Webinar Transcript - Dry Granulation Formulation Development

webinar dry granulation roll compaction illustration V2

Feature article


Nov. 25, 2021

The webinar, which took place on October 27th, 2021 illustrates the key principles of Dry Granulation/roll compaction in a pharmaceutical process. Hanna Lou Keizer, head of Production at G. Pohl-Boskamp in Germany, and PhD graduate from the University of Düsseldorf and Institute of Pharmaceutics and Biopharmaceutics presented her work and research on hybrid modeling of roll compaction with the STYL’One Evo, as well as case studies. The webinar concluded with a Q&A session.

Read the transcript below!


Note: registered member of MySTYL’One can access the full video of the webinar HERE.

#webinar #'dry granulation' #transcript #'roll compaction'

Transcript - Dry Granulation Formulation Development

webinar dry granulation roll compaction illustration V2

Read below the webinar’s full transcript


[Bruno Leclercq – MEDELPHARM]
Good morning. Good afternoon, and good evening to all of you and welcome to this MySTYL'One Live Session. Today we have scientists from all over the globe, from academia to university, from beginners in dry granulation to experts in the field. Thank you for your interest in this event, and for joining the community of STYL'One users. My name is Bruno from MEDELPHARM and I will guide you through this webinar today, where Hannah Lou Keizer and Adrien Pelloux will share their expertise with you on dry granulation mimicking on a compaction simulator.

But before we get started, just a few words on this platform and how you can interact with us. You will notice this webinar is browser based, so if you disconnect for any reason, please just click on the link that you received by email to rejoin the platform. You will find a HELP button at the bottom left corner of your screen to fix any audio issue you may have. To improve your event experience you can hide or show the widget section to increase your screen size and turn off or turn on the notifications thanks to these two buttons. Feel free to meet the STYL'One community and MEDELPHARM in the chatbox. Ingrid COYLE will be more than happy to see you there. Please use the Questions tab to raise any questions or thoughts you may have during this presentation. We will only select questions from this section, not the chat section, for the Q&A session at the end of the webinar. Let's get started.

Today's session will be divided into four parts. First, I will briefly introduce MEDELPHARM. Hannah Lou will then share with us her work on dry granulation mimicking and showcase practical examples where she used our STYL'One Evo compaction simulator.  Adrien Pelloux will then illustrate the theory with hands-on practical demonstrations. We will conclude with an open Q&A.

Introduction on MEDELPHARM

Just a few words on MEDELPHARM, the global leader in compaction simulators. MEDELPHARM'S core business leitmotiv is and has always been to innovate by the design, development and manufacture of STYL'One tableting solutions for R&D, scale-up and production support. As experts in powder processing we are very proud to have brought innovative and disruptive solutions to the market with STYL'One compaction simulators. More than 200 MEDELPHARM compaction simulators are in use all over the world including containment solutions, and our Science Lab is helping every customer to develop their formulation or to solve tableting issues.

Medelpharm New Building

Innovative Technologies and Services for Powder Processing

Enough for the introductions. Let me present to you to the speaker. Please welcome Hannah Lou Keizer for this webinar. Hannah is Deputy Head of production at G. Pohl- Boskamp in Germany. Previously, she completed a PhD program at the Heinrich Heine University in Düsseldorf under the guidance of Professor Peter Kleinebudde. Her PhD was entitled "Hybrid modeling of roll compaction with an unaxial compaction simulator". She published at least two papers, many poster and was a great speaker at many conferences in Europe on the topic of roller compaction. So please welcome Hannah Lou for the for a presentation entitled "Dry Granulation formulation development: How to save time and costs with roll compaction mimicking". On to you Hannah Lou.

[MySTYL'One members, head to the Papers section]

[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

Okay, so thank you for the nice introduction. Welcome to today's webinar about dry regulation formulation development. So today I would like to show you how to save time and cost with roll compaction mimicking with the STYL'One Evo. The data I will show today and the presentation were generated during my time as PhD student at the Heinrich Heine University and the working group of Professor Kleinebudde.


[MySTYL’One members: contact Professor Kleinebudde]


Today we'll learn about the benefits of roll compaction / dry granulation to your formulation. We will show you how a compaction simulator can be used to mimic the roll compaction process. And we will learn how to determine the optimal process parameters for roll compaction in little time and with only a few grams of the formulation.

Dry Granulation, Roll compaction & Hybrid Modeling with STYL’One Evo

Principles of Dry Granulation / Roll Compaction

Roll compaction dry granulation is a dry granulation method which is widely used in the pharmaceutical field. The main goal is to enlarge the particle size of your starting material. So, the increase in particle size is connected with several advantages: an improved flowability, an increased bulk density and reduction of dosage and mass fluctuations during tableting. An important advantage of this technique over other granulation methods is its applicability for materials which are sensitive to heat or moisture.


