Webinar Transcript - Fundamental Investigations on Bilayer Tablets

webinar visual Multilayer Jan Finke - 2 no IST

Feature article

MySTYL'One

Sept. 8, 2022

Access the transcript of the webinar "Fundamental Investigations on Bilayer tablets - Effects of Process Parameters and Geometry on Interfacial Strength" 

Speakers:
*Jan Finke, Division Head Pharma & Bioparticle Technology, iPAT, TU Braunschweig & Senior Scientist, Fraunhofer IST
*Bruno Leclercq, Science Lab Head and Business Development Manager, MEDELPHARM

Webinar agenda: 

  • General Introduction
  • Measurement of interfacial adhesion strength 
  • Influence of material deformation behaviour & impact of process parameters and tablet geometry
  • Detection of signs of internal stresses before delamination 

#bilayer tablets #webinar #transcript

Transcript - Fundamental investigations on bilayer tablets - effects of process parameters on interfacial strength

webinar visual Multilayer Jan Finke - 2 no IST

Fundamental Investigations on Bilayer Tablets



Read below the webinar's transcript


General Introduction


[Bruno Leclercq – MEDELPHARM]

Good morning, good afternoon, and good evening to all of you, and welcome to this MySTYL'One live session. It has been too long since the last session, so thank you to all of you, scientists from academia or industry, beginners or experts in the field of bilayer tablet development, for your interest in this event, and for joining the community of STYL'One users from all over the globe. I'm Bruno Leclercq from MEDELPHARM, and I will guide you through this webinar today, where Jan Finke will share his expertise with you on bilayer tablet development on a compaction simulator.

Today's session will be divided in two parts. First, I will briefly introduce MEDELPHARM then Jan Finke will share with us his scientific work on bilayer tablets and showcase practical examples where he used STYL'One Evo compaction simulator. 


Introducing MEDELPHARM and activities

[Bruno Leclercq – Science Lab Head & Business Development, MEDELPHARM]

Just a few words on MEDELPHARM, the global leader in compaction simulators. MEDELPHARM's core business 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 the STYL'One series including containment executions. More than 200 MEDELPHARM compaction simulators are in use all over the world and our Science Lab is helping customers to develop their formulations or to solve tableting issues.

On the picture, you now see the inside of the OEB5 STYL'One Evo that has been recently developed by our engineering department.

STYL'One OEB5 close up inside

The STYL'One allows R&D at production speeds, not only for single layer but also for multilayer formulation development. It is helping scientists to determine quickly the critical material attributes and the critical process parameters.

Enough for the introduction. Let me welcome to you today's speaker, Jan Finke. As Jan has many responsibilities I will leave it to him to introduce himself. Jan's presentation today is entitled "Fundamental investigations on bilayer tablets- effects of process parameters and geometry on interfacial strength". Up to you Jan.

Jan Finke's presentation


Introducing Jan Finke


[Jan Finke – Division Head Pharma & Bioparticle Technolog, iPAT, TU Braunschweig & Senior Scentist, Fraunhofer IST] 

Welcome to the MySTYL’One webinar on “fundamental investigations of bilayer tablets”, which we rerecorded due to technical issues during the original broadcast. My name is Jan Henrik Finke and I first would like to talk you through my background.

I studied pharmacy, became a pharmacist and then had a doctorate in pharmaceutical technology, after which I changed to the Faculty of Mechanical Engineering and became a division head at the Institute for Particle Technology. At this institute, our department, our division of pharma and bio particle technology is quite one of some. And we are situated at the center of pharmaceutical engineering where I'm recording your web session right here.

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Let's talk a bit about what we're doing at the Division of Pharma and Bioparticle technology. First of all we put the patient into the center of our attention. We always know that we need to start with some materials, one of them being the A like API - active pharmaceutical ingredient - and usually mixed with different components, excipient and liquids for example, to get the final dosage form.

