However, depending on the literature you’re looking at, you mostly find that mini-tablets are described as solid dosage forms with a diameter from one to three millimeter and an aspect ratio close to one.

In this picture, you can see example of 1 millimeter, 2 millimeters, and 3 millimeters mini-tablets.

mini tablets size comparison

1, 2 and 3 mm mini-tablets 

Main question of course: Why should we do mini tablets?

What we know so far is that in several acceptance studies the clinical benefit for mini-tablets for especially the paediatric population was proven already. We have a very high acceptance but also biopharmaceutical advantages due to the small size and the higher specific surface of mini-tablets.

From the technological point of view, we know that mini-tablets that have several advantages towards tablets. So why is that so?

Due to the production of the mini tablets, we get highly reproducible dosage forms, which are already of predefined size. We can have a smoother surface which when you perform a tablet coating, you will get a more evenly coating and also less coating time. So in total you will get lower production costs.


Why should we do mini-tablets? The clinical benefit for the paediatric population was proven already
Ard Lura, Heinrich Heine University

So next question is : "How can we actually produce mini-tablets?

In comparison to bigger size tablet, they are 3 main types of compression or production for mini-tablets.

First of all, the simplest one is the direct compression that we just have our blending step and then perform the tableting.

If especially flowability is not very good enough. You have to implement the granulation step in between (either by a dry granulation or by a wet granulation) and then perform all the granulation steps.

One thing you have always to keep in mind, if you have a look at this picture here in the bottom, you can see the small orifices of the die section.

tip toolings for mini-tablets

2 mm single tip, 7 tip and 19 tip tooling

Linked to this, one can also estimate that success of the production step is highly linked on the one hand to the flow properties of your powders but also, on the other end, to the actual particle size.

So the formulation which should be mini-tableted should always keep a balance between good flowability properties (which you can increase for example with an intermediate granulation step), but also in the particle size. In other cases you cannot perform the mini tableting as dies will be blocked.

However, if you’ve found a suitable formulation (and you will find in literature lots of examples for data compression, dry granulation, but also wet granulation products) you can perform the tableting on, for example, compaction simulators, like the STYL’One Evolution, but also to rotary tablet presses like the Korsch XM 12.

So, now we have produced our tablets and what I want to emphasize within the next two slides is the characterization of mini-tablets.

As you also may know, due to their size we do not have standardized methods to characterize the mini-tablets. I want to point out now two of the characterization methods.

First, the breaking force or the calculation of tensile strengths.

For those who are familiar with the mini-tableting you may have noticed that many of the conventional hardness tests you may have in the production or an academy data are not precise enough or suitable enough to measure exactly the breaking force of mini-tablets. Due to the very low breaking force compared to the conventionally sized tablets.

There are some semi- or fully- automatic running systems with a rotating plate. However, if you put the mini-tablet, for example on this rotating plate, it cannot be fixed. And so also the measurement will fail.

But what we actually use in our university is this device called a “texture analyzer”. What you're doing actually with this device is that you place the mini-tablet on this position and then you have the flat face punched with a predefined speed on the tablet and then you will ensure a diameter break and then you can measure the breaking force.

If you want to go a step further and calculate afterwards the tensile strength, there are two main possibilities to do so.

In this graph you can see tabletability plots of isomalt mini-tablets of 1, 2 and 3 milimeters.

tabletability plots isomalt mini-tablets

Tabletability plot of isomalt mini-tablets (1, 2 and 3 mm); n=10, mean ± standard deviation

What we did in this investigation, as the mini tablets were biconvex, we used the equation of Pitt and Newton and compared it to the simpler one, by Fell and Newton, who employed actually flat faced tablets.

So what you can see immediately from this graph is that there is no significant statistical difference between the two calculations.

So for simplification all the measurements and all our calculations were performed with the equation of Fell and Newton.

The next critical quality attribute for our dispersible mini-tablet is of course the disintegration time.

To measure the disintegration time, you will not find clear instruction in none of the pharmacopoeias for mini-tablets. This is due to the tablet size which is obviously a limiting factor for the current devices which cannot measure properly the disintegration time.

The mesh seats which is expressed in the pharmacopoeias should have a max size of about 2 millimeters. So of course too big for mini-tablets, which are 2 millimeters or smaller than 2 millimeters.

