Hi, everyone, and welcome. My name is Naimas Peron and I will serve as your moderator today. Thank you for joining us for today's webinar, Poly Vinyl Alcohol, One Polymer Multiple Solutions for Oral Solid Dosages. As your moderator, it is my role to ensure that we make the most of your time with us. I'm here today with Lena Miller and Marcus Lupta. Lena is a pharmacist by training from the University of Keel with a PhD in Organic Chemistry and Biochemistry from TE Udamstadt. As Head of Functional Excipients, she leads a team that concentrates on the development and application of functional excipients designed for oral delivery. Solubility, enhancement of polio soluble APIs, continuous manufacturing and the delivery of large molecules are the focus areas of her lab team. Marcus holds a PhD in Biochemistry from the Technical University of Darmstadt and is by Academical Education. A biomolecular engineer. Marcus is responsible for the strategic development and positioning of an excipient portfolio for oral solid dosage form applications. Thereby, the focus is to enhance solubility and bioavailability of the most challenging AP is with specifically engineered excipients for oral solid application. He is the right person to contact to identify the perfect solution for your solubility problem by using a broad solubility enhancement toolbox approach. Before I turn things over to our presenters, I'd like to cover a few housekeeping items. At the bottom of your screen are multiple application widgets you can use, where you can also find our reaction button, indicated by the thumbs up emoji that allows you to give immediate feedback on the presentations, topics or anything that stands out. All the pictures are resizable and movable, so feel free to move them around to get the most out of your desktop space. 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And on demand version of the webinar will be available after and can be accessed using the same link that was sent to you earlier. So that's it from my side. It's my pleasure to turn things over to Lena and Marcus. Also warm welcome from my side. Let's take a look at the agenda together. So first of all, we start with an introduction to Poly vinyl alcohol. We'll move then into the first technology that will like to cover today, which is wedge granulation. Afterward granulation we'll we'll move into a dosage form which is sustained release using PVA and after that we will switch gears and Marcos will cover the following topic. We will then look at solubility enhancement and cover three different technologies, one is hot Med extrusion, the other one 3D printing and the third one spray drying. After the Solubility Enhancement chapter, we'll move over to oral dispersible films and then stop with a summary and then we'll have lots of time for your questions. So let's move into the topic of Poly vinyl alcohol. Poly vinyl alcohol is a synthetic and chemically defined polymer. It is produced by the polymerization of vinyl acetate. This Poly vinyl acetate is then subsequently hydrolyzed to yield Poly vinyl alcohol. It's a partial hydrolysis. So therefore if you look at the structure down here, you can see that we have hydrophilic groups that are the Poly vinyl alcohol groups as well as some of the hydrophobic acetate groups that are still present in this polymer. Why is it an advantage to use Poly vinyl alcohol? It is has a high batch to batch consistency because it is purely synthetic and therefore this consistent quality that you get from this synthesis helps you to do quality by design and quality by design is great to minimize risks that you might cover in your development and manufacturing. It is also multi compendium and has grass status. It is well known and safe for pharma users. Let's take a look at the nomenclature. We'll talk a lot about PVA today and it's usually followed by two digits. So right here we have an example of PVA 588. The five stands for the viscosity of a 4% solution in Millipascal per second at 20°C. The 2nd digit, the 88 in this example, is the degree of hydrolysis in percent. So 88% of the polyacetate groups are hydrolyzed to yield the OH groups. Where can we use PVA or where can we find PVA, especially in pharmaceutical applications? PVA has been extensively used in liquid applications. You can find it in ophthalmics where it's used as a viscosity enhancer or for stabilization. It is also used in semi solids, so you can find it in topical gels in creams or transdermal patches. But today we'd really like to focus on the third Pella here, which is our solid bucket. So let's take a look at solid formulation. PVA can be used in tablets. We can use it as a film former encodings for example, or as a matrix for enhanced solubility of poorly soluble APIs. We'll cover that in the second part of this webinar. The controlled release is another topic that we'll cover pretty soon, but before we go into sustained release, we'll look at granulation using PVA as a binder. Our last topic today that we'll cover is the OR dispersible films where PVA can be used as a film forming agent. And this brings me to our first question. Are you using PVA to manufacture one of the following Dosage forms, solid tablets or capsules, liquids, semi solids, gels, creams, films or ophthalmics? Looking forward to see your answers. There's still answers coming in, so I wait a bit longer. Thank you very much for your replies. It's good to see such an active audience and very interesting results. I pass on and back to Lena. Thank you so much. So as you've seen already in the introduction or maybe in the abstract of this webinar, we will cover so many technologies today. So the PBA is really addressable to to many formulations, to many dosage forms and many technologies. Here you can see a few that we'll cover today, which is spray drying, hot meal, extrusion, 3D printing and we'll get going and look at wet granulation in our next chapter. So why are we granulating material? Why are we using white granulation? There are some advantages when granulating, for example, you can increase the homogeneity of your mixture. So if you for example have contents in your formulation that only are there in a very small concentration range, that might be for example your API. Granulation is a nice technique to enhance advance your homogenization because it'll enlarge the particles and you can add the filler with the API that might be in a low concentration. That enlargement of particles usually also goes hand in hand with an improved flow ability, so you'll be able to have an API that might not flow that freely because it's micronized, for example, and use a granulation technique to to make it into a flowable powder. Also you can increase the compact ability. So with the size enlargement that takes place in the granulation, you will yield particles that can be used in tabletting and really straightforward