Webinar transcript – External Lubrication: How to mitigate the impact of lubricants on your quality attributes

[Quentin Boulay - MEDELPHARM] – Introducing the webinar

Good morning, good afternoon and good evening to all of you. I 'm pleased to welcome you to the second MySTYL'One live session.

These live 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 Manager at MEDELPHARM and I will guide you through this webinar today.

But before we get started just a few words on this session and how you can interact with us. You'll 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. In order to ask questions, you can send them in via the question widget on the right side of your screen. Just type them into the box and click "Submit". You have until the end of the session to address any questions or thoughts you may have. We will select the questions for the Q&A session at the end of the webinar.

This session will be divided in four parts. First, I will start with a brief introduction of MEDELPHARM and MySTYL'One and then  Cedrine de Backere from Ghent University will introduce her work on external lubrication. After, Bruno Leclercq, our Science Lab and Business Development Manager will present some innovations useful for material characterization and formulation development. We will end this session with an open Q&A to address your questions.

So MEDELPHARM is the global leader in compaction simulators with more than 35 years of experience in tablet compression technology, and more than 200 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. The brand STYL'One that you know has always been developed and manufactured by MEDELPHARM in Lyon, France and KORSCH is now the global exclusive distributor of STYL'One products, except in France and Belgium, where we remain direct.

Last summer, we moved to a new building that you can see in the background in order to support our growth and host MEDELPHARM activities, including: our innovation center with the design and development of STYL'One solutions and the associated software ;  our production workshop, where we manufacture STYL'One Evo and STYL'One Nano and offer after sales services ; our Science Lab where we perform customer studies, machine demos and internal testing to support the design and development team and also our customers.

Some of you are still using our first fully mechanical compaction simulators, the STYLCAM. You can see on the left the standard configuration and on the right wash in place configuration.

We kept innovating and we brought disruptive solutions to the market with the STYL'One series including the STYL'One Nano, our benchtop research press with some compaction dynamic capability. The STYL'One Evo, the most advanced compaction simulator with multi-layer capabilities including Tab-in-Tab and containment solutions to answer the growing needs to handle high potent API.

A few words on MySTYL'One before we start. MySTYL'One.com is the website you've all registered on. The website is built for users of STYL'One and STYLCAM equipment.
So, if you are a user of our machines, do not hesitate to create your MySTYL'One account. 

So, enough chat from me!

Today we're honored to have one of our long term partners Ghent University in Belgium. So please welcome Cedrine, PhD student at the Laboratory of Pharmaceutical Development Technology for this webinar entitled "How to mitigate the impact of lubricants on your quality attributes".

Please Cedrine, take over.

[Edit] – MySTYL’One members, remember you can access the full video replay & presentation slides HERE.

[Cedrine de Backere – Ghent University] Thank you for the introduction Quentin. And hello everyone and thank you for joining this webinar.

My name is Cedrine and I'm a PhD researcher at the Laboratory of Pharmaceutical Technology at Ghent University under supervision of Professor Vervaet and Professor Vanhoorne.

In the next 20 to 25 minutes, I will talk about lubrication and more specifically, external lubrication.

Introduction on tablet compression

So, the process of compressing powder into a tablet can be divided into three different operations.

So, first of all the die filling, then compression, which mostly consists of a pre-compression followed by a main compression and finally, the ejection of the tablet out of the die. And the last step, the ejection phase will be the main focus of this webinar.

During ejection, the amount of friction and die-wall forces between the tablet surface and die wall determine the ejection force. The ejection force can be defined as the force needed to push the tablet out of the die.

High ejection forces should be avoided as this can results in tablet defects like chipping but also wearing to the tablet tooling. Therefore, a lubricant is added to the formulation to reduce friction and subsequently, the ejection forces.

Today internal lubrication is still the conventional lubrication method.

So the lubricant is added to the powder blend prior to the tableting process. And Magnesium Stearate is the most used lubricant but other commonly used lubricants include sodium stearyl fumarate and stearic acids.