According to the method, this would mean that all tablets which were measured with current devices will show immediate disintegration.

In literature, you can also see various testing methods which orientate from biopharmaceutical aspects to more complicated measurement methods where they for example try to measure some resistance and then link it to the disintegration time.

To simplify: the disadvantage of this prescribed method in literature is that you hardly can standardize those methods in several labs.

What we did, is that we took the developed disintegration method by Prof. Kleinebudde in his thesis for pellets.

Here, you have a predefined disintegration basket which you can lock with these two seats of 7.10 microns of the main size. 

You can put one mini-tablet into it. And then you can put this disintegration basket in the apparatus for disintegration according to the pharmacopoeia.

Then, you can measure the disintegration time. So all the disintegration time measurements were performed with these disintegration baskets.

So this was some basic statements from my side.

What I want to talk to you about now is the comparison between mini tablets and conventionally sized tablets.

Comparison between mini tablets and conventionally sized tablets

So, why should we do that?

We have still the main question: Are there any benefits for mini-tablets?

When you screen again literature, you will find various papers. I took three of them as examples.

In this patent by Dr Pich and Moest, you will find that they tried to develop pancreatin tablets that contained I think of 99 % of pancreatin and wanted to compress it into a 10 millimeter tablet.

They saw during the development phase that it completely failed. But when they reduced the tablet size to a mini-tablet size, they saw that the tablet was a showing the proper mechanical strength.

Another paper, which most of you may know, is by Lennartz and Mielck. They show in this paper that the compactibility and so on the mechanical stability of paracetamol and lactosa tablets was higher when they produced actually minitablets.

Another example was described by Ryshkewitch and Duckworth in this discussion for non-pharmaceutical excipients.

So they took ceramides and they also showed that when they decreased the tablet dimensions, there was an observation of increasing mechanical strength.

So the main question is now: is that even a benefit for mini-tableting? Do we reach higher compactibility? Is tabletability improved?

In some of the papers it is stated that in the deformation behavior towards more plastic deformation is enhanced with mini-tableting.

To test these questions, we chose four different excipients we wanted to test.

We chose MCC and lactose as they are really frequently used excipients in pharmaceutical development. But also novel ready-to-use excipients like Isomalt (the GalenIQ grade) or Ludiflash ® which is a co-processed excipient, both suitable for developing oro-dispersible mini-tablets.


We tableted everything on the STYL’One Evolution into one compression mode.

We did the manual die filling, and to avoid the effect of internal lubricants we performed an external lubrication either with magnesium stearate or with sodium stearyl fumarate for especially Ludiflash ® tablets.

In this picture, you can see all the products, as we developed 1, 2, 3,8 and 11.28 millimeter tablets.

minitablet webinar picture

1, 2 and 3 mm mini-tablets in comparison with 8 and 11.28 mm tablets

To answer the previous questions, we looked the compressibility and deformation behavior. In this case, I will show you results of in-die Heckel plot.

We checked the compatibility (so actually the plot between tensile strength and solid fraction) and furthermore kept our focus on the tabletability.

We will have a look on the tableting pressure where actually 1.2 MPa are reached according to recommendations of the manufacturing specifications. Furthermore, we performed the linear regression and determined the slopes.

 Now, let's go to the Heckel plots.

I don't want to go too much into details on the obtained yield pressures with the Heckel plot. What I want to point out in this slide is actually that in most case for MCC, Isomalt, Lactose and Ludiflash ® we’ve found the highest yield pressure when we actually performed the mini-tablets.

The trends for the much lower yield pressures were obtained with conventionally sized tablets.

And these results go hand in hand with other observations and other methods we tested to test the deformation behavior like modified variable function or the specific classic energy.

However, we have to keep always in mind to the Heckel limitations.

As most of you may know the Heckel plot is not reproducible material constant.

So there’s plenty of literature where you will find for the same excipient, very significant differences in the obtained yield pressure.

Furthermore, we have to keep to be aware that the conventional sized tablets are produced with a flat-faced punch, and the mini tablets with a concave one.

Which means that actually the pressure distribution in the flat face tablet is of course more homogeneous than in the convex ones.

It also actually recommended that you should actually perform the Heckel plot with flat faced punches.

However, comparing these results, we see a clear trend that the highest yield pressures are obtained with mini-tablets.