and tabletting and this is another benefit of wet granulation or granulation or size enlargement in general. What is a very interesting topic and emerging topic is the platform approach. Just think about how you can add every component of your formulation into a granulation process. You yield granules out of that granulation process that are made from all components. Those are free flowing. They are very good in in their compaction behavior and you can go to the tablet press directly. So that is also something that is a benefit for wet granulation or granulation techniques. PVA has been investigated in technologies covering wet granulation, such as fluidized bed granulation or high shear granulation, and today we'd like to look at twin screw granulation. This really is an emerging technology, especially looking at continuous manufacturing because it'll facilitate the continuous process because you don't have to stop at some point when the batch is ready, but you can really use it in a continuous setup. Main binders that are usually used for wet granulation are for example PVEPVP&PVPVAHPMC or other cellulose steroid rates as well as starch. So now let's take a look at Quinn screw granulation. As said, it's an emerging technology especially for continuous manufacturing. It's also great granulation method because due to all the different setups that you can use, needing elements, conveying elements, angle of your needing elements, you can really define and engineer the particles or the granules that you get out of that concept and out of that process. So it's a great technology that has lots of interest in the pharmaceutical market. What do we see here on this slide? Let's just focus on the table for a second before we go into the image that you can see at the top of the slide. What we can see here is that we've tested the Partec MXP 488 which is APVA 488 and the Partec as AP80 which is APVA 4088 using twin screw granulation. That means we put this compound into a twin screw granulator and then looked at how it performs in this twin screw granulator as the excipient itself. So it's only the raw material that we've used here and it's really nice to see that this really shows that the feeding of the material is really good. Through that Twins granulator, we've covered different gearboxes, so we've covered high throughput of 16 kilograms per hour as well as a low throughput of 2 kilograms per hour. And I'd like to focus on the average deviation also in percent, you can see we are way below 1% in average deviation regarding the mass flow. So really the kilograms that can be that can be transported through the granulator per hour. And as you can see, we are way beyond, beyond the 1%, so down 1% and under 1% is seen as excellent. So we are in the excellent range here. 123 percent is even seen as as a good performance here, but we are way below 1%. Therefore we can really see that we have a very good fitting performance of the Par Tech MXP 488 and SRP 80 in a trans screw grant later and this data can then be seen in the image as well. Here you can see really high throughput. So we have to 16 kilograms per hour. So it's the gearbox 63 to one and you can see the data from SRP 80 and especially the mass flow here in blue is a really nice indicator on how the feeding performance is very good in this setup because you don't see a lot of variation in that line. It is very constant and you can see that in the deviation as well. And of course we don't want to just look into how our Poly vinyl alcohol is transported through the granulator, how good the feeding performance is, of course, that is good to know. But now we definitely want to see how we can use PBA as a binder and not just to transport it through our granulator. So we'll cover some of our results in the next section. So you can see what we've used here, You can see the experiment setup. We chose the calcium phosphate as a hydrophobic excipient and money told as a hydrophilic excipient. And then we generated a physical mixture containing 5% of PVA 488-1888 and 4088. This is our binder. So we'll look at this data being the placebo data and then we'll also take a look at some real data using a model compound. We will then use paracetamol or acetaminophen as our model compound and we'll add that in 50%. Afterwards, we'll show some data on the analytics that we performed. So we looked at the size especially to determine how many fines are still in our granulated product. We investigated the friability of the granules and then we looked at the compact abilities of the performance on the tablet press using a style one. You can see the screw configuration. So we have different needing elements and also conveying elements here in our twin screw granulator set up. So let's take a look at the data. We have the friability here and the fines over here. You can find either the friability or the fines on the Y axis and then we have on the X axis the liquid to solid ratio. This is a very important characteristic in twin screw granulation to determine how good your performance of the process is, how good the particles and the granules are being generated. You can see the money tool here and the decalcium phosphate here. This is also the same for the fines on the left. On the right side for all the following graphs, PVA 488 is seen in pink, PVA 1888 in yellow and then in purple we have the PVA 4088. I will not take too much time to look at the placebo data because the model compound is coming up in just a second. But what you can see already here is that we have a decrease of the decrease of friability. This means that the granules become harder with the addition and the increase of the liquid to solid ratio and this is the same for all our PVA grades that were tested either with money tool or with our D calcium phosphate. So also looking at the data with very slow liquid to low liquid to solid ratio, you can see that we already generate very hard granules that can further be then used in other processes without yielding fines. Because if we look at the fines, you can see that also these decreased very steeply and significantly with the addition of or with the higher liquid to solid ratio. And this is the same case for all PVA rates. So let's look at the model compound. So here are the is the data for the acetaminophen or paracetamol and you can see the data for our money tool samples. Again, we have the friability here on the left and the fines on the right. Again, the color code is the same, 488 in pink, 80 and 88 in yellow, and then 4088 in purple. Let's take a look at the 488. We can see that 488 generates the hardest granules with the littlest amount of water at it. So you can see that right here I'll put my pointer. You can also say, and that goes hand in hand of course with the hardness of the granules, that the littlest amount of fines is generated with the littlest amount of water