Typical lubricant concentrations are somewhere between 0.5% and 5% dependent on the lubricant and the formulation.

And although the excellent lubrication efficiency of Magnesium Stearate, the internal blending of Magnesium Stearate is often associated with negative effects like a reduction of the hardness, tensile strength and prolonged disintegration and dissolution. A few factors can further enhance these negative effects, which is a high concentration of lubricants, long mixing time and a high mixing intensity and also specifically, the effect on tensile strength is dependent on the deformation mechanism of your formulation.

And this slide shows the influence of deformation mechanisms on the tensile strength.

MCC is known to be a plastically deforming material and therefore, highly susceptible to the internal blending of magnesium stearate. And this can be seen on the left graph in green, where the tensile strength of internally lubricated MCC tablets was decreased by a factor of 2 compared to external lubrication.

In contrast, for DCP, which is visualized in the right graph in blue, overlapping tabletability profiles were recorded for both lubrication methods. And this can be explained by the brittle behavior of DCP where clean, lubricant-free surfaces available for binding are generated during compression, whereas for MCC, the deformed particles are still covered with lubricant causing weak bonds and a reduced tensile strength as a result.

Sprayed dried lactose can be considered as a material with intermediate compaction properties, so a combination of fragmentation and plastic deformation and is therefore situated in the middle.

In addition, the influence of lubricant type, blending time and paddle speed on the tensile strength of MCC and lactose tablets was investigated.

The lubricants showed equal lubrication efficiency when added in concentrations of 1% for stearic acid and Sodium Stearyl Fumerate, and a half percent of Magnesium Stearate.

All lubricants caused a decrease in the tensile strength and a higher pedal speed and a longer blending time intensified this decline in tensile strength.

However, stearic acid was found to have the smallest decrease in tensile strength for MCC and lactose compared to the other two lubricants. And this can be seen on the graphs below where a decrease in tensile strength for Magnesium Stearate is clearly higher compared to stearic acid, especially at higher pedal speeds.

Magnesium Stearate is shown on the left 2 graphs while stearic acid is shown on the right 2 graphs. 

Additionally, the decrease in tensile strength was high for MCC compared to lactose as seen on the graph below, which is in accordance with the data on the previous slide.

And the difference in lubricant sensitivity could be attributed to the particle size, specific surface area and particle shape of the lubricants. In addition, the effect of paddle speed of the forced feeder should not be underestimated, as the impact of paddle speed was higher than the impacts of lubricant blending time.

A good correlation of lubricant sensitivity was found between the STYL'One Evolution compaction stimulator and the MODUL™ P rotary tablet press, based on the calculations of paddle passes. Therefore lubricant sensitivity can already be assessed during early developments on the compaction simulator, which can avoid issues during upscaling to the rotary tablet press.

So now we can start with the first case study, which is the evaluation of an external lubrication system implemented in the STYL'One Evolution compaction simulator.

Internal lubrication with Magnesium Stearate is often associated with negative effects and therefore, there is a current interest for an alternative lubrication method.

Applying external lubrication, the lubricant is sprayed directly onto the tablet tooling and thereby minimizing the effects that are involved with the internal blending of the lubricant. External lubrication can be applied on a non-lubricated blend but also in combination with internal lubrication. 

And many manufacturers of rotary presses do offer an external lubrication system, either designed and produced by themselves or produced by an external manufacturer that can be retrofitted on multiple types of presses. And for compaction simulators MEDELPHARM has designed an external lubrication system ready for implementation on the STYL'One Evolution. 

And this video shows the lubrication process and this video is also available on YouTube.

So, as we can see before every die filling the upper punch, lower punch and die wall are lubricated by spraying Magnesium Stearate. Only a small spray could be seen on the video as it is only a small amount that is being sprayed every time.

Some additional information about the working principle and different parts of the external lubrication system are visualized in this slide.