And this final dosage form should have some specific properties, that we would like to learn and we have an interest in how the application can be done to achieve certain properties. We have processes that are involved to build up structures of those final dosage forms, and so we need to develop process models to describe how the materials are processed via processes into those structures. 

And the structures on the other hand, have certain properties that they convey. Accordingly, we build a triangle with process models and properties.

Regarding the different starting points, we do have challenges from the API. This may be a poorly soluble API for the small chemical entities or a sensitive molecule, like for bio, technologically derived biopharmaceuticals. And accordingly, we start with this and we have quite a variety of different processes we apply. For example, we start, for the API, with particle engineering coming bottom up with precipitation or top down with milling to achieve, for example, nanoparticles of the API mechanics. Let's go further with granulation and drying to transfer it to a dry powder, for example. We of course go for blending with different excipients, compression - where the focus will be - applying the STYL'One Evolution - and also with individualization, for example, via 3d printing.


On the other hand, to characterize our structures we build up with these processes, we need to apply a variety of different analytical methods. And we finally also determine not only the structure but also the properties which may be water uptake, disintegration, dissolution, and the integrity of the API after release.

A special point of interest is the mechanics, on the one hand of the material, on the other hand of the final dosage form. Then we start with different applications and also at different size ranges.

With the atomic force microscope, we can characterize the mechanical properties of the API surface for example, or on the surfaces of the final dosage form. Nanoindentation can also be applied to both in form of micro compression of single particles, for example, or surface indentation of final dosage forms like tablets. And mechanical testing, where we will focus on in this talk is usually applied to gain properties of the final dosage form.

Additionally, we all do these efforts to provide the patient with benefits. And this may be an improved compliance by individualization, the enabling of the formulation and application of, for example, pretty soluble or sensitive drugs, safety and efficacy of the dosage form. 


Why multilayer tablets?


But now let's dive into the topic of today which is bilayer tablets. Why should we do this?

In bilayer tablets, we can combine different incompatible API's in one dosage form which is convenient for the patient, of course. We can also provide different dissolution profiles like immediate and sustained release.

Advanced delivery approach is often also applied to bilayer tablets, or osmotic systems which are enabled by this. 

When we're looking at tableting in general, we do see some challenges: we need to have sufficient mechanical strength of the tablet at the end, we need a uniform mass and content, adequate disintegration time and adequate dissolution profile. When we now add different layers together, we see that we of course, multiply the challenges we have for a single layer tablet or mono material tablet by the number of the layers.

Additionally, the interface comes into play, which is a specific challenge. The first layers can also in the process influence the later layers in the process. And we need to have sufficient interlayer strength so that the layers don't detach right after the compaction. And the stresses within the multilayer tablets are not comprehensively understood yet and we would like to add a little bit of understanding with this talk.

Let's now first have a look how bilayer compaction process works.



Bilayer tableting


bilayer tableting process evo Jan Finke

We have the punches and die and it is used to fill the first layer of a powder into the die. This is then tamped meaning that we exert a certain stress. Afterwards, the height of filling is determined by the surface of the first layer and the upper phase of the die of course. And the second layer is filled in here and then usually pre-compression, and the main compression to gain at the end the final dosage form, a bilayer tablet which is ejected.

In worst case, already at this stage (ejection), a delamination could take place. And of course we'd like to avoid this and we would like to understand when and why this failure is taking place.  

Having a look at this process, we have different process parameters that can be influenced and potentially studied. This is stress at the temping, stresses at pre- and main compression and also the whole speed of the process at which it is run, which is of course of very industrial interest, because it determines the production capacity. 

Bilayer tableting on rotary presses

When we have a look at the rotary presses that are used in industry, we do see that they look quite the same as monolayer tablet rotary presses, but the layout may be a bit different. 