used here in the granulation process with the PVA 488. Therefore we can say that 488 really here outperforms. But also the other Pvas are very good in using them as a binder in trans group granulation because if you look at the values, we are in the friability range below 25, where 30 is a value that is is targeted to be under 30 and we are well under 30 and can significantly decrease the friability with the addition of little amounts of water. Another thing that we tested then was the performance on the tablet press, because ultimately that's what you want to do with your granules. You want to compress them into tablets. What we see here which was very nice is that the 488, the 1888 and the 1488 show a similar compaction profile. So with increasing main compression pressure that you can find on the X axis, you have an increase in the tensile strength and we do see very nice tensile strength. So we have very hard tablets that come out of that went through granulation process and this is for the model compound. So this is really with a 50% of acetaminophen paracetamol in this formulation. You have to think though, and we'll get to that in the next chapter, that even though we have a very similar profile here regarding the tensile strength, that you might have different dissolution values because of the higher viscosity of the PVA 4088 for example, which will cover in the sustained release. So therefore you'll have to see if you want to use your API in a immediate release or sustained release formulation to then choose the right PVA for your twin screw granulation process. And this brings me to the summary of this chapter on wet granulation where we took a look at twin screw granulation. We can see and that was the first slide we covered then all milled Pvas. So the Partech MXP 488 and the SRP 80 are suitable for continuous processes, especially for twin screw granulation because they show excellent feeding. All the PVA grades that were evaluated are effective binders. They lead to very hard tablets with very low liquid to solid ratio. We've seen that especially with the model model formulation, PVA 488 is most efficient because the lowest liquid to solid ratio already leads to the hardest granules. What is very advantageous about a low liquid to solid ratio is that you introduce a very little amount of water into your formulation, which means you don't need to dry it for too long. That means you have can reduce the drying time and this is something that is definitely an advantage in your manufacturing process. And we also see that hard tablets can be achieved after granulating with PVA. And with that I'll come to the sustained release. I touched upon it a couple of times in the chapter before, but let's let's take a look at PVA and sustained release formulations. So why would we use a sustained release formulation or what is a sustained release formulation? If we want to have a sustained release, we want to have a desired concentration of the drug being released for a prolonged period of time. And how does that work? If we think of PVA, it's a water soluble polymer, therefore it's a hydrophilic matrix system. What is the nice thing about hydrophilic matrixes matrices is that you can either disperse A soluble API, but you can also disperse a non soluble API. It's both possible and the nice thing is this hydrophilic matrix system. When it comes into contact with our gastrointestinal fluids, it starts to swell and that's where the sustained release starts. So there is a gel layer that then builds at the surface and through that gel layer the different API particles can then be diffused into the git fluid and then, you know, be taken up by the bloodstream and brought to the side of action. Eventually. You can here see the the blue circles. Those are the API molecules and this then covers a whole range of time because it takes some time for that hydrophilic matrix system to erode completely. And through that erosion process, a defined amount of API is released over a very long period of time. So let's take another look at sustained release and then made it to release into delayed release. You can see here the concentration of API on the Y axis and the time on the X axis. You can also see that yellow band. This is our therapeutic window. That therapeutic window is flanked by the maximum tolerated dose and the minimum tolerated dose. As a formulation scientist, we would definitely want to be in that therapeutic window. So you'll try to design A dosage form that gives the right amount of API at the right amount of time where it's needed. So you might want to have an immediate release formulation when you have pain medication, for example. With immediate release, you release the API amount very early and in a very short period of time, so you you reach a maximum and that decreases to significantly. In a small amount of time. You might overshoot the therapeutic window with immediate release formulations. So that's the downside. On the other hand, you have delayed releases that might take some time to then release your API. With a sustained release, you can try to target that therapeutic window over a very prolonged period of time. There are several advantages of having sustained release formulations and one other example here or one other advantage is of course the patient compliance. A sustained release might be a good formulation for something that needs to be taken for a long period of time. Chronic disease, for example, where the patient doesn't have to take a tablet every three hours, but only has to take a tablet every two, two times a day. So this is something where a sustained release comes into play. So let's take a look at Pertec SRP 80. This is the product that covers the sustained release. Pertec stands for Particle technology. Those are products that have a certain particle size and are particle engineered. The SRP AD stands for sustained released PVA and the AD is the medium particle size in micrometers. Again, this is 100% Poly vinyl alcohol as explained in the introduction slide, and it's fully synthetic. It's milled with a specific particle size, and that specific particle size makes it an optimal candidate for direct compression. So you can use it in, in direct compression. You can use this optimized particle size to have an optimized drug release and drug dissolution profile. It's also compliant with a major pharmacopoeia and it has a low content of protein aldehyde. So I was talking about direct compression. So let's take a look at that. So on the right side, you see the formulation that we used for this experiment set up. It's made of 1/3 of Propranolol. It's a beta blocker, so it's good to have that in a sustained release formulation. And then we have 30% of Pardec SF80 that has been used in this setup. We also have further excipients that are being used and they are used in a direct compression setup. You