So, the lubricant is dispersed from the micro-dosing unit (which is not shown on the slide) to the spray nozzle. The spray nozzle is attached to the feed shoe and consists of a double output to lubricate the upper punch but also lower punch and die well. A dust extraction system is available to suction away the excess of Magnesium Stearate in order to avoid the buildup of Magnesium Stearate inside the machine and contamination of your blends. 

The objective of this study was to investigate the possible benefits of external lubrication and to make a comparison with internal lubrication.

Additionally, the effect of different process parameters like main compaction pressure, spraying time and atomizing pressure on the responses, the ejection force, tensile strength and disintegration time was investigated. 

And additionally the concentration of Magnesium Stearate in externally lubricated tablets was determined as well.

Case study - Material and Methods

Experiments were conducted on the STYL'One Evolution equipped with the external lubrication system.

The spraying time was varied between 0 and 1000 milliseconds.
But the atomizing pressure was set at 3 levels (one, three and five bar).
All experiments were conducted at two different main compaction pressures.

Formulations consisted of 90% of filler and 10% of API with one additional placebo formulation of 80% mannitol and 20% MCC was added to the study. And as a reference internally lubricated blends with 0.75 and/or 1.25% of Magnesium Stearate were processed, applying two paddle speeds of the force feeder. A higher concentration of Magnesium Stearate was needed for the formulations containing metroprolol in combination with lactose and mannitol.

The choice of fillers and API's used in this study was based on their differences in need for lubrication, and different compaction properties.

The wall friction angle measured by the ring shear tester was used as an indication for the ejection forces. Regarding the fillers, MCC showed the lowest wall friction, while mannitol showed the highest wall friction. Metoprolol showed an increased wall friction compared to the other API, caffeine, but also to the fillers, and was therefore an interesting model API to study regarding lubrication.

Compaction properties, such as specific work of compaction, which is an indication for plasticity and tablet brittleness index measured with the texture analyzer confirmed the brittle behavior of DCP and lactose, but MCC showed ductile properties. Mannitol can be considered as a material with intermediate compaction properties.

 Results - Ejection Forces

Now you go to the results and the first response to discuss is the ejection forces.

So the spraying time highly influenced the ejection forces.  Applying low spraying times (below 350 milliseconds), the time for dispersing Magnesium Stearate was inadequate to result in a complete layer of lubricant on the tablet tooling which is needed to have proper lubrication and therefore high ejection forces were recorded for those spraying times.

And this can be seen in the graphs below where non-lubricated experiments are highlighted in red and externally lubricated experiments in green and internally lubricated experiments in blue or purple depending on the Magnesium Stearate concentration.

However, at higher spraying times, so above 350 or 400 milliseconds, the ejection forces dropped to levels similar to those obtained by internal lubrication.

Moreover, formulations containing mannitol or metroprolol, sticking and high ejection forces were observed when not well lubricated, and even lower ejection forces were obtained with external lubrication compared to internal lubrication, as can be seen on the graphs below.

And these findings confirm the high efficiency of external lubrication in lowering the ejection forces and minimizing sticking. Furthermore, once a low level of ejection forces was obtained, a further increase in the spraying time (from 500 to 1000 milliseconds) did not lead to a further decrease in the ejection forces. And the effect of atomizing pressure on the ejection forces was noticeable for challenging formulations where an atomizing pressure of 1 bar seemed to be insufficient compared to 3 and 5 bar.

Based on the performed experience, we have set up some recommendations for the external lubrication system settings.

So applying a spraying time of 500 milliseconds and using an atomizing pressure of three or five bar should be sufficient for most formulations, but dependent on the formulation and tooling size, some tweaking might be needed. 

So now, the second response, the tensile strength: external lubrication did not lead to a decreased tensile strength for all process parameters - spraying time and atomizing pressure. For internal lubrication a decreased tensile strength was observed from multiple formulations, except for the brittle formulations based on DCP.

In addition, the link between the ejection forces and tensile strength was also visualized in the graphs below. 