An important advantage of this technique over other granulation methods is its applicability for materials which are sensitive to heat or moisture.
Hannah Lou Keizer

How does this process work? On the right hand side pictures of two roll compactors I used in my thesis are displayed. The starting powder, a powder mixture, is transported to the two counter rotating rolls, here just densified to an adjustable gap width. In practice the specific compaction force is currently the most common parameter to describe the compaction process, and it is described in kilonewton per centimeter roll width.

Here the roll compaction process is shown schematically and it can be divided into three zones. First zone is the material feeding. The second zone is the compaction zone. It starts at the nip angle alpha followed by the gap width, which is the minimal distance between the rolls. And then third, the extrusion zone, where the intermediate compacts called ribbons leave the rolls. Their critical quality attribute is the solid fraction which is of importance later in the presentation. The ribbons are subsequently milled into granules and these granules can be the final dosage form, but they can also be filled into capsules or be further processed to tablets. During my doctoral thesis and during this webinar, I will focus mostly on the roll compaction part of this process.


hybrid modelling of roll compaction

Hybrid Modelling of Roll Compaction with STYL'One Evo

So, why do we need roll compaction simulation? The need for simulating the process resolves mainly from three motives.

 First, roll compaction processes can be material consuming, but especially in the early phase of research and development of a new product, the amount of the new chemical entity is often small.

Second, it can be useful for the scale-up from a small to a large scale equipment.

And third, it is always desirable to gain more knowledge about the process in order to be able to optimize it and to find better solutions for problems that may arise.

There are various approaches based for example on multivariate data analysis, and uniaxial compaction, instrumented roll technology or FEM-DEM methods. All of those approaches have their advantages and disadvantages, but many of them are complex in terms of calculation and equipment.

Hybrid Modelling with STYL'One Evo

This leads me to the method I used in my thesis and which I will present today and this is the hybrid modeling of roll compaction with a STYL'One Evo. This approach is a combination of simulating and mimicking the roll compaction process. 

On the right hand side, MEDELPHARM's tablet STYL'One Evo is depicted. So, this R&D tablet press is, as you may know, equipped with one pair of punches and is mainly used for simulation of industrial scale tablet presses as well as for material characterization. But it can be used as well for the simulation of roll compaction process. One important goal of hybrid modeling is to find the correct process parameters for formulation to obtain products with a desired quality and to do so, in a short time and with low material inputs.

First, the mimicking part of the approach. On the left hand side, the roll compactor is shown schematically. On the right hand side, you'll see the compaction simulator STYL'One, with its upper and lower punch in the different states of the compression cycle. The rolls of the compactor are mimicked by rectangular 10 millimeter by 20 millimeter flat face punches. The roll movement and its speed are represented by the sine shaped movement of the punches. The feed screw speed and the gap width are mimicked by the dosage height of the powder bed and the minimum distance between upper and lower punch. The specific compaction force on the roll compactor expressed in kN/cm roll width, corresponds to the compression pressure expressed in mega Pascal on the compaction simulator.


ribblets compressed with STYL'One Evo

Ribblet (ribbon tablet) compressed with STYL’One Evo compaction simulator

The intermediate products in roll compaction are, as already mentioned, the ribbons. For the equivalent compacts produced by the STYL'One we introduced the term "ribblets" - it's a combination of the words ribbon and tablet.


The critical quality attribute for both ribbons and ribblets is the solid fraction. It was used as the comparative property since it is strongly influencing the downstream products. Solid fraction is basically the part of the compact which is not air and it is calculated by dividing the envelope density of the compact by the powder density of the starting powder. The envelope density is determined by powder pycnometry and the power density is determined by helium pycnometry. So, the aim of the mimicking is to produce ribbons and ribblets with the same solid fraction at the same specific compaction force and gap width.


Depending on the roll compactor you wish to mimic, you can choose different compaction profiles on the STYL'One Evo. The figure shows the punch displacement and pressure of upper and lower punch exemplarily for two roll compactors of the company Alexanderwerk, they differ in their roll diameter.

Hybrid modeling is an extension of the thin layer model introduced by Peter, Steffens and Lammens. The power between the roles is divided into infinitely small layers. And those layers do neither change in height nor in width but they decrease in their length approaching the minimum gap width. The compaction force which is applied to these layers during roll compaction is calculated by integrating the product of the roll pressure and roll surface within the limits of the nip angle alpha and the relaxation angle beta.


When you mimic the process on the STYL'One you collect data and these data from uniaxial compaction are used to convert the compression pressure on the tablet press to the specific compaction force on the roll compactor.