can see on the Y axis on the left side the tablet hardness, Newton on the Y right side. You'll see the ejection force in Newton coming from the tableting unit and then we have an increase in compression force from 5 to 30 kilonewton. What you can see is that when increasing compression force, we have an increase in tablet hardness. So this is exactly what we want. We also see we have very nice tablet hardnesses that also show very good ejection forces. So we have low ejection forces which means your tablet press is going to like that process with this formulation. So let's take another second to look at these values because in the next slide we'll go over the different tablet hardnesses and how they perform, perform in the dissolution. So here you can really see we have a 10 kilonewton, about a 150 Newton hard tablet, but with 30 kilonewton we are double above of that from the 1010 kilonewton compression, we are at 318 kilonewton and let's see if that changes something in the dissolution of Propranolol in our next experiment. You can see here in purple is our partake SRP eighty example formulation at 10 kilonewton. So we have 100 Newton, 150 Newton tablet hardness. In pink we have it compressed at 20 kilonewton and in green we have the 30 kilonewton that has a tablet hardness of 318. And here you can see the release, the dissolution of Propranolol in our media and then we have the time covering 12 hours of release. And as you can see, there is no great or no significant difference in the dissolution of Propranolol from these different tablets that have absolute significant difference in their tablet hardness. Another aspect I'd like to cover is dose dumping. So what is dose dumping? It's the unintended rapid drug release in a short period of time. That might be, for example, the entire amount of API that is released from your sustained release formulation. Or it can be a part of the API that is released in a burst. So how can that happen? For example, through tampering, grinding or crushing. Or you divide a dose that is not intended to be divided. It can also happen when you take the medication with alcoholic beverages or with food because food might change the pH values that you have in the gastrointestinal fluid. So we've investigated the dose dumping. So we tried to really simulate A dose dumping scenario and here you can see the dissolution of propanolol here at the Y axis and then again the time at the X axis. In purple you can see the normal formulation. It again is propanolol, it's the normal formulation at HCL 1.0.1 molar. Then we have this with 5% of ethanol in the dissolution media followed in green by 20% of ethanol in the dissolution media and then 40% of ethanol in the dissolution media. Again the same results comparable to the tablet hardness. You can see there is no significant difference in the dissolution covering no ethanol up to 40% ethanol in the dissolution media. Another effect was the pH that we talked about. Let's take a look at that again. We have the sample form example formulation, it's an HCL. Then we have an HCL buffer at pH 1.2 and blue. In green we have the phosphate buffer at pH 6.8 and then in yellow we have aph shift. So after two hours in HCL we then transferred it to a phosphate buffer pH 6.8. And again as before, we don't see a significant difference in the dissolution of Propranolol using our model formulation. This brings me to the summary of SRP 80 for sustained release. So we see a consistent API release over several hours. We also see it's a very convenient product because it can be applied in direct compression. It has a reliable product performance because it's fully synthetic. And we also saw that we have reduced risked of those dumping. So we've seen in our results with Propranolol that we have a reliable alcohol resistance and constant API release over a broad pH range. So here we've covered really sustained release. So we want to have that API be released over a very long period of time. So we will definitely switch gears now and I'll hand over to Marcos who will bring bring us closer to the solubility enhancement. Thank you very much Lena for this nice handing over and for covering the 1st 3 topics and also for introducing Poly venom cultas. Now I will introduce the fourth topic which would be solubility enhancement and thereby we will cover different technologies like hot melt, extrusion, 3D printing and spray drawing and so let's get this started. Solubility of AP is in the development overall, poor soluble molecules are becoming more prevalent. What does that mean and why is this important? If you think about solubility and if you think about active pharmaceutical ingredients, you first of all take a tablet and this is then going through the oral route. We are the GI tract and was in the intestine and ideally in the small intestine. It gets fully dissolved, permeates through the intestinal membrane and gets into systemic circulation to achieve a therapeutic effect. If it is not fully dissolved in the GI tract, it goes right through the body into the dump and doesn't achieve the therapeutic effect. And this is of course something what you don't want to have. So you need to make sure that your API is fully dissolved in the GI tract. Here you can see the Biopharmaceutical Classification system on the left hand side and this is the framework of permeability and solubility from low to high. And what you can see are the BCS Class 2 and class 4 compounds and those are the compounds which are having low solubility. So they are really tricky to handle. And it is really important that you do some solubility enhancement to those by looking at the pie chart which you can see in yellow are the class 4 compounds and in pink the Class 2 compounds. About 40, maybe 50% of the AP is are suffering right now and from poor solubility. So those are the marketed drug substances for today and depending on which literature you look at this is about 40% of the AP is which suffer from poor solubility. Now coming to the pipeline drug substances. So 10 maybe 15 years from now and looking into the poor solubility profiling and this is where where I started out, that poor soluble molecules are becoming more prevalent. That about 10 to 20% of the API's will be considered as class 4 molecules and between 60, maybe 70% of the API's will be in the Class 2. So overall 70 to 90% of the API's will suffer from poor solubility and poor solubility can lead to low and variable absorption and a low therapeutic effect. In the variant. How can you tackle this? You have the chance of amorphous solid dispersions and how does it actually help to enhance the solubility? If you have individual drug molecules, those individual drug molecules are normal held together with crystal lattice interaction. But instead of having the crystal lattice you can also have the amorphous form. The amorphous form is something