We can see that non-lubricated tablets and externally lubricated tablets produced at low spraying time, show a lower tensile strength compared to those compared at higher spraying time. And this can be linked to the high ejection forces at those settings causing tablet defects like chipping and tablet quality increases at higher spraying times as the ejection forces drop. Additionally the internally lubricated tablets showed a lower tensile strength. 

So, more examples of the tensile strength.

So, above we can see that we have equal tensile strength for DCP formulations for all lubrication methods, and explained by the brittle behavior of DCP. For a plastic formulation containing MCC, decreased tensile strength was observed when applying internal lubrication shown in blue.

Results - Disintegration time

For the next results - the disintegration time - we have observed no negative effects of process parameters like spraying time and atomizing pressure on the disintegration time.

And similar disintegration times to non-lubricated tablets were recorded for external lubrication, whereas for most formulations an increased disintegration was observed when processing internal lubrication as visualized by the graphs below.

And even for DCP based formulations we have an increased disintegration.

So, an important aspect is the amount of Magnesium Stearate that is present on externally lubricated tablets, but this can be quite challenging due to the low concentrations.

I have listed several methods that have been used in literature for Magnesium Stearate determination.
 
However, sensitivity can be an issue and the determination is often limited to a qualitative detection. And the first two methods, highlighted in blue, have been used for the quantitative detection of Magnesium Stearate in externally lubricated tablets.

In this study, inductively coupled plasma optical emission spectroscopy was used to determine the amounts of Magnesium Stearate.

Some basic information about the methods:

First of all, it's a destructive method and for analysis, the solid sample must be completely into solution. And this by means of a digestion step which is quite time consuming. And the sensitivity of this method is demonstrated by the very low limit of quantification, and the method measures Magnesium and not Magnesium Stearate. So, be aware of doing a baseline correction of your material/ blends in order to avoid confounding.

Now the results of the Magnesium Stearate concentrations.

The left graph shows the concentration of Magnesium Stearate of externally lubricated tablets of different formulations. And a spraying time of 500 milliseconds and an atomizing pressure of one three and five bar are chosen for analysis.

Concentration between 0.01 and 0.06 percent Magnesium Stearate were found, corresponding to 0.05 and 0.2 milligram of Magnesium Stearate per tablets. Thus, concentrations were only one to 10% of internally lubricated tablets with 0.75 % Magnesium Stearate.

The reproducibility of the system was evaluated by analyzing 25 consecutively produced tablets, with a spraying time of 500 milliseconds, and an atomizing pressure of five bar. Concentrations between 0.02 and 0.06 were found while the standard deviation of the ejection force was only 25 Newton. And this indicated reproducible lubrication at the investigated settings.

Additionally, the amount of Magnesium Stearate sprayed from the nozzle was measured as well. And the method to capture the amount that is being sprayed was not validated, but still, it can give an indication about the amount that is being sprayed, which is interesting to compare with the amount on the tablets.

And these results showed that the amount of Magnesium Stearate being sprayed is higher than the amount found on the tablets which is shown in the table below. And this indicates that not all of the Magnesium Stearate that is being dispersed from the system is present on the tablet surface. So, some amount may be sucked away by the vacuum cleaner, some amount may be left on the tooling or inside the machine.

In addition, the amount of Magnesium Stearate in internally lubricated tablets is shown as well in the table below. And there we can see clearly differences in those concentrations between internal and external lubrication. And this highlights the very low concentrations that are involved with external lubrication, but still enough Magnesium Stearate to result in proper lubrication.

Results - Conclusion part 1

So, in conclusion, this study showed the potential of external lubrication as an alternative lubrication method to internal lubrication. 

So, applying external lubrication, low ejection forces can be obtained without decreasing the tensile strength and prolonging disintegration and with a significant lower concentration of Magnesium Stearate. Therefore, external lubrication can be used for lubricant sensitive formulations or challenging formulations with regard to excessively high ejection forces or sticking.

Other applications of external lubrication will be shown in the next slides. 