The equivalent to the nip angle on the STYL'One is the so-called deaeration thickness. This is the point where the first significant increase in force is detected by the force sensors of the STYL'One. Equivalent to the relaxation angle Beta is the elastic recovery thickness.

This is the powder bed thickness at the upper punch position when the force decreases to zero in the upward movement after compression.


Last but important step of the simulation is a correction factor. And we established this correction factor - the so called KP factor - which is determined experimentally to consider influencing factors which are not accounted for in the model. So this is for example, the feeding system, the sealing system - rim rolls and cheek plates,  powder velocity gradients and feeding patterns resulting in an inhomogeneous density distribution within the ribbons.

Determine the KP factor

So, how to determine the KP factor, if it is not already known for the compactor you use?


First is you produce ribbons on the roll compactor, in the case as shown here, the Gerteis Mini-Pactor, and you produce ribblets with the STYL'One at different specific compaction forces and gap width.


You measure the solid fraction.


In our case we use two pure excipients, MCC, the curves and blue and lactose, curves in green. The results are shown here. So, if you look at the symbols which are filled, they represent the ribbon solid fraction. The symbols, which are empty, they represent the ribblet solid faction and they are depicted and dependent on the specific complexion force. For these results, we see here no correction factor was used. And we get similar curve shapes, but the Ribblet solid faction is always systematically higher at the same specific compaction force. So, this indicates that the computer specific compaction force might not be correct.

Since the specific compaction force necessary to obtain a certain ribblet solid fraction is lower on the STYL'One than on the Mini-Pactor.

So, the reason for this could be differences in the compaction on roll compactor and on a tablet press like the different feeding system, which might result in different starting bulk densities or shear and frictional forces on the roll compactor which may reduce the pressure. And this is where the KP correction factor comes into play.


The simulated specific compaction force was adapted until the ribbon and ribblet solid fractions were aligned, so that ribbons and ribblets showed the same solid fraction and the same specific compaction force. This was the case with a factor of 0.667 for the Mini-Pactor.


The next step was to simulate roll compaction with DCPA, and the factor of 0.667 was applied as well, resulting in an acceptable alignment.


So from these results, it can be stated first that a common KP factor was found for the three tested excipients, so that we can assume a material independence for the correction factor. And second, that it's possible to produce ribbons and ribblets with the same average solid fraction.


So enough theory for now, I hand the presentation over to MEDELPHARM for a video showing the practical use of the roll compaction simulation with the STYL'One Evo.

Roll Compaction Simulation with STYL'One Evo

[Adrien Pelloux– MEDELPHARM]

Hello, my name is Adrien Pelloux, and I'm Lab Manager at MEDELPHARM Science Lab. Today I will show you how we can mimic a dry granulation process with the STYL'One Evo and a small amount of material. 


Adrien Pelloux roll compaction webinar

Adrien Pelloux, Lab Manager, explains roll compaction simulation with STYL’One Evo

Dry granulation is a process widely used in the industry that allows drug product manufacturers to improve the flowability of their product, to increase the powder density and to lessen the risk of segregation in a single step that saves energy compared to the wet granulation. However, you need to find a good balance between those improvements and the risk of loss of plasticity.


The RoCo software for the STYL'One EVO allows to mimic roll compactors from the industry and to produce ribblets at a given gap targeting a specified solid fraction or hydraulic pressure. For that, we provide a rectangular tooling and a library of roll compactors.


STYL'One Evo makes it possible to assess the dry granulation process with only a few grams of material while kilograms of material would have been required with an industrial equipment. 

STYL'One Evo makes it possible to assess the dry granulation process with only a few grams of material
Adrien Pelloux, Lab Manager MEDELPHARM

Here is Analis home page. Analis is a piece of software that drives the machine and retrieves the information from the equipment. To perform the manufacturing of the ribblets we need to set the parameters.


We have entered the properties of our finished product and the name of the test. Here are the punches that we will use for this test. As long as the cycle, here we have decided to mimic the LB Bohle BRC 25 with those properties. On the screen you can see the list of editable parameters for your run. At the lab we mainly use the solid fraction and gap feature. To do so let's choose a gap of 2 and a solid fractions of 0.6. You can see that the target pressure is a consequence of the solid fraction and the gap. Here, you can notice the specific compaction force used on a roller compactor to get this solid fraction at this gap. Let's click on OK, let's launch the acquisition.


Here you can see the manufacturing of the ribblets.

Let's collect some ribblets produced at 60% of solid fraction, place it in a bottle and we'll keep it for the next steps. This experiment will be performed twice again, once at 70% of solid fraction, and the last time at 80% of solid fraction.