which you can see on the right hand side, so individual drug molecules which are more soluble. The most common technique are amorphous formulations with polymeric matrix. Why do you need this and how do you do this? So you have the amorphous form and the amorphous form tends to recrystallize and this is something which you of course don't want to have. So starting from left to right you have your API and your API. With a polymer you can either do a spray drying approach. So you dissolve your API and your polymer, go through spray drying equipment, achieve an STD and then you have an amorphous solid dispersion which you can see on the right hand side. So you have your amorphous form of the API and this is incorporated into a nice polymeric matrix and this really helps a lot that the API is prevented from recrystallization and has thereby a higher solubility. Now going back to the left side, we have the API and the polymer, we can mix and melt everything together within the HME equipment, so hot melt extrusion equipment and have then also the possibility to achieve the right hand side, the amorphous solid dispersion. What is important about that is basically that you achieve homogeneously dispersed drug was in a polymeric. Matrix. This is the overall goal to it. Partik MXP. So the excipients for hot melt, extrusion coming down to the nomenclature and the benefits. So what is Partik MXP? Lena already covered quite well. That Partik stands for particle technology and thereby specifically engineering to those particles. And the MXP stands for melt extrusion, Poly vinyl alcohol. So what are the benefits of Partik MXP? Of course, since it is designed for the Hotmail extrusion space, it can enhance the solubility and it has also the possibility of high drug loadings. You can achieve stable, amorphous solid dispersions. It is applicable to a broad range of APIs and this is really important. Then you can modify the release and the dissolution kinetics by adding additional excipients to your formulation and you can the powder. So the exceedant by itself, the partic MXP is optimized and has optimized powder properties for the HME process. That doesn't mean that you exclusively have to use it for HME processing, but you should. Or you can use it for the HME process, which is really beneficial. We have two different partic MXP grades. First of all MXP 488 which is specifically designed and has improved thermal stability. Thermal stability is really important if it comes to Hotmail extrusion and thereby we have a process ability of a broad range of APIs and a high thermal stability up to 250°C. And then secondly we have partake MXP 382 and thereby this is specifically designed to. For improved hydrophobic interactions and thereby the improved hydrophobic interaction leads to all the prolongation of the Super saturation state and have a precipitation inhibition effect and thereby precipitation inhibition in solution and also in the ASD form. With this, I come to the second poll question and I hand it over to Naima. Thank you Marcus. Our part question is have you used PVA as a matrix polymer for solubility enhancement? A yes I have used it. B no but have heard about it. C no but I would like to learn more or D no I have not heard about it. Looking forward to your responses and while we are waiting for the answers, I would like to draw your attention to our upcoming webinar also with Marcus Lupta that fits exactly this topic and it's titled Unleashing the Potential for Poly Vinyl Alcohol in Spray Drying for Oral Solid dosage forms. Click on the corresponding widget which is the call to action. Register now in your widget windows and you can do this throughout the webinar. Yeah, and we have still answers coming in, a lot of them, which is great to see that we have such a amazing participation today. Yeah, And these are the results. Thank you very much for all your answers. And with this I give back to Marcus. Thank you very much and happy to see those results. And this is basically leading us to a deeper dive into solubility enhancement and into Hotmail extrusion. Here you can see the Hotmail extrusion equipment and what are the advantages of the overall HME process. First of all the API and the matrix polymer are coming into a hopper into the HME equipment and then a melting and mixing is happening and you achieve the homogeneously dispersed amorphous solid dispersion at the very end which is then cooled down and can be chopped into different pellets or anything else. So the the filament can be can be chopped in that and has AASD form was in. So the the amorphous form is stabilized within the polymeric matrix. What are the advantages of HME? Of course solubility enhancement and thereby bioavailability enhancement. You have stable hydrox loading capacities and you can control really release profiling. And then the very last three advantages are the most beneficial. You have a continuous effective process with HME in place which is really important. Then coming to the most important aspect to my opinion would be you have a solvent free manufacturing process, so no solvents are needed which is really good and environmentally friendly. Then thirdly, you have a support of various dosage form which makes the whole process really really flexible. Now I have two case studies for you and two case studies for the two different products which are already promoted you before. So Poly van alcohol for Hotmail extrusion and starting out with Partik MXP 488 and if you remember correctly this is a polymer for thermal stability. So for application of high melting point APIs and if you think about it, high melting point APIs are really critical to handle within the hot melt extrusion process on the right hand side. So it's a pie chart. You can see that this is a breakdown of BCS two and four compounds. So 67 BCS two and four compounds with low solubility are actually clustered into the melting points, and you can see that there's not really a clear trend for the melting point of the different API. So going from less than 100°C over to 150 sixty degrees Celsius all the way up to 240°C is something for the API. And what I want to point out is the pink and the purple are so basically about 35, maybe 40% of the AP is are having a higher melting point than 200°C and normal often polymers degradate around 200. Degrees Celsius so those AP is. Could not and would not be considered to be used for the HME process. If you think about classical polymers on the left hand side you can see multiple different AP is within the different categories of the melting points. And what I want to point out again is also the pink and the purple AP is you achieve really good truck loading capacity, you achieve really good solubility enhancement throughout all the different melting points and you can even have an HME process done to tell masartan which has a melting point of 260°C