But we start with the first filling, we fill the first layer in this feed frame, then the tamping force is exerted with this pair of quite small rollers because we just need to exert little forces, the second layer is filled then the pre-compression and the main-compression and this with bigger rollers for higher pressures is exerted before the tablets are scraped and ejected and taken from the machine. We didn't apply this big a rotary press, but we applied a smaller rotary press which is an XM12 from the company KORSCH. We just transferred the process parameters to study it after the compaction simulator STYL'One Evolution from MEDELPHARM. And on the formulation side, we decided to take two excipients that are quite opposite in the deformation behavior. 

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To do so, we filled the first layer with Dicalcium phosphate (DCP) which was then lubricated with 1% of Magnesium Stearate and we use microcrystalline cellulose (MCC) at the top layer to have a very ductile material in contrast to the very brittle and very stiff Dicalcium phosphate. And of course, the main interest is into the interface between those two phases.

To investigate the strength of this interface, different research was done and different methods were developed, which will be presented in the coming slides.


Methods of measuring interfacial strength

Tensile test

The most direct method may be the direct tensile test of bilayer tablets. To do so the tablet, which was integral before it was taken out of each other, is glued to two platforms, to two planes, which are in this case stubs that are usually used for SEM investigation. Those stubs are glued to the tablet faces with superglue. And those stubs are then mounted onto these holders and the strain gauges. Afterwards, the tablet is pulled apart, and we do see that of course with running distance, the force is rising until the failure of the tablet takes place and pulls apart the two parts of the tablet right at the interface.


Of course, this is quite laborsome so it was also compared to different other approaches. 


Here's another direct tensile test - how it was performed by another group. This is of course, the more direct and mechanistic and reliable test, but it has high efforts and you also need to take care of whether the superglue intrudes into the tablet and it changes the properties. And of course, this situation is quite mechanistic for tensile strength determination, but it is an unrealistic stress condition in real life of the bilateral tablets. Because it would mean that someone or something needs to grip both layers each separately and pull them directly apart against the direction of compression.


Shear test

The perhaps more realistic case is shear tests, where one of the layers is fixed on an apparatus and the other layer is stressed for example by a blade which is coming down, and which should then by this application, apply a shear stress right in the interface between those. This is of course easier to use: we don't need to use the glues, we don't need to care about the infringement of the mechanical properties by the glue. This is the case also with the quality of the interface equally as the direct tensile strengh. And those conditions are more realistic as if we assume the diametral compression or that goes over the edges of the tablet. Then a shear bend may develop in the interface.

And those colleagues of this publication also compared the results for the sheer strength and the tensile strength, and they saw that we of course, have a linear relation about between those two informations and we do see against the equilibrium line, shear strength improves tensile strength that will always yield higher values for the shear strength. And this is due to the fact that of course, if we have a look at our tablet in detail, we may have some roughness between those layers in the interface and this may lead to mechanical interlocking, but usually not in the normal direction if you pull it off, of course, it is easier than shearing it off against the mechanical interlocking alongside this interface.


Mechanical characterization of the interfacial strength


Other colleagues around Mazel also studied the different shear tests for the individual strengths different determination, the direct diametral test, which is usually used for one-faced tablets is not capable of investigating the interlayer strength. 

The second is an indentation test which is better visible and how we did it in our lab, in this photo: a finn is coming down into the right on top of the interface, the tablet is standing on its band on a funnel, which holds it upright and accordingly then the stress, the compressive stress from the top will be transfused into the tensile stress and the tablet and will detach the layers. But this is also quite laborsome and it is not preferred. Accordingly the shear test already introduced in the last slide here in different setup is the one which was chosen for our tests.


Analysis of tablet strength parameters


Accordingly, we applied different tests, in general the tensile strength of the whole tablet was applied also to the bilayer tablet with its so called diametral compression or Brazilian test applying the equation of fallot to determine the tensile strength.


Influence of tamping stress on shear strength


And the more interesting interlayer strength was measured by shear test with a very simplistic approach, which we developed at our institute. We took our usual breakage test for tablets, which is a Sotax MT 50, and we applied differently high blocks of metal to only stress the lower or only stress the upper part of the bilayer tablet. Of course, you need to very precisely position and also clamp these these barriers to really meet the interface of a tablet to then gain meaningful information on its strength. Then the shear strength can be calculated with this formula up here.