Now let's use the ribblets, mill it with the Quadro SLS mill equipped with a conical head and a one millimeter sieve. Once the Ribblets will be milled, we will use these granulates and mix it with the external phase and lubricate prior the compression study.


Here are the three final blends we are going to use to assess the loss of plasticity.

So now we are going to perform a compaction study from the final blend with the solid fraction of 60% using some punches from the manufacturing area, and the rotary press we have got on our manufacturing unit.


For that we will click on "launch study", and we will set five points from 5 kN to 30 kN. And we are going to make 10 tablets per run and call it conduction study. Once we have done this experiment at 0.6 solid fraction, you need to repeat it twice, once at 0.7 and the other one at 0.8. And we'll show you the results of those experiments after Hannah Lou's presentation. Hannah Lou?

Case study

The downstream process, from powder to tablet

[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

After this video on the practical side, I will share a case study about the downstream process with you.


We have been looking into the question of whether it is possible to mimic the whole downstream process, so from the starting powder to the tablet. 

the downstream process - webinar dry granulation

The downstream process

This table shows the model formulation chosen for the mimicking of the downstream process. Our powder blend consisted of 25% Hydrochlorothiazide as model API, 50% lactose as filler and 15% MCC as filler/binder.  Copovidone was used as binder and crospovidone as disintegrant, both of them present in a fraction of 5%. Hydrochlorothiazide was used as model API because of its poor compaction properties and its difficult handling.

From Powder to Tablets

So from the powder to the final tablets, three ways were used.


First is direct compression, so where the powder blend is directly compressed to tablets.


The second way is the hybrid modeling, where ribblets were produced, which were subsequently granulated and then compressed to tablets. From hybrid modeling, the required specific compaction force was determined for the production of ribbons by roll compaction. Ribbons and ribblets were compared regarding the solid fraction. The ribbons were as well granulated, and the granule sizes were compared between the ribbon and Ribblet granules. The granules from ribbons were as far compressed and in the end, we did obtain three sorts of tablets and we compared them regarding tensile strength, disintegration time and uniformity of mass. The question was whether the mimicking of roll compaction results in tablets with the same properties and if it is enough to consider only the solid fraction as the comparative quality attribute.

Hybrid modeling & Roll Compaction

So the aim of the roller compaction simulation with a STYL’One was in this case to find the correct specific compaction force to produce ribbons with the desired solid fraction at a certain gap width. And the software of the STYL’One, you've seen it in the video, this is done by two learning steps.


In the first learning three compressions at different dosage heights at maximum pressure are carried out, and the operator has to enter the ribblet mass, the out of die ribblet height and the power density of the starting material.


The second learning is more specific, since the software can use the pressure density profile, which was collected in the first learning. Here the specific compaction force to obtain the desired solid fraction is determined and it's now possible to produce ribblets with the desired solid fraction. When the process is transferred to the roll compactor with the calculated specific compaction force, ribbons should result with equal solid fractions as the ribblets.


So the aim was to produce ribbons with a solid fraction between 60 and 80%. Since ribbons within this range of solid faction are usually sufficiently robust for further processing. In preliminary experiments, it was found in our case, that ribblets with 60% solid fraction were not processable, so that we use the two to the power of two full factorial design of experiment with target solid fractions between 70 and 80%. Gap width of 2 and 4 millimeter with a center point of 3 millimeter chosen and the constant roll speed of 3 RPM was set. So with only a small amount of powder, it was less than five grams, it was possible to predict the specific compaction force needed to obtain Ribblets with a certain solid fraction. The table shows the different predicted specific compaction forces for each combination of solid fraction and gap width. In order to test whether the predicted values really lead to the desired results, they were transferred to the roll compactor.

So you see here in the columns on the right that the ribbon solid faction was similar to the Ribblet solid fraction and both are close to the targeted solid fraction. So the mimicking of ribbons seems to work for a formulation even with multiple ingredients.


And we can say that the first part of this case study was successful: it was possible to predict the correct settings and to produce compacts with the desired properties. The center point settings, so three millimeter gap width and 6.5 kilo Newton per centimeter specific compaction force were used for the production of a larger amount of ribbons and ribblets, which were then granulated in the star granulator unit of the Mini-pactor.

Particle Size Distribution

The granule size distribution of the ribbon and ribblet granules was compared. This measurement was performed by dynamic image analysis. And the figure on the left shows the cumulative density distribution, you can see that there's an increase in particle size for the ribbon and ribblet granules compared to the uncompacted HCT powder. The bimodal density distribution in the right figure is typical for roll compaction dry granulation. It reveals that the granules which are produced from ribblets show a higher solid fraction of fines compared to the ribbon granules. This was related to the different shapes of the compacts. The have a more defined cuboid shape, in contrast to the more rounded shape of the ribbons and the formation of the fines may be due to the abrasion during the milling step where shear and collision forces occur. Next and last step was tableting.