We see a clear trend that the highest yield pressures are obtained with mini-tablets
Ard Lura, Heinrich Heine University


What was stated also in previous literature is that you actually increase the compactibility when you perform mini-tablets.

In this graph, you can see our four excipients: MCC, lactose, Isomalt and Ludiflash ® and their compactibility test. We plotted and calculated the tensile strength against the solid fraction.

I will show you with the example of MCC what actually the result is.

compactibility mini-tablets

Compactibility plots of MCC, lactose, isomalt and Ludiflash® at different tablet sizes;  n= 10; mean ± confidence intervals (95 %) 

In this graph, you can see our four excipients: MCC, lactose, Isomalt and Ludiflash ® and their compactibility test. We plotted and calculated the tensile strength against the solid fraction.

I will show you with the example of MCC what actually the result is.

In most cases, you see that we obtained a lower solid fraction, with the same tensile strengths with mini-tablets.

For the same tensile strength to obtain you should have increased the solid fraction of the conventionally sized tablets.

And this trend is more or less noticeable for MCC, and also for Lactose, for Isomalt. Just for Ludiflash ® you cannot see the trend as for the other three excipients. Here we have some higher scattering of the two millimeter mini-tablets which show actually the highest compactibility between 1 and 2 Mega Pascal which you actually reach with the 2 millimeters at a solid fraction of about 0.7.

However, the conclusion of this graph is that you actually can improve compactibility with decreasing the tablet size to mini-tablets.

You actually can improve compactibility with decreasing the tablet size to mini-tablets
Ard Lura, Heinrich Heine University Düsseldorf


The next question will deal with the tabletability.

Here again, you can see for MCC, lactose, Isomalt and Ludiflash ® the tabletability plots of tensile strength versus tableting pressure.

Here, you can estimate and you can clearly see that you have nearly no significant differences in tabletability. So the conclusion would be that tabletability is not actually improved when you perform mini-tableting.

On the contrary, in some cases, for MCC or for lactose for example, you will even have poorer tabletability performances when you use mini-tablet tool.

So the conclusion of this first part of this talk would be that you can achieve higher yield pressures for mini-tablets. No clear trends could be seen for mini-tableting regarding the tabletability. But we found better compactibility.

So with all these observations which were made, my opinion is that whether your formulation can be produced as a mini tablet, or a conventionally sized tablet highly depends on the formulation itself, and you cannot actually do a general statement.

Whether your formulation can be produced as a mini-tablet highly depends on the formulation itself
Ard Lura, Heinrich Heine University Düsseldorf

Formulation Development Bi-Layer mini-tablets

After we clarified some of the basic results we go now more into formulation development.

I want to show you now parts of the development of bilayer mini-tablets for the treatment of peadiatric paratonia.

So on this slide, you can see our manufacturing steps.

We have a lower layer with on the one hand API Hydrochlorothiazide, and an upper layer with the enalapril maleate. We’ve chosen both of these drugs as they are stated in the WHO’s list of essential medicine for children.

The machine settings were as followed.

We compressed the lower layer, and the upper layer. And as you can see on the compaction forces, actually you will see that the compaction forces did not exceed 1 kilo Newton, which is very low.

So we performed this with a flat face single tip and thanks to the dual-scale, which Bruno will inform you later on, we were able to perform this compression in very low tableting pressure.

The result of the bilayer tablets are described on this slide.

So, we could produce bilayer mini tablets with a mass of about 10.3 milligrams, very high and also suitable tensile strength of about 3.9 megapascal. We had disintegration times below 10 seconds in the tablet showed immediate drug release.

In this picture you can also clearly see as we colored one layer in red, with the red oxide.

bi-layer mini-tablet

2 mm Bilayer mini-tablets

We further performed the micro CT scan through the bilayer mini-tablet.

What you can see in the small videos are mainly brighter area turn into darker areas. These comes from the different density regions of our model API enalapril and HCT. So you cannot see mixing between the two layers also in the micro CT.

However to emphasize or to show a clear phase separation you want to test how precise actually our bilayer mini tablets were produced, regarding the drug content.

To do, so we performed the drug content according pharmacopoeia 296 to test the Precision.

So we tested two mini-tablets and you can see that for both model API’s that we fully fulfilled all specifications regarding the pharmacopoeia.

So the conclusion on this slide would be that we are able to produce bilayer mini-tablets with the STYL’One Evo.