which is really great. So basically APIs which have a range of melting points. There you need to consider good thermal stability and this can be covered and has a wide range for Patek MXP 488. Now shifting gears in the matter of which partic MXP we are talking about, now we talk about partic MXP 382 and if you can remember correctly what Lena mentioned in the beginning, the 82 mentioned that hydrophilicity of the the polymer. So 82% of the units are hydrophilic units and 18% and this is important in part, this is the important part for here 18% are hydrophobic units and those hydrophobic units lead to the aspect which we designed the polymer for. So basically superior super saturation maintenance via stabilization of the precipitation inhibition and also hydrophobic interactions. On the left hand side you can see a Bi Phi 6 GI tract dissolution of hydroconosol. Hydroconosol is often considered to be a stone and really tricky to handle. So a shift from PH1 to a shift of pH 6.8 and thereby we incorporate Itraconosol in Partik MXP 382 but also into other polymers which are available on the market. And in pink you can see the performance. And the difference within the PH1PH1 is not the most tricky part for Itraconosol because this is not the mode of action where you want to have it in place, which is really important. This for hydroconosole, the pH 6.8 and the shift from PH1 to the higher pH shift is something where normally hydroconosole crashes out in solution. If it crashes out in solution you don't have the amorphous form available anymore and you don't have the solubility enhancement aspect. And this is of course tricky and this is of course something which you don't want to have and what you can see you prolongate with pink. So with partake MXP 382 in comparison to the other polymers, I'm not saying that those are not good polymers, but if you compare it for maintaining the Super saturation, partake MXP 382 just really outstanding and it stabilizes the amorphous form really well in solution and also in the amorphous solid dispersion. And you can see here that it stabilizes this over hours which is really good. And if you take a look at the area under the curve you can also see that you have a 2 1/2 three fold increase and of chance that it can still permeate through the intestinal membranes. What other polymers maybe would not give you. So bottom line, improved hydrophobicity of partake MXP 382 leads to a prolongated release profile and thereby outperforms other commercially available polymers. Now solubility enhancement and covering the topic of 3D printing. So PVA can be used for 3D printing. There are multiple technologies which are used for 3D printing. Today. We will talk about the advanced MELT drop deposition and this is basically coming from the Arbor plastic free form process, so from the plastics industry and it's really comparable to injection molding and this is something what I want to walk and guide you through today. So here you have a feeding unit and within the feeding unit you feed your API and your polymer into a single screw and thereby trans. Translational movement goes from right to left and generates high pressure this. Pressure goes up to 500 bars within the whole equipment and thereby the nozzle tip filled up with the liquid polymer API mixture and the reservoir fills up and you have the nozzle tip and that's the nozzle tip. You have a needle which is coupled to a pietzo actuator, and this pietzo actuator operates at. Really. High frequencies, so high frequencies up to 250, maybe even a little bit higher. Hertz. So that means it can open and close 250 times a second. So you can really control the process and by defining and having a guilt melt viscosity of the whole process itself, you can really fine tune the outcome of your 3D printed tablet and you can really fine tune the whole process from tablet to tablet. What does that mean and how does it look like? So on the right hand side you can see a top view of a SEM picture and you can see here a tablet which is printed with a 30% infill volume and what you can see. First of all, here and also nicely here are the individual droplets which are generated during the advanced melt drop deposition and those come together to a perfectly strand and build then a nice little tablet which is having different info or which can have different infill. Volumes, talking about infill volumes, you can really have a broad range of infill volumes and why and how would that be important, so coming from 30 to 40? All the way. Up to 100% of infill. You can really play around with that. With playing around with that, you change overall the surface area, you change the. Pore volume. You change the density and you change also the release profile, so you can individual fine tune your tablet and the porosity of the tablet by itself and adjust it to your. Own needs. How does it now translate into the process itself? If you think about melt trap deposition and the mass distribution of different tablets, we have first of all a placebo formulation, then we have a caffeine formulation and a catechosanal ketoconosol formulation. So by taking a look. At the axis we have on the Y axis the mass distribution and on the X axis the infill volume. And what you can see really nicely is going from 30 to 100%, you have a homogeneity. Of the overall process and you have a really influence of the final mass. Homogeneity is of course something what you want to have, so there you need to have. A good reproducibility and with the placebo you can see this. Really well by. Looking at the caffeine standard formulation, you can see that you have a little bit more of a deviation within the system, but this deviation is still within the homogeneity which is needed for the target of the limits from the pharmacopeia from the different. Pharmacopeia's as well, so therefore looking at caffeine. Even so it has a higher standard deviation. It is still within the limits of acceptance. Coming to Keto Croissant Ketoconosol. Oh, I don't today. That's not working out for me either this. Word. Ketoconosol is an API which is considered as Abcs Class 2 compound and also there's a homogeneity is really important and all the way down from 30 to 100% infill you can see a really constant mass distribution of course also with a little bit more of a deviation, but also this is really good in the limits of the overall Pharmacopeia limitations. So how does now the infill volume translate into a dissolution? Profiling. First of all, we did also test the mechanical stability. We also did test this friability. We achieved really good tablets. But how does a dissolution profile and more specifically solubility enhancement look like now with ketoconosol in FOSF media? So basically Ketoconosol was dissolved in FOSF. FOSF stands for facet state simulated intestinal fluid, so by relevant media. And thereby you can see nicely