 But now, let's have a look at the results of our stats. We had a look at the shear strength in our tablets with DCP at the bottom and MCC at the top. The shear strength is here presented as a function of the tamping stress, so, the first compression of only the first layer material. Additionally, we have displayed the main compression stress, which with rising main compression stress also elevates the shear strength. Over the tamping stress we also see that we have a slight loss in tamping stress which can be traced back to the fact that within the tablet with raising tamping stress, of course, the roughness of the surface of the first layer material after the tamping is reduced with increasing tamping strength. 


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This means those disparities and this roughness is reduced and the shearing off is much more simple. Accordingly the interlayer roughness is reduced and the shear strength is also reduced. Now, we may think whether this factor of differently strong interfaces may also affect the tensile strength of the material.


Influence of tamping stress on tensile strength


We do see if we plot the tensile strength in the same manner we did the shear stress before that also the tensile stress reduces just a little bit.

Now, you might say okay, if we compress the layer, the first layer during the tamping process more, we have a lower porosity and this may result in also changed porosity within the final tablet. To investigate this applied to in-die analysis of the STYL'One Evolution, and we saw starting from 5 mPA or 50 mPA tamping stress, we of course, start at different starting conditions when we compress the bilayer template as a whole, but when we reach the highest tamping stress, both lines fall together and the further development of the porosity is the same for both stamping stresses and especially at the end when the upper punch leaves the tablet, we still have the same porosity.


Influence of compression speed on shear strength


Accordingly, the change in the tensile strength can also be traced back to a contribution of the interface between those two layers and not to changes in the porosity.

Additionally, we had a look at the compression speed, so the simulated turret speed of the compression. Having a look at the low tamping stress first we do see with the turret frequency, we come to lower shear strength in our bilayer tablet as a trend, of course, we see that it is of course not a significant, but in all main compaction stresses we see the same trend. This may be due to the fact that with rising turret speed, we come to lower compression and by that too high porosities at the end which of course would mean that we can expect a lower strength in the shear or tensile strength.


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Additionally, when we look at the high tamping stresses, we see that we see also a trend towards lower values for high turret frequencies and we do see that we can overdo it. In the case of the highest compression stress, we can go up to a simulated frequency of 35 and if we look for the 55 turret frequency result, we do see that the delamination takes place during tableting already, so, the strength is just simply reduced if we go faster, and this is of course interesting for the industrial application. Accordingly, the final porosity may be one of the explanations and the shear strength decreases with the turret speed.


Influence of compression speed on tensile strength


webinar multilayer influcence speed tensile strength

Having a look again at the tensile strength, we might think that the contribution might be different, but we also see a trend towards lower tensile strength. And we also of course, see this trend towards the failure of the tablet at high main compression and high tamping stresses. Now, you might say it is the same effect because if the shear strength changes, we saw it for the main compression stress and the tamping strength in the slides before, then it is also the reason that the strength of the interface is reduced.

In this case, we also applied the in-die investigation on the compaction simulator and we saw that we have quite the same slope for all the compression cycles at different speeds. But we do see especially in the decompression phase that we end up with different porosities meaning that in the order of frequencies with elevated frequencies, we also have elevated porosities and by that it can be clarified that this is a factor that also influences on the one hand the shear strength and on the other hand directly the tensile strength even more.

Now it is the question whether we can also see these differences especially for the shear strength and also the tensile strength in the properties of the tablet from the outside, meaning that we can see and determine whether and when such a failure will happen. To do so, we had a look at the diameters of the different layers.


Influence of process parameters on layer diameters


We can see that for dicalcium phosphate and MCC in this sketch, we expect different diameters which is due to the different deformation behaviors. For Dicalcium phosphate we see a higher radial relaxation after the compression, which also is part of the problem, why it is causing high ejection forces if it is not lubricated for example. But back to this case, we do see for the MCC that we come close to the diameter of the die which is 11.28 millimeters and it is quite independent of the applied stress. Accordingly this is also easy to eject. 