So with the powder blend, with the ribblet granules and with the ribbon granules, tablets with a target mass of 200 milligrams were produced on the STYL'One Evo at five compression pressures between 50 and 250 megaPascal. Thanks to the granulation step, it was possible to use the feed shoe to compress the granules whereas direct compression had to be carried out by filling by hand due to its poor flowability.

Thanks to the granulation step, it was possible to use the feed shoe to compress the granules whereas direct compression had to be carried out by filling by hand due to its poor flowability.
Hannah Lou Keizer

Tensile strength

The tablets were characterized by their tensile strength. This is a measure of how resistant tablets are against mechanical stress during coating processes, storage or transport. And the tensile strength of at least 2 MPa is generally considered sufficient for this. In the figure, it's shown that all tablets exceed this 2 MPa threshold. The tensile strength of the direct compressed tablets, this is the curve in red, is higher compared to the tablets from the granules. And this is due to the loss in tabletability which can occur after granulation. Interestingly, the curves of the tensile strength for ribblet and ribbon granules, so, the curves in blue and orange they are practically equal. And this indicates that the pressure that was exerted on both granules during the compression was the same for roll compaction and for mimicking.

 Disintegration time

The tablets were characterized as well regarding their disintegration time. No relevant differences were found between the three different types of tablets, so roll compaction/dry granulation step did not affect the disintegration. The disintegration was finished within 120 seconds for all tested tablets, so all of them easily meet the specifications of the European Pharmacopoeia.

Summary of case study

Let me summarize the case study. The prediction of the specific compaction force was successful: it was feasible to produce ribblets and ribbons with the same solid fraction. It was shown that hybrid modeling is not only applicable for pure excipients, but also for powder mixtures. A bimodal granule size distribution was found for both types of granules. The granules produced from ribblets have a higher fraction of fines, but that didn't influence the properties of the tablets made from ribbons and ribblets, they had an equal tensile strength, which was a little smaller than the one of the directly compressed tablets. So it was shown in this case study that it is possible to simulate and mimic roll compaction with a small amount of material in a short time using the hybrid modeling approach.


As a take home message from my side I will leave you with the following.


So compaction simulators can be used for mimicking the roll compaction process. With the hybrid modeling approach it is possible to determine the correct machine parameters for roll compaction with only a small amount of material and to do so in short time. And the ribbon and ribblet solid faction is the relevant critical quality attribute for mimicking the downstream process. I would like to thank you for your attention and I'm now handing over again to MEDELPHARM.

'webinar dry granulation screenshot'

Hannah Lou Keizer, Adrien Pelloux & Bruno Leclercq during the webinar

Q&A session

[Bruno Leclercq – MEDELPHARM]
Thanks Hannah Lou for your presentation and also thanks Adrien for the video. We will now start the Q&A session to conclude this webinar. You can ask your questions in the "questions tab" and then we will select them on the fly.


[Quentin Boulay – MEDELPHARM]
Hello everybody, this is Quentin from the marketing team. I will moderate this Q&A session, don't hesitate to ask your questions, your comments or any thoughts you have on the platform. So let's start.


[Quentin Boulay – MEDELPHARM]
Hannah Lou, during development stage, why can't we use roll compactor with smaller rollers to use less material?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
Good question. Due to the small amount of powder I think there's no roll compactor, even a small one, which could close the gap - so the gap won't adjust because the amount of powder is too small, you need several hundreds of grams outputs. So if you wish to find the correct settings, you will need more power. And the advantage of the mimicking is that you will only need less than five grams or so. And that's why I think it's not the best, or the easiest way to use a small compactor to do so.


[Quentin Boulay – MEDELPHARM]
What are the limitations of roll compaction mimicking, Bruno?


[Bruno Leclercq – MEDELPHARM]
We know that the STYL'One is a good way to to look at the feasiblity of roller compaction, but there might be some limitations. Obviously, one of the limitations, as you saw on the video from Adrien, is that the filling of the powder is done through a hopper and is filling a die, whereas when you look at the filling on a roller compaction, in that case, the powder is fed by different kinds of screws, forcing the product into the two dies. And there might be some kind of pre-compaction on the powder, or sometimes some deaeration you don't see. Therefore this is, I will say already, one of the limitations of the product but with the study that's been done by Hannah Lou we have proven that even though the feeding process is a little bit different, we actually achieve a similar kind of result between the STYL'One Evolution and a roller compactor like the Gerteis or the LB Bohle roller compaction.