that ketoconosol crystalline wise reaches quite far the solubilation limits and if it cannot be solubilized anymore, it doesn't achieve A therapeutic effect. So what you want to have in here? On the Y axis, you can see the concentrations. We incorporated that in 3D printed tablets with 30% fifty percent, 70% and 100%. Infill volumes and what you can see in blue. And in green are the 30 and 50% infill volume tablets and you can see a really fast onset of the tablets. You can see a good solubility enhancement effect and what you also can see an outstanding prolongation of the release profile and also a maintenance of the Super saturation. By looking at the yellow and pink line, you can see that 70% and 100% info volumes of the tablet don't achieve a fast onset or such a fast onset like the 30 and 50%. But they achieve a little bit higher solubilization and solubility enhancement aspect and also achieve a good maintenance of the Super saturation. So overall we can achieve good solubility enhancement, we can achieve a fast release. Kinetics if we want to and this can be done by lower infill volumes. So you can play around with and playing around with this really critical if you think about target final dosing and personalized medicine for future perspectives of 3D printing and main technology approaches of that. So solubility, enhancement and the last topic would be spray drying. If you look at a spray drying equipment you already saw this before. This is through liquid feet. Then you can contain or you can produce with a nozzle little droplets. Those droplets are cooled then down in a drying chamber going through a cyclone and a collection vessel and down here you achieve nice little particles and those are having the amorphous solid dispersion so the amorphous forms stabilized in the polymeric matrix. What are the advantages overall for spray drying that you can see on the right hand side? So overall you can check the box of solubility and bioavailability enhancement. If you have low API amounts, this is a go to option because you don't need really high volumes of your API or high quantities of your API. To achieve this process. Then thirdly, heat sensitive APIs are a class of APIs which are really considered if you want to. If you have a heat sensitive API, you should really consider spray drying on that. Then the second last and the third last kind of come together. Spray drying have been around for decades, so upscaling is really known. High throughput is also really known. A lot of people have that equipment and also continuous technology approaches can be tied to spray drying as well. And last but not least, we come to the last advantage. Would be particle engineering. So you really can fine tune with the knowledge which you have about the equipment and about the whole process. The particles which you achieve at the variant. So how does it look like that you use Poly vinyl alcohol for spray drying? Overall thermal and viscosity related behavior ensures a wide processing range and a hydraulic loading during the spray drying ASD process. Here we will take a look at the viscosity and more likely or even more the viscosity related and correlated. To the polymer concentration. So on the left axis of the rear meter data you can see the viscosity and here you can see the concentration and and the graph you can see that we used four different polymers. In pink and in turquoise you can see that Partick MXP was used and in yellow and green you can see that other polymers were used. What you can see for all of the polymers is from zero. Concentration to 15% the viscosity is increasing but also. What you can see for partake MXP it is just slightly increasing and for the other polymers you can see really a clear shift around 5 and 10% of concentration that the viscosity is increasing a lot. Of course this is important or a downside for the overall spray drying process, but most importantly this is also an outcome the difficulty. So if you look at the outcome for a spray drying process of 50% of 15% of concentration of a polymer on the left hand side, Partec MXP 382 on the right hand side HPMCAS you can see for MXP 382 you have a really homogeneously dispersed material. You have Raisin like looking shapes which are really good, which provide a good flow ability and also a good process ability. At the very end to a tablet on the right hand side you can see filaments. Those filaments are not to be considered as good flowable material. Those also are not compressible really well and will lead to difficulties in the very end for formulation. Prospectives. This is something which needs to be considered and which can be considered during the whole process. So overall we have a constant low viscosity for different concentrations for partic MXP and thereby, and this is important why you also consider higher concentrations of polymers. You can achieve hydrox loading capacity for your ASD at the very end. So shifting gears now to dissolution profiles of indomethacin. So we incorporated 30% indomethacin into an amorphous solid dispersion and amorphous solid dispersion with different polymeric matrices and did the dissolution profiling in different or in acidic conditions, because this is really critical and important to understand for endomethacin. So here on the right side you can see the XRPD data. So if you're API is within the amorphous form. So if in the methods, then is in the amorphous form in your different ASD formulations and except one formulation which you see in purple, you can see that in the methods then has the amorphous form proven by XRPD data. This is of course nicely and important to improve the dissolution profiling. And the dissolution profiling shows really well in turquoise and in yellow how Partick MXP 382 and MXP 488 provide a really nice onset of the overall material of Indomethacin in solution. And they also provide a good prolongation of the Super saturation and thereby the superior performance in comparison to in pink the crystalline endomethacin and also in green, purple and light turquoise to other polymers on the market Of course. Now this is a comparison of different amorphous solid dispersions and different polymers, but how would be a comparison for marketed drug formulations which are on the market right now. So looking at the dissolution profile of 30% of ritonavir in Partek MXP 382 and also comparing this to marketed drug formulations. I'm not saying that marketed drug formulations have a downside to it, but I'm just saying maybe people can consider for future formulations also to use Partek MXP 382 in some manner and the some manner can be shown in this graph. So if you look at crystalline ritonavir you can see in pink that it reaches really fast the it's a saturation concentration and in green and turquoise you can see that a really fast onset of fraternal we have was a nice solubility enhancement