So first of all, the determination of compaction properties of materials and blends and the determination of compaction properties such as elastic energy and plastic energy can be highly interesting to learn more about your formulation or the components of your formulation.

 Compaction properties can be calculated from the force-displacement curve of a single-ended compression, as seen below, where we can see the unloading and loading in function of punch separation. 

But why would you apply external lubrication? So, first of all, to avoid confounding due to friction. The compression of mannitol, for example, would lead to a high amount of friction causing a disruption in the force-displacement profile, which could lead to confounding.

Secondly, to avoid the influence of the internal blending of the lubricant.

Some examples of energy profiles of different raw materials. 

So first of all, we have three commonly used fillers: MCC, lactose and DCP, two binders (hpmc and starch), one API (APAP) and also Magnesium Stearate. The specific work of compaction was the highest for MCC and lowest for DCP, concerning the fillers, confirming its brittle and ductile behavior respectively.

The fillers were characterized by a low amount of elasticity, while starch and HPMC has a higher amount of elasticity. The low specific work of compaction and high elasticity of APAP indicate a poor compactibiliy. And furthermore, Magnesium Stearate is characterized by a large amount of elasticity.

A high elastic recovery should be avoided as this could break the formed inter-partical bonds, resulting in a lower tensile strength and tablet defects like chipping.

And even low concentrations of a material with a high elasticity like Magnesium Stearate can influence or affect your formulation, which can be identified through these compaction properties. And this type of data can be helpful in formulation development, but of course, other powder properties like particle size, density and flow would affect your formulation. 

Assessment of lubricant sensitivity of fillers and binders

For the second application of external lubrication is the assessment of lubricant sensitivity of fillers and binders, the lubricant sensitivity of fillers and the influence of deformation mechanism was already discussed earlier during this webinar. 

Binders for direct compression are often added to a formulation to increase tensile strength, to reduce friability and avoid tablet defects. They can be added in concentrations between 5 and 30% and commonly used binders for direct compression are MCC, HPMC, HPC, povidone.

However, most of these binders are often highly ductile materials and therefore, they should be sensitive to the internal blending of Magnesium Stearate.

Instead of focusing on the pure binders, the binders were combined with DCP as the tensile strength of DCP proved to be lubrication independent, and therefore, any effect (between internal and external lubrication) could be linked to the binder.

So, first of all the binder efficacy was dependent on the binder type, but all binders showed a lubricant sensitivity with regard to the tensile strength, so an increased tensile strength when applying external lubrication.

The graphs below show the tabletability profiles of DCP combined with copovidone, povidone, HPMC and MCC and the illustrated binders and so, DCP with 20% can be seen on top and DCP with 30% binder can be seen below. External lubrication is visualized in red while internal lubrication is visualized in blue. And generally the effect of lubricant sensitivity was further enhanced at higher binder concentration. So, going from 10 to 20 to 30% of binder.

Lubrication method was less influential on the disintegration behavior of the binders. As disintegration was mainly driven by binder type which was well correlated with the contact angle and this external lubrication did not lead to an increased disintegration despite increased tensile strength.

Conclusion

So now, we go on to the conclusion of my presentation. 

So, this presentation once more confirmed the negative effects of internal lubrication for tensile strength and disintegration. 

Furthermore, lubricant sensitivity depends on the deformation mechanism of your formulation and the used lubricant. 

The paddle speed should be carefully chosen as it acts as another mixer and therefore, further decreases the tensile strength. This effect is especially visible for Magnesium Stearate, even when added in concentrations of 0.5%. Lubricant sensitivity can already be assessed on the STYL'One Evolution to avoid scaling-up issues.

External lubrication proved highly valuable as an alternative lubrication method for challenging formulations - high ejection forces and sticking but also for lubricant sensitive formulations.

 Low ejection forces could be obtained without decreasing the tensile strength and prolonging disintegration, and this would much lower concentrations of Magnesium Stearate. The recommended settings of the system are a spraying time of 500 milliseconds and an atomizing pressure of three bar. External lubrication can also be applied for other things like material characterization.