[Adrien Pelloux– MEDELPHARM]

And I would like to add maybe a point - you have also something you cannot consider is the density distribution within the ribblets or in the ribbons. Due to the feeding you have some some patterns and while you can't mimic them with a roll compactor, but nevertheless you get the same average solid fraction. And that is important thing you need in the end.


[Quentin Boulay – MEDELPHARM]
Thank you both for your input. Someone is doing dry granulation mimicking on STYL'One - so it's a STYL'One user- but during production of ribbons he has high ejection forces. Have you experienced this? And what was your solution in this case?

[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So for the case study I just showed we used external lubrication. And normally, it should be possible to solve the problem with this. But maybe Adrien you have another suggestion?


[Adrien Pelloux– MEDELPHARM]

Yeah, exactly, I would recommend to use the external lubrication, that's what we do at the lab. It allows to use only a small amount of magnesium stearate and to avoid gripping of the ribblets. And you have a pure caraterization of your product.


I think the important thing is that you don't lubricate internally, because then you would change the properties of your formulation, and that's the great advantage if you use the external lubrication.



[Quentin Boulay – MEDELPHARM]
Thank you, both of you. Does the surface of the punch tip make sense to mimic dry granulation on the STYL'One Evo, as I find we usually get a smooth surface punch. But I think the question is, can we use other types of punches?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So the idea was to use punches which are near to the dimensions of the rolls we used so the Mini-Pactor was equipped with rolls which had a roll width of 2.5 centimeters, and they were smooth rolls. So that's why the punches were chosen like this. However, I also did some experiments I didn't show today but I used compactors with rolls which were not smooth. And the results we obtained there were as well fine. So as long as you have an average gap, it shouldn't change your thing.


[Adrien Pelloux– MEDELPHARM]

Yeah, I would just add that according to roll compaction manufacturers, the structured roll are for improving the nip angle and so the grip of the material to the rolls, but the more structure are the rolls, the higher will be the heterogeneity of the solid fraction of your ribblets.

[Bruno Leclercq – MEDELPHARM]
Just to add to that that, if you really want to have a different kind of surface of the punch, it is always possible to actually order some punches like 10 by 20 to try to mimic what happens on a roller compactor, but we don't believe it will have a major effect because it has got no effect on nip angle and the putting of the powder in the die, but if you want this is actually feasible to order some special punches.


[Quentin Boulay – MEDELPHARM]

Thank you all of you for this nice reply.

Hannah Lou, you said" small amount of material", do you have ballpark figures to estimate what amount of material will be needed?

[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So it's, of course, depending on the formulation you use, and the bulk density and so on. But for the formulation I used in my case study, I used in the first learning, I produced 3 ribblets during the first learning, and it was approximately 2.5 grams for those three ribblets. And then for the second learning, another ribblet was produced. And together, this was around 3.5 grams to find the correct settings. Of course, when you go further then to the downstream process - so you produce more ribblets and ribbons and you need to have granules -  of course you need more material, but until the point, finding the correct settings, it's enough to have less than five grams.


[Adrien Pelloux– MEDELPHARM]

Currently at the lab we do the reverse way. Currently we ask our customer, how much samples they need, then what is the average weight of their tablets, and then we need to compute the yield of each step from the tableting. Then the milling. And then the roller compaction simulation. So currently to make full characterization profile for one solid fraction, it's around 400 grams with 20 tablets per point when we do the tableting after.


[Quentin Boulay – MEDELPHARM]

And when you measured the solid fraction, Hannah Lou, what equipment did you use for that?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
I used two different methods actually. For the ribbons, a powder pycnometer was used -in our case the GeoPyc and  if you have your ribbons, they are not that defined in their shape. So they are rounded and they are bigger or smaller. And so for these kinds of compact it's it's good to have a powder pycnometer. Of course you can put into it also your Ribblets or tablets. But for the Ribblets I used also a micrometer screw - a caliper -to measure the dimensions. It's easier, and you get in the end similar results.

Ribbons vs ribblets

Ribbons vs ribblets

[Quentin Boulay – MEDELPHARM]

Thank you. Don't forget that you can still ask questions on the platform. So Hannah Lou, you said that roll compaction is used to improve flowability which means that the initial flowability is pretty bad. Do you have ways to fill the die other than the hand filling? And maybe it's a question more for Adrien?


[Adrien Pelloux– MEDELPHARM]

Currently at the lab, we have a large range of feeders for the machine, so even for difficult material, we can use some very specific feed shoes that help us a lot to fill the die and to have a consistency of filling for these steps.


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

Maybe from practical side, so for the case study, the direct compression I had to do filling by hand and after granulation of the ribbon and Ribblets - so the granules - I could use the feed shoe. So definitely there was improved flowability compared to the uncompacted formulation.