However, as I mentioned also the beginning the die-filling process is a very critical manufacturing step when you want to produce mini-tablets.

In this picture, you can see for example bilayer mini-tablets which we tried to produce with the current feed shoe. You can see, by the color, that mixing of the two layers occurred.

However, Bruno will tell you afterwards in this session that there is a new feed shoe in the pipeline to overcome actually this type of output.

Now we focused on basic features of mini-tablets and conventionally sized tablets.

We showed in very short that we can produce bilayer mini-tablets.

And now we want to transfer from STYL’One and perform scale-up.

Transfer and scale-up

First definition of course, what is actually a scale up?

If you have a look in the FDA and the EMA guidelines, they more or less commonly say that a scale up is defined by a change in batch size by a factor of 10.

So all I aim to do now is to produce orodispersible mini-tablets from the STYL’One Evolution to a Korsch and transfer them and scale up to a Korsch XM 12 with isomalt and ludiflash ®.

As I mentioned previously, both excipients the showed their ability in further studies to develop drug loaded oro dispersible mini-tablets.

We had a batch size of about 50 grams for the STYL’One and 1.5 kilograms for the Korsch. We set at mass of 6.85 milligram per mini tablet and the scale-up was then performed according to FDA guidelines by factor 10.

So we produced from 570 min-tablets, to 5.700 mini-tablets and finally 57.000 mini-tablets.

We used a tableting pressure of about 100 around 100 MPa for isomalt and 120 MPa for the Ludiflash®.

As we wanted to have orodispersible mini-tablets to be included into the critical quality attribute besides: Mass variation, tensile strengths and disintegration time.

First I want to show you results of the transfer.

You can see on this slide the tabletability and compactibility plots for Isomalt and Ludiflash ®.

You stick close to this, in this tabletability plot. In that one are the results with the real data from Korsch, and in that one on the right the data predicted by the STYL’One using the compression profile of the Korsch.

You can see hardly any differences for isomalt in the tabletability profiles, nor in the compactibility profiles. So they're very highly reproducible and the transfer hopefully succeeds.

When you have a look on Ludiflash ® in the tabletability plot. You can see here that the STYL’One over estimated a bit the course of the tabletability plot in comparison with the real data of the Korsch.

However, the results are also not statistically significant, but the trend is observable.

Regarding the compactibility of Ludiflash ® in comparison of Korsch and of the STYL’One, you can also then hardly find any differences in the compactibility profile.

So, the transfer succeeded and we then started the scale-up.

What I wanted to show you first is the mass.

On the top is depicted the development of mass for Isomalt, and here, for Ludiflash ®.

We you can see if you take a look actually is a slight trend of increasing mass for Isomalt but also a small decrease in the mass for Ludiflash ® over the first 570 mini-tablets produced on the STYL’One compared to the first 570 mini-tablets produced on the Korsch and then an increase with batch size.

The differences might not be statistically significant when you compare them. However, you could observe that there’s an increase in mass over production time.

When you regard a mini tablet, you know that they're usually used for low drug content.

The change of mass would also mean that your API load might not be according to the label claim you have. So the change of load would also be a change of content.

So the recommendation would be obviously to have a very precise mass control over your production time when you perform especially mini-tablets.

Tensile strength

Next part will consider the development of the tensile strength.

Again above you can see the results of Isomalt starting with the first 570 mini-tablets on a STYL’One over to development on the Korsch. The same for Ludiflash ® on the bottom.

You can see that there are for Isomalt no differences for the first 570 mini-tablets. But with increasing batch size up to 57,000 mini-tablets you can see a very slight, non-significant decrease of tensile strength.

For Ludiflash ® the decrease is more emphasized. We targeted in the beginning a tensile strength of about 1.6 Mega Pascal.

After producing the first 570 mini-tablets on the Korsch, we observed a drop in the tensile strength of approximately 0.4 MPa.

Which means if you for example targeted in the beginning a tensile strength of 1 MPa and wanted to be in the specific case specifications following the manufacturer classification systems. A drop of 0.5 MPa would have meant that when you would have performed the scale-up, you would be out of your own specifications.

However, and comparable to Isomalt, with increase in batch size the tensile strength drops a little bit.