For the Dicalcium phosphate, we do see that the diameter of this layer and bilayer tablets is increasing with increasing stress of the main compression. This shows that we also have a higher difference between the layer diameters, when we apply higher stresses. We also see that we quite have no influence of the tamping stress in this condition.

How can we then explain? Is it like this? Is it a step on the side, on the back of the tablet - because the layers start to detach already-, or is it that we have a tilted band of the tablet because the MCC pulls everything together why the DCP layer tries to stretch out everything. Anyhow, we do see that we always have a remaining stress within this interface due to these counteracting dynamics to these stresses that are left in the interface. To investigate whether we have the first or the second case, we tilted tablets on the band and investigated the top band.


In-depth analysis of band topography


We did it with Raman microscope we have in place but we didn't use the Raman application we just used the advanced optical profilometry, this is not our results, but quite very nice results displayed by Vtech.


Quantative evaluation of tablet band tilt


So when we investigate the tablet on its band we see that we have a tilt angle which is alpha and that of course at the top of the tablet when we put it like this on a plane surface, we will determine two alpha. And having a look at the profilometry results we do see, yes, the height is tilted, and we have over the x position a change in the height of tablets. And then of course, the two alpha can be determined and can be calculated back to one alpha.


Effect of stresses on tablet band tilt

And results are displayed here. Again the tamping stress is plotted. When you see the tamping stress has perhaps a little influence with higher tilt angles for higher tamping stresses. But we do see that we definitely have a higher value of this tilt angle with applying higher compaction stresses, which is indeed in line with the results for the measured diameters. Accordingly we can also see with this profilometry.


Quantitative evaluation of tablet band step height


But more interestingly, we can also determine those steps. Of course, this is directly measurable as delta H - so the step height - and this can also be found in the data, which can look like this and of course, they can directly determine the delta H.


Effect of selected parameters on step height


When we have a look at these results, we do see that for the low main compression stress, with a higher turret speed, we by trend come to also higher step heights. So, if we go faster, the starting failure at the end is larger. And we also see the main influence of the tamping stress with the higher tamping stress we always come to higher step heights and by that higher starting failures of the tablet in its interfacial region. Accordingly, we can see with the turret speed we have an increase of the step height and also this can be traced back to the influence of the interlayer roughness.


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When we now have a look at the high main compression stresses, we come to the result that those lines for the low tamping stress and the high tamping stress are elevated, for the high tamping stress the effect is even higher accordingly, the step height the beginning of the failure of the tablet is very pronounced for high tamping stress and high main compression stress. 

Accordingly, the elastic recovery can also play into this which is the case for the radial elastic recovery especially for the dicalcium phosphate which will really strongly expensive radially after the compression. And accordingly then the step height is increasing with those properties. 

Now it is not only interesting to see the effects on one diameter, one geometry of a tablet, but we also investigated different sizes of tablets.


Effect of punch size and curvature


Accordingly, we looked at 9 mm, 11.28 millimeters and 14 millimeter bilayer tablets. We see that with increasing punch size, the shear strength of interface is reduced. Additionally in the progress over main compression stress, we do see that for the smallest nine millimeter punches, the interface strength levels out while with increasing punch diameter, more pronounced drop of shear strength is seen for higher compression strength. This is the case for the bi-planner tablets. 

We also applied concave punches producing convex tablets and there the case is a bit different. With the same diameter we always start at lower strength of the interface, at medium compression stresses and high compression stresses, this tends to further increase for tablets with convex geometry. This is the case due to the convex or concave depends on the face you look from, interface between those two faces.

The Dicalcium phosphate is the lower layer and expands further to the outside, the more the higher the compression stress. And the MCC is on top (concave), sitting on top of the Dicalcium phosphate. With the concave shape of the interface we have of course a higher interface for interlocking, and additionally by pushing outside and MCC keeping it together, we have a higher potential for this interlocking as well, which is more pronounced at high compression stresses.