There was an improved flowability compared to the uncompacted formulation
Hannah Lou Keizer

[Quentin Boulay – MEDELPHARM]

Okay, thank you for your input. And what type of milling was used for the ribblets for your experiments? Do you have a set of recommended conditions like this screen size, speed, and so on?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

Yeah, so during my experiments I used for both types, the granulation unit of the Mini-Pactor. But I think Adrien you have used another mill?


[Adrien Pelloux– MEDELPHARM]

Yes, exactly, when we are very small amount of material, we are obliged to use a screen and to mill the tablets by hand. But at the lab, we use a conical mill, and we can choose several screens. And it's not as accurate as you will have on the scale up, but it will give you some ideas on the particular size distribution you will get with several solid fractions.


[Bruno Leclercq – MEDELPHARM]
And maybe to add on a previous question, one of the questions from one the participants was "what was a limitation of our system?"

One of the limitation will also be that we are not using exactly the same mill that will be normally below a roller compactor. Then the milling process will be maybe a little bit different. But don't forget that the idea of this Roco Pack is really to look at feasibility. Obviously, the validation of the milling will have to be done on the roller compactor with its mill, which is associated to it.


[Quentin Boulay – MEDELPHARM]

Hannah Lou, would you suggest to see differences in tablet properties with other tablet formulations, for example, in disintegration time,? Your disintegration times where rather short, around 20 seconds? So the differences could be maybe not that significant, but can you comment on this?

[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

Yes, of course. And so I have to mention it was the last experiment during my PhD. So I used the formulation, I could show that could be sure it will disintegrate. Because I didn't have time to repeat it. So the amount of disintegrant was quite high with 5%. I guess if it had been less, maybe we would have seen larger differences. And it could be that we have then maybe differences, but it's really depending on the mechanism of the disintegrant, how it is. And then roll compaction might have an influence on disintegration, but it not does not necessarily have to be like that.


[Quentin Boulay – MEDELPHARM]

Which instruments were used to measure the porosity?



[Adrien Pelloux– MEDELPHARM]

Currently the porosity is computed by dividing the density of the ribbon by the true density, so we can do it with the STYL'One Evo because when we measure the dimensions of the ribblets, then Analis software will perform the auto calculation of the porosity.

[Quentin Boulay – MEDELPHARM]

Hannah Lou do you have a comment?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

Well yes I agree and just to enter the powder true density, in my case, I used a helium pycnometer. But often the vendor for the different excipients, they provide already data for the true density. So if you don't have a pycnometer, you can maybe calculate average true density. And then like Adrien said, it's possible that the STYL'One just calculates that for you.


[Adrien Pelloux– MEDELPHARM]

At the lab we also use a helium pycnometer to measure the true density prior starting the studies.

[Quentin Boulay – MEDELPHARM]

Thank you for your reply all of you. You mentioned a Gerteis Mini-Pactor in your study. Is it possible to use different roll compactors profile - because I assume that not all users have a Gerteis?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]

So in my thesis I used four different roll compactors. I worked with a Bohle BRC 25 and I worked with two Alexanderwerk compactors. So, it is possible yes, and maybe Bruno you can add something to that?


[Bruno Leclercq – MEDELPHARM]
In the Analis software like you mentioned, you can actually choose a roller compactor you want to mimic - like the LB Bohle or the Gerties is that you used, the Fitzpatrick or other kinds of roller compactors. Or if you use another roller compactor from another supplier from Asia, for example, we can actually build a profile for this specific roller compactor. Then we can actually have the profile of all the rollor compactor you may be using.


[Quentin Boulay – MEDELPHARM]

I think this leads to the next question because we have a user of STYL'One asking if it's possible to do this kind of study with an existing simulator or do we need to update the software?


[Bruno Leclercq – MEDELPHARM]
Yes, obviously, if you have a STYL'One Evolution, you can upgrade your simulator by acquiring a license to deal with roller compactor and this could actually be kind of adapted to your machine and there's no need for any kind of intervention, we send you a license and some specific punches of 10 by 20 to mimic a ribbon. Then yes the answer yes is is feasible.


[Quentin Boulay – MEDELPHARM]

And another question in the same direction, people are asking: Can we use this - the STYL'One Evo equipment-  as a single punch tablet press, not as a roll compaction simulator?


[Bruno Leclercq – MEDELPHARM]

Yes, obviously in the study that was performed by Hannah during her PhD, she produced some ribblets, after it was grinded, and then after tableted, with any kind of punch you may want then. Obviously you can do all the development work, you have your mix of powders to start with, you granulated them, you grind them, and then you get your powder and then you can actually produce some tablets with the format of a punch, emulating a tablet press that you may use in your production.