These observations are actually not new. If you screen literature you will have plenty of examples where with continuing process time and increase in batch size, due to for example, a higher residence time and over lubrication of your powder, a decrease in tensile strength will automatically occur.

So when you want to perform mini-tableting, you have to be aware how lubricant sensitive for example your formulation might be. And then take those into account, or keep it in mind when you perform a scale up with increasing batch size for longer process.

When you want to perform mini-tableting you have to be aware of how lubricant sensitive your formulation might be
Ard Lura, Heinrich Heine University Düsseldorf

Disintegration time

Last result I want to show you today is dealing with the disintegration time.

As we wanted to perform or to develop orodispersible formulations, there are two specifications we have to meet.

The one regarding the FDA who wants a disintegration time of about 30 seconds. And the other one regarding the European Pharmacopoeia who claim a disintegration time of about 180 seconds.

In those two pictures you can clearly see that for both excipients the disintegration time increases with an increase in batch size.

mini-tablet desintegration time

Desintegration time

Until the last point where we actually produce 50,000 mini-tablets neither for Isomalt nor for Ludiflash ® the specifications from European Pharmacopea could not be met anymore.

There’s still a clear difference between the two excipients. For Ludiflash ®, up to 5.700 minitablets, the tests of the mini-tablets fulfilled the FDA requirements.

Whereas for Isomalt, the disintegration time increases slightly that up to 570 and 5.700 minitablets meet only the specifications of the European Pharmacopea.

What could be the reason for these difference in results?

Well, we have to remind the Ludiflash ® (contrary to isomalt) is a co-processed excipient. We have in Ludiflash ® a super disintegrant which accelerate (until 5.700 mini tablets obviously) the disintegration which leads to a disintegration time below 30 seconds.

Whereas for Isomalt, we do not have a disintegration component in the formulation.

But, however, the disintegration time for both excipient rises over time.

What could be the reason?

We must not forget that during a longer process time, temperature development also occurs.

What we did here was to measure the temperature of an infrared image of produced isomalt mini-tablets when they were ejected. So, directly after production.

And we ran again 0.5 Kg of Isomalt formulation up to 104,000 mini-tablets produced.

You can see that the product temperature which was measured in this point increases from the start.

Actually after 570 tablets from about 24 degrees Celsius up to in the end to 26 degrees Celsius.

And as both excipients are derived actually from sugars. You may know the sugars tend to perform sintering phenomena.

This sintering might avoid water penetration as it forms like a protective shell around the tablet.

With this work and submitted already in a paper that can say that the disintegration times of the mini-tablets at the end of production are highly comparable with the one which were collected at 57,000 min-tablets.

The key message from these last two slides is when you want to have orodispersible formulations, you cannot neglect the increasing product temperature over time.

Main Conclusions

What are now the main conclusions of this talk?

We’ve compared mini tablets and commercially sized tablets and saw that part of previous observations could be established and proved actually correct.

Furthermore, we saw that the development of bilayer mini-tablets is highly feasible with a STYL’One Evolution.

With the transfer and scale up from STYL’One Evolution to our rotary tablet press also being quite successful.

However, we have to keep always in mind the increase of product temperature or potential of over lubrication with increasing process time.


As I mentioned before most of the experiments were performed with manual die-filling. So there is a new feed shoe in the pipeline to overcome this stifling process and still investigations remain to the successors of my work to investigate these phenomena.

I want to thank MEDELPHARM, my Institute, students who helped or contributed during their internship in time in this work. And I'm happy to answer some of the questions, live or in the MySTYL’One forum.


Thank you very much.

The development of bilayer mini-tablets is highly feasible with a STYL’One Evolution
Ard Lura, Heinrich Heine University Düsseldorf

Part 2 - Innovations from MEDELPHARM for mini-tableting

[Quentin Boulay, MEDELPHARM]

Thanks a lot, Ard.

Now Bruno will add some more information on the STYL’One innovation that are useful for mini-tableting.

Do not forget that you can still ask your questions with the widget on the right side of your screen. Your question will be answered by Ard Lura or Bruno at the end of this webinar.

So, on to you Bruno.

[Bruno Leclercq, MEDELPHARM]

Thanks Ard for your presentation on mini tablets development.

I will introduce now a few features available on the STYL’One Evo and that could be used during formulation development including obviously Minitablets.