The upscaling of external lubrication to a rotary press could be an interesting topic for the future but remains challenging as the operation mechanism of the two tableting equipments and their external lubrication systems are very different. 

However, external lubrication on the STYL'One can be used as a feasibility test for your formulation. 

This was my presentation. Thank you for listening. And I think I give the word back to Bruno.

[Quentin Boulay - MEDELPHARM] Thanks a lot Cedrine for your nice presentation. So now Bruno, our Science Lab Head and Business Development Manager will add some more information on the STYL'One innovation that can be useful for the use of external lubrication during development stage. Do not forget that you can still ask your questions with the widget on the right side of your screen. Your questions will be answered by Cedrine or Bruno at the end of this webinar. On to you Bruno

[Bruno Leclercq - MEDELPHARM] Thank you Quentin. I will quickly introduce two external lubrication devices that were developed by Medelpharm. Both of those devices have been used by Cedrine during her PhD. 

Let me first introduced the MIST or manual external lubrication device. 

The MIST is an aerosol spray to manually dispense Magnesium Stearate or another lubricant, on the punches and the die to avoid both build-up on the punch and to reduce friction during tablet ejection. Obviously the propellant used in the MIST is safe and non-flammable. The MIST is actually easier to use than alternative methods that we used in the past by formulators, such as a small swap of Magnesium Stearate dispersed in Isopropanol Alcohol.

External Lubrication with the MIST is often used for API characterization, or to characterize excipients. And the goal, obviously, is to minimize the negative effects of the presence of Magnesium Stearate in the powder mix. Obviously, the Mist can also be used when you do material characterization, and you just have a small amount of API -  especially when you have high, very expensive API and you don't have too much to use -using the STYL'One filling by hand but before the filling by hand spraying some lubricant is an ideal method.

Let me now go to the second device we have for external lubrication, and that is the one that Cedrine has been using during her PhD. 

This is actually the external lubrication box. This device has been developed by our engineering department, specifically for the STYL'One.

It's actually composed of two parts. If you see the graphic on the right on your slide, you see that on the bottom we have what we call a pulsed-air cabinet. On the top, we have a micro-dispensing unit, and on top of the micro- dispensing unit, you see a small lubricant reservoir, where you can actually enter the lubricant - that could be Magnesium Stearate or could be other lubricants. 

With this system, only a minimum amount of lubricant is sprayed on the tooling as has been highlighted by Cedrine during her presentation. Therefore, if you need to do material characterization or feasibility assessment of external lubrication, the external lubrication box is a perfect tool for this.

Just to conclude, our MEDELPHARM Science lab can perform trials for you, including testing of lubrication on your formulation, especially if you like to look at the external lubrication and the feasibility of the process. Now let's turn to the last part of the seminar, which is the Q&Q and feel free to ask any questions

[Quentin Boulay - MEDELPHARM] Thank you Bruno. We will now start the Q&A session to conclude this webinar.

[Quentin Boulay - MEDELPHARM] I have a question for you Cedrine: Did you did you test different specific surface area of Magnesium Stearate? And if yes, what is the impact?

[Cedrine de Backere – Ghent University] I have tested two types of Magnesium Stearate but I did not see any difference regarding the ejection forces. They both did well regarding lowering the ejection forces.

[Quentin Boulay - MEDELPHARM] And what is the effect of external lubrication process on the tableting speed? I guess it's on the STYL'One Evo but also on a rotary tablet press? Do you have insight for this?

[Cedrine de Backere – Ghent University] The ejection forces will definitely be higher if you have a higher tableting speed, but on the STYL'One you can just set up a lower spraying time in order to have good lubrication. On a rotary tablet press, if you have a higher tableting speed, then the time for lubricating the dice will be shorter. So then you will also need to have a higher feed rate of Magnesium Stearate in order to have to have proper lubrication.