[Quentin Boulay – MEDELPHARM]
Thank you Bruno. Hannah Lou, can you explain why it's not recommended to lubricate internally the roll compaction stage?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So if you lubricate internally, your internal friction in the powder mixture will change. And this has an influence on the compression / on the compaction of the powder on the roll compactor itself, as well as in the tablet press. And if you have for example, formulation on the roll compactor without internal lubrication, and then you go to the tablet press to mimic it and you use internal lubrication, I think there might be differences between the results. I haven't tried it to be honest but I think it's really likely that it would change.


[Adrien Pelloux– MEDELPHARM]

At the lab, we have some customers that make some small internal lubrication and then we add an extra phase - an external phase, and then lubricate. It might be also a way to avoid the sticking on the rolls.


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So I don't want to say avoid internal lubrication for your formulation on roll compactor. It can of course make sense, but I recommend to use the same formulation if you really do roll compaction, and if you mimic it.


[Bruno Leclercq – MEDELPHARM]           

Maybe one thing to add on that is that if you need to use internal lubricant to avoid sticking on your roller compaction, try to minimize the amount because if you have too much you may actually affect the bonding during the production of Ribblets, and then afterwards, after milling you can also affect your product quality.


[Adrien Pelloux– MEDELPHARM]

I will just add that then you might have some issues with over lubrication due to the screw on your roller compactor. So I would, as Bruno said, make as little as possible the amount of magnesium stearate in your internal phase.


[Quentin Boulay – MEDELPHARM]
Thank you for for your comments. We still have time for one or two questions, so don't hesitate to ask them on the platform. There is a lot of questions and a lot of specific questions for individuals. So we will reply to that after the the Q&A No problem.

One question for you Hannah Lou: When you do a study on one formulation, can you replicate this? Is it valid for all the formulations, or you have to to redo the experiment?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
So I use the method for three formulations for the one I showed today. And then I cooperated with colleagues at university with roller compaction, and they didn't have so much material, so they asked me "Hannah could you could you help me and could you try to find the correct settings for me?" So it was feasible, also for other formulations, yes.


[Quentin Boulay – MEDELPHARM]
Okay, and maybe the last question before Bruno concludes:


You have made experiments on the STYL'One Evo and then you did the same experiment on an industrial roll compactor. Did you determine the process parameters of the roll compactor from the STYL'One Evo? Can you explain a little bit more this scale-up phase if you have made it?


[Hannah Lou Keizer – G. Pohl-Boskamp/PhD University Düsseldorf]
Yes of course. So the the main idea is that you, as I said, it's a bit like I explained. So I tried to explain it another way maybe.


So if you wish to find the correct settings for roll compaction, you say okay, I want to have ribbons with this and this solid fraction, and I want to use the gap width of two millimeter. And with this, this is your starting point. And you produce a small amount of your mixture, and then you directly go to the STYL'One, you do not have to go to the compactor. As long as you have the KP factor - that's the thing you need at first, but if you have it, then you can go directly to the STYL'One. And then you can determine with the hybrid modeling approach the necessary machine parameters. And when you have them, you can go directly back to the roll compactor. So that's basically the way how to do it.


[Quentin Boulay – MEDELPHARM]
Thank you Hannah Lou.



[Bruno Leclercq – MEDELPHARM]

Thank you everybody for your attendance and all the questions. Like Quentin said there were many other questions that we will answer offline.

Your presentation demonstrates the feasibility of dry granulation mimicking with a small amount of product
Bruno Leclercq, Medelpharm

Thank you, Hannah Lou, for the hard work, for all the work you did during your PhD on the STYL'One Evolution & on the roller compaction model.

Your presentation obviously demonstrates the feasibility of dry granulation mimicking with a small amount of product.

And also 'thank you' to the MEDELPHARM team for organizing this event.

MEDELPHARM Science Lab represented by Adrien here, can assist you in the development of dry granulation formulation on the STYL'One Evo compaction simulator, but we can also assist you for material characterization, formulation, development to troubleshooting. If you have any kind of trouble, don't hesitate to contact us, especially Adrien who will be driving your project.


The Q&A session continues on the MySTYL'One forum with Hannah Lou and Adrien.


This presentation and the replay will be available on MySTYL'One.com Obviously stay tuned for other events and we're already planning the events for next year. We at MEDELPHARM wish you a pleasant day and do not hesitate to contact us directly for any additional questions or comments. Thank you, and have a good day.


[Edit: end of transcript]

MySTYL'One members, access Hannah Lou's research papers : 

Hybrid modeling of roll compaction processes with the STYL'One Evolution: Granule size distribution

Elastic recovery in roll compaction simulation

Estimation of nip angle by roll compaction simulation

Want to read more?