.First, one unique feature that was developed on the STYL'One Evo is the Dual scale.​

Dual Scale

On this system, we have an additional force sensor for higher accuracy when measuring low forces. The system is composed of two piezoelectric force sensors.

The force sensors are located on both lower & upper piston.​

As it can been seen on the graph, the first force sensor has a range up to 5KNewton and the second sensor from 5 to 50KN. Resolution of 1 N. Obviously this a seamless operation for the operator as the switch is automatic between the two signals.​


Now let’s find out the application of Dual scale​.
Two applications for dual scale are Multilayers tablets and Mini tablets.​

In the case of Multilayers, tamping forces are usually very low between 0.1 and 1 kN, whereas main compression force can be much higher. In this example up to 25+ kN. 

Dual scale will allow high definition on both very low forces like tamping and precompresion and also on high definition on the main compression forces.​

In the second case, for mini-tablets.

As we said, mini-tablets are typically defined to be of 2 or 3 mm diameter.

Multitips are often used to increase productivity, however when using single tip punch for characterization or formulation development usual main compression forces are very low, often between 0.5-1.0 kN. Therefore higher accuracy at low forces given by the dual scale is desired in the development stage. ​

The STYL'One Evo used by Ard during his PhD work at the university of Düsseldorf is equipped with the dual scale option​.

As you have already seen with the dual scale, MEDELPHARM is always working on innovations. Our engineering department is always looking for continuous improvement in order to enhance our user experience.​

Let me show you now two innovations, the first one is on the feeding of the die and the second one on tablet ejection. Those two steps are critical while producing mini-tablets​.

Paddle force feeder & Linear ejection system

We have developed a new force feeder where the paddle is flushed with the die table to ensure constant filling. This is especially interesting for formulations like Mini-tablets where feeding of the die is a critical process parameter.

The second system that has been developed is a linear ejection especially interesting for multi-tip mini-tablet but also for shaped tablets or in case of the production of small clinical batches where sorting of good and bad tablets is critical.​

Let me play the video that will show you both the new feeder and the linear ejection in action while the STYL'One is producing Minitablets.​

With this video, you see the feeding of mini-tablet, then compression, and ejection.

I will play it again for you: feeding, compression, and ejection.

So, this was the last part of the presentation, talking about the different kind of innovations that MEDELPHARM has done, and that can be used for mini-tablets.

With this video, you see the feeding of mini-tablet, then compression, and ejection.

I will play it again for you: feeding, compression, and ejection.

So, this was the last part of the presentation, talking about the different kind of innovations that MEDELPHARM has done, and that can be used for mini-tablets.

Part 3 - Q&A session

Ard, during your second part of your presentation on multi-layer mini-tableting, there was no lubricant in the formulation. Have you experienced any ejection problems, and if “no” is it due to the low tablet surface, do you think?

Actually, no we had no internal lubrication, we used an external lubrication system. So therefore we did not have problems with high ejection forces, we used external lubrication.

What are the challenges of mini-tablet for handling and processing?

So as I mentioned in the beginning of the talk, for the main challenge I think would be the flowability problems you face when you want to have an evenly die filling and also the resulting particular size. If you for example need a further granulation step to improve your flowability.

The tableting itself. The thing is that when you use especially multi-tips and with high amount of tips, of course, you can have higher deviations in the product afterwards. If for example the tips are damaged or are not maintained very well, but after you produce a mini-tablets, I think the main problem is actually the characterization.

As the mini tablets are not listed in pharmacopoeias and there are also no standardized methods to characterize them, actually that would be also a main challenge.

And also when you perform the next step, dosing is also very critical step for mini-tablets because there are some dosing devices yet or in development, but applied as multi-particulate dosage form, or single-dosage form, the dosing could also then be a difficult path.

To come back on the multi-layer topic. Do you have any idea of the tensile strength that you were able to obtain from your bilayer mini-tab?

The tensile strength was about 3.9 MPa (Megapascal).

We measured it with a Texture Analyser.

We placed the mini tablet diameter and measure the point actually where the two layers met and then we had the resulting tensile strength of 3.9 Mega Pascal, which is very high.

Did you use the same tablet press tooling on the STYL’One and on the KORSCH machine for your scale-up work?

We used 19 tip Euro D punches, so the same one for the KORSCH as for the STYL’One, we did not have changes in the punches, it was the same punch.