[Quentin Boulay - MEDELPHARM] Thank you. Is it possible to use another lubricant than Magnesium Stearate on the external lubrication system, maybe for you Bruno?

[Bruno Leclercq - MEDELPHARM] Yes, that's actually a good question. I mean, as a lot of people use Magnesium Stearate as a lubricant, that's the one that Cedrine has been using in her work. However in the Science Lab in MEDELPHARM, we also use other lubricants. For example, we use sodium stearyl fumarate, and but we also use stearic acid. And we also use the Compritol® ATO from Gattefossé. And all those have been working with the external education system.

[Quentin Boulay - MEDELPHARM] Do you have vacuum included in the external lubrication box? I guess it's to avoid build-up or contamination?

[Bruno Leclercq - MEDELPHARM] Yes, in the external lubrication system, we actually have a vacuum system that is actually plugged on the upper punch and also attached on the table die. And the idea there is to actually minimize the amount of Magnesium Stearate that could actually be in the compression zone. So, this is also for safety reasons- to avoid too much Magnesium Stearate to be in the compression zone.

[Quentin Boulay - MEDELPHARM] Cedrine a question for you: Have you looked at the influence of external lubrication on dissolution profiles?

[Cedrine de Backere – Ghent University] We did not do any dissolution tests as the disintegration was already very fast. So, therefore, it did not seem interesting to study dissolution. And in addition, we did not see any negative effects of external lubrication on disintegration. So, therefore, we do not expect any negative effects on dissolution as well.

[Bruno Leclercq - MEDELPHARM] And maybe to add on that Cedrine: because the lubricant with external lubrication is added on the external face of the tablet, there would be no measures to it inside of the tablet that could actually cote the API. Therefore, with the external lubrication we're not expecting second effects on the dissolution.

[Quentin Boulay - MEDELPHARM]Thank you to both of you. A question for a user of STYL'One:  I fill the die by hand - not with the feeder because I have a limited amount of material. Can I use the external lubrication system?

[Cedrine de Backere – Ghent University] Yes of course. The external lubrication system is attached to the feed shoe, but you can still manually die fill but still use a feeder as a tool to have external lubrication, so that's definitely possible. For example, if you don't have enough powder or bad flowing powder, you can just manually fill the die, but use the external lubrication system that is attached to the feeder.

[Quentin Boulay - MEDELPHARM] If we stay with the manual fillings, did you use manual lubrication in your study - with the MIST?

[Cedrine de Backere – Ghent University] I did not use the MIST in this study, but we sometimes use the MIST for tablets to be tested for brittleness because tablets to be tested for brittleness there needs to be a low porosity. So they need to be compressed at high compaction pressure, but due to friction it is not always possible to make tablets without lubrication. But if you would add Magnesium Stearate, internally, this would definitely affect the brittleness and therefore, we just use the MIST on the lower punch, to lubricate and to make a tablet. But we can still use the upper part of the tablet tool to perform the brittleness test.

[Quentin Boulay - MEDELPHARM] Bruno, do you need a specific grade of stearic acid or external lubrication or will all grades work?

[Bruno Leclercq - MEDELPHARM] I don't really have the answer to that one but obviously do you will need a grade of Stearic Acid which is rather fine because if it's too large they can actually blocked the spraying spraying system, but I can come back to this question. I can find more information about the grade of Stearic Acid which was used in the lab and come back to the person who asked the question.

[Quentin Boulay - MEDELPHARM] Cedrine, have you worked on other external lubrication methods like spraying a liquid -paraffin oil, for example?

[Cedrine de Backere – Ghent University] No I only used the external lubrication system implemented on the STYL'One or the MIST to lubricate the punches or die wall.

[Quentin Boulay - MEDELPHARM]: Thank you. A question regarding more the production side of it: Is the external lubrication feasible at the industrial scale? And which industrial press do you know for this kind of external lubrication system?