is achieved for the market attract substance and also for the ASD with MXP 382, MXP 382 maybe is having even a little bit higher solubility enhancement aspect but but this is not what I want to point out. This is really API specific. What I want to point out is the Super saturation aspect, which is really helpful that not after 1020 thirty minutes your API crashes out in solution, but also it maintains the Super saturation state and also gives the chance that the API can still permeate through the intestinal membrane. With Sys we close now the topic of solubility enhancement, but still talking about solubilization. And with this I open the topic of oral dispersible films. Oral dispersible films are an innovative path forward and an emerging trend and this trend is really or should really considered. So what if you could take a medicine that would melt in your mouth, so you could really broaden the patient compliance and also the people what would be willing to take certain types of medicine, of course not all of them but in some aspects. So oral dispersible films or short Odfs making it easier for elderly and younger patients to take medicine. So basically pediatric and geriatric formulations can be clustered with that as well and it provides or gifts solid or a mucosal preparations intended for administration in the mouth where they disperse rapidly to deliver the active pharmaceutical ingredient. This is the definition from the European pharmacopoeia. But how does it translate now within a formulation and within an application? So if you look at the formulation at the left side here you can see that there are some major ingredients which need to be considered. So first of all the API or the different AP is which need to be incorporated into the film. Secondly and secondly is even most importantly because it is the most bulk of the overall system film forming agent. So you have the film falling, forming polymer with HPMC, with PvP or with PVA and this is really critical because this is a major bulk of the whole formulation. Then you can add plasticizers to the whole aspect, so glycerol or different polyols and also you can add other excipients like sweetener like colorant like lubricants. I mentioned that film forming agents are important to be considered and thereby Poly Vinyl alcohol is the most widely used film forming polymer for ODF preparation except HPMC. And how can you produce now such an ODF? An emergent approach to produce ODF or to manufacture ODF is the HME process and this is really recognized and on the right hand side you can see the sheet takeoff units. So first of all you need to have an HME equipment with a twin screw extruder and to this the sheet takeoff unit can be tied. So basically you achieve a nice little thin film. This thin film is then cool down on A roll and then wind up on the roll down here and you achieve a thin film roll which you can see on the next hand side here. This thin film role is really important and shows you the single layer of ODF and the ODF feasibility study you can see here. So basically partake MXP 488 is Poly vinyl alcohol. I already introduced this polymer before so you can see the versatility also here that it is not exclusively just used for normal hot melt extrusion but also for different downstream process abilities and having here the flexibility for using it as an ODF. Here's a feasibility study where we did check the influences of different process parameters and here in pink we marked influence of temperature. So just taking purely 100% partic MXP 488 and changing the extrusion temperature from left to right to from 230 to 180°C. And what you can see that by changing the extrusion temperature you also change some of the process parameters. And what is really important to point out are the process parameters of the torque and also of the dye pressure and what you can see around 200°C. So around here you can see by increasing the temperature more the torque and the dye pressure is decreasing, which is really good. So by increasing that you have better processability and the very end and the chief still about the Salem film properties by looking at the disintegration time. The disintegration time does not really vary a lot depending on the extrusion temperature. Now taking a look at the pictures, on the left hand side you can see the single layers and within the single layers you can see from. Right to left. From 180°C to 230°C, around 230, around 200°C that you have still so. Little. White dots so still unmelted material and this is something which you don't want to have. So partake. MXP 488 has very good film forming properties with the hot melt extrusion process and higher temperatures help to get a smooth film and to complete melting with that and thereby terminal energy helps with that melting not just thermal energy can help with that melting. Also we checked the influence of the screw speed. So the screw speed going from 200 all the way up to 500 RPM. And if you look or if you take a look at the different process parameters in film properties here you don't see much of a difference. But where you see a difference are again again the single layers and the single layers from left to right from 200 RPM to 500 RPM. You can see that there is an influence of higher screw speed and this is beneficial for smooth films. And the film appearance improved significantly for 400 RPM and above screw speed due to higher mechanical shearing and also to better energy transmission. This is something which can be seen here are still some parts of unmelted material and here you really have translucent material for 400 and 500 RPM screw speed. So of course the polymer is really important, so the film forming agent but also other excipients should be considered in the whole process and thereby plasticizers are really critical. And plasticization occurs by reducing the relative number of polymer to polymer contacts, which decreases the rigidity of overall the three-dimensional structure. So what does that mean? By taking a look at a three-dimensional structure here and here you can see without a plasticizer that you don't have enough flexibility and that a rupture can occur to the three-dimensional structure. And by taking a rigid structure and adding plasticizers here in pink to the whole process, you can see that a higher flexibility is allowed and also a higher deforming. And this leads not just to less rupturing, this also leads to lower operational temperatures, which is really good. This leads also to lower glass temperatures to increase processability and also to good workability, which is overall really nice and helpful. What plasticizers can be used and this can be seen on the right hand side. So we can use solid plasticizers and we can also use use liquid plasticizers. Solid plasticizers would be for instance paloximer or different polyols. Liquid plasticizers can