Implications of the diameter differences between mono- and bilayer tablets


To further elucidate how the difference between the deformation behaviors and by that the differences in radial relaxation can be used to investigate the failure of the shear strength of the interface, we tried to compact the single faces as mono layer tablets and compare the diameters of those which is shown here also for the different sizes and concave and convex punches. The difference of the diameters is calculated by the diameter of Dicalcium phosphate minus the diameter MCC layer - in this case of the single tablets produced individually. 


We do see that we have quite a rising potential - rising difference with of course rising diameter because the relaxation is a relative and valid percentile effect, it also rises with the compression stress.


But when we now will take the numbers which are achieved and compare it to the differences we can measure in the Tablets of the bilayer tablets we see that they are much lower. Accordingly, the difference between those values for the two single mono layer tablets and the bilayer tablets regarding their diameter differences can give us a hint at how much stress is kept in this inter layer region.


Normalization of relaxation differences


To further use this difference in mono layer tablets, we calculated a normalized relaxation differences by subtracting the difference in bilayer tablets from the difference in monolayer tablets and of course, to normalize, divided by the diameter of the die to be produced with. And when we have a look at these effects, we do see that with higher size of the tablets, we do see that although it is normalized, we still have a higher difference and by that higher stresses that remain in the interface for the larger tablets.

And this means that they are more tense on the inside and by that can easier the broken which is again facilitated and shown by the sheer strength.

Additionally, we do see the effect that we come to higher differences, but not failing for the concave punches again.


Correlation of shear strength with diameter difference


But now, the most interesting thing is comparing this difference of the layer diameters and their effect with directly the shear strength. We measured this so, we plotted the shear strength over the diameter difference divided by punch diameter, and we do see for the plane punches that shear strength falls with the normalized diameter difference.

Obviously, there is an apparent boundary over which the shear strength cannot go for a certain punch time into difference.

Accordingly high residual stresses definitely weaken the interfacial layer.

For the concave punches, it is the case that this boundary seems not to be existent, which we saw is also true here with higher main compression stresses and also higher diameter differences we see a further increase of the shear strength.

Accordingly, the additional strength seems to  be XX overweight XX by the externally measured differences.


Outlook


By then I'd like to give a short outlook of course we need to further investigate and holistically understand the compaction and the strength of bilateral tablets. The effect of particle size and formulation would be of more interest. The dependence of interlayer on single layer strength is also to be investigated and to derive at the end, a model for the description and prediction of the interfacial properties based on the material properties and the process parameters will be defined.


Conclusions

To conclude everything, regarding the process parameters, tamping stress should be as low as possible, the negative effect of production speed should be kept in mind.

Regarding the tablet geometry, we have higher challenges with larger tablets, so lower shear strength, and the convex shape can really be advantageous to produce intact tablets if it is possible to use concave punches and convex tablets.

Regarding the materials, the differences in deformation and relaxation cause residual stresses in the interfacial layer.

The diameter differences can be measured outside the tablet, and can be used to determine the potential of shear strength reduction. Accordingly, you can start with compacting your single faces, just seeing the formulations for each layer and see the difference in relaxation to try and predict bit of the trouble that may come during the production processes.

By now I'd like to thank you for your attention and acknowledge the contribution of the different partners. And I'm happy if you connect and answer your questions that may still arise. 


[Bruno Leclercq – MEDELPHARM]

Thank you everybody for your attendance. Thank you, Jan Finke for this very nice presentation on Bilayer formulation, and thank you MEDELPHARM team for organizing the event.

MEDELPHARM ScienceLab can assist you in the development of bilayer formulation on STYL’One Evo compaction simulator. We can also assist you from material characterization, formulation development to troubleshooting.

This presentation and the replay will be available on my mystylone.com. Stay tuned for next events. We have MEDELPHARM wish you a pleasant day. Do not hesitate to contact us directly for any additional questions or comments. Take care. Bye bye

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