[Cedrine de Backere – Ghent University] I think multiple manufacturers of tablet presses have external lubrication systems but it’s a different system than the one on the STYL’One. So there are definitely systems available for multiple types of presses. But then they are a little bit different because now we are just spraying one time before the die filling but on a rotary tablet press you have a constant spraying of Magnesium Stearate because you have a rotating turret table. So it’s a different system but there are definitely systems available for rotary tablet presses.

[Quentin Boulay - MEDELPHARM]  How do you make sure of no accumulation of lubricant on the die?

[Cedrine de Backere – Ghent University] I think we are using the suction system to really avoid build-up of Magnesium Stearate inside the machine.

[Bruno Leclercq - MEDELPHARM] Maybe one thing to add – Cedrine, I guess you also measure a constant amount of Magnesium Stereate on different tablets and you get a constant level of Magnesium Stereate on the tablet. That also shows that you always have the same amount.

[Cedrine de Backere – Ghent University]  Indeed correct, there is no increase in concentration between the different tablets.

[Bruno Leclercq - MEDELPHARM] And also you could also maybe see that in the ejection forces: If you get an accumulation you might actually see a change in the ejection force maybe at some point, and I don’t think that was the case in your study [Cedrine]?

[Cedrine de Backere – Ghent University] No indeed. Once a low level of ejection force is obtained the ejection force will not be further lowered even in you would spray more Magnesium Stearate. I think the concentrations confirm that there is no accumulation of Magnesium Stearate inside.

[Quentin Boulay - MEDELPHARM] From a regulatory stand-point : How can we justify the use of external lubrication?

[Bruno Leclercq - MEDELPHARM] This has to be declared in the registration – this is an ingredient that would be added and would stay on the formulation, because if you look at the study that Cedrine has been doing, it’s clearly showing that you still have Magnesium Stearate left on your tablet. Then the question is that there’s normally no need to be registered – but I’m not an expert in regulatory, not the best person to answer.

[Cedrine de Backere – Ghent University] I do share the same opinion, but I’m not a registration expert myself [either]. 

[Quentin Boulay - MEDELPHARM] Can we apply external lubrication on bi-layer tablets?

[Bruno Leclercq - MEDELPHARM] External lubrication on bi-layer tablets is interesting because then you would first of all add the lubricant before the addition of the 1^st layer. But on our system, when we start to fill up the 2^nd layer then there would just be a certain measure left on the die and the punch but there would be no new spray. At least the system is not configured like that.

[Quentin Boulay - MEDELPHARM] Ok. So we have our participants who added some information on the regulatory standpoint: If you are under 0.1% of lubricant it does not need to be registered. We have several people saying that.

[Bruno Leclercq - MEDELPHARM] Ok that’s good.

[Quentin Boulay - MEDELPHARM] Cedrine, you performed some work on external lubrication comparison on STYL’One Evo and the Modul P. Do you plan on doing a bit more research on the comparison of the 2 systems?

[Cedrine de Backere – Ghent University] Yes, we plan on investigating the upscaling from the external lubrication system from the STYL’One to the Modul P in the future, so hopefully there will be some data to be published in the near future. But it will not be that straightforward, as they are totally different operation mechanisms, so we have to see if we have the same level of lubrication – same level of

[Quentin Boulay - MEDELPHARM] Ok, looking forward to this information.

 [Quentin Boulay - MEDELPHARM] We have a question regarding humidity impact: Have you done some research on the humidity effect on lubrication?

 [Cedrine de Backere – Ghent University] I have not investigated the impact of humidity on the lubrication, no.

Conclusion of Q&A

 [Quentin Boulay - MEDELPHARM] Thank you very much for all the answers, and thank you for your numerous questions. Cedrine and Bruno will be glad to answer your new questions or concerns, any comments you may have directly on the MySTYL’One forum.

This presentation and the replay will be available on MySTYL’One.com [for registered members only].

Stay tuned for our next event. The next session will be held in April and we will for sure keep you posted. We at MEDELPHARM wish you a very good end of the day, and do not hesitate to contact us directly for additional questions. Thank you very much. Bye.