On the KORSCH, we equipped the KORSCH fully with six pairs of punches. And of course the STYL’One with one of them, it was 19 tip Euro D tooling.

Do you think that the compactability variability between the tablet sizes could be a limitation of the small tablet size because they are more prone to errors since it’s difficult to measure their dimensions?

That's always a possible error. You have to take into account, especially what we observed when we produced the 1 millimeters. So we had to use microscopy to actually relate the tablet dimensions.

And of course when you have smaller tablets and you are not very good at handling, you can occur some deviations during the measurements which of course will result in different results.

Regarding then afterwards the calculated tensile strengths but also porosity and so on. So yeah, you have always to be aware of what your measurement systems.

Have you done any coating of mini-tabs after the tableting?

Not myself but there was some works while also performing a coating experiment, yes. But to my knowledge, it’s also no problem to coat mini-tablets if there is enough suitable tensile strength and shown mechanical stability, like I said in the beginning, I think that there are advantages to pellets– you have very low friability and coating works quite well. 

You mentioned using external lubrication on the STYL’One to avoid over-lubrication. Do you use any lubricant in your formulation on the production machine? 

There we performed internal lubrication. So we had to perform internal lubrication because it was not feasible at the time to perform external lubrication. And also regarding to previous formulations, we had always internal lubricants. We also wanted to check how this or if there is a possible over-lubrication with these two excipients.

Therefore we decided to have an internal lubrication and not an external, because we wanted to see actually the effect on our production time, what will happen with tensile strength, disintegration time and so on.

Don't forget that you can ask additional questions via the FORUM!

When you perform the external lubrication on the STYL’One, how did you manage it?

We actually used this external lubrication box from MEDELPHARM and then we used the feeder.
So we performed the external lubrication with the feeder. So we ran it, there was no powder, so we did the manual die filling but made use of the force feeders to perform the external lubrication.

We have a question regarding ejection force on the 19-tip punch. Do you think that the ejection force will be linear with the number of tip per punch? That the more tips you have the higher the ejection will be?

Yes, that's for sure because you increase die wall frictions, obviously.

So when we have more amount of tips, your die wall friction will also increase and linked to that also, your ejection.
Yes, what we observed when we performed the mini-tableting experiments with either in the past with formulations or now: we had main ejection force for the 19 tips between 200 to 300 Newton in the best case,

And in the worst case it increased up to like 500 600 Newton which is to my opinion way too high.

But yes, of course, we have to keep all this in mind that ejection force will increase with the amount of tips. But also if you turn for example from two millimeters to three millimeter tablets, for example that the ejection force will be much higher.

Are there any recommendations for use for certain size of tablet particularly regarding causing choking?

There are acceptance studies by Dr. Klingmann where they also tested mini-tablets as a multiparticulate dosage form. I don’t know by heart how many tablets the characteristics of children had to swallow but I think was very high amount of number that could swallow it without further problems, but I don't know by heart the exact number.

But there are other papers by Dr. Klingmann, she did a lot of work with the acceptability and swallowability studies of 2 millimeter mini-tablets.

During the introduction, you mentioned 1 millimeter minitabs. Is it something that is feasible on the industrial scale?

In my personal opinion, no not really. I think the 1 millimeter mini-tablet is more for academia as the drug load would be also very low for 1 millimeter.
So usually in the best cases when you are developing mini-tablets you may achieve a drug load of about 30 to maximum 40 %, and when you consider this for 1 millimeter mini-tablets, that's nearly nothing in absolute minimum score for treatment of a certain disease.

So what I can only imagine is that 1 millimeter mini-tablets could be only produced as an alternative to pellets, to perform afterwards for example API loaded coating. Like carrier systems, but not actually as a final dosage form. I think they are too small and too hard to handle as well.



 [Quentin Boulay, MEDELPHARM] 

Okay. Thank you very much Ard and Bruno.

Thank you for your time and for all your answers.

Ard and Bruno will be glad to reply to your new questions directly on the MySTYL’One  FORUM, so don't forget to connect on this platform.

We will repeat this kinds of events. So stay tuned.

MySTYL’One live session #2 will be held next February and we will for sure keep you updated.

For the time being we wish you a very good end of the year and do not hesitate to contact us directly for any additional questions or comments.


Thank you very much for your participation today. Take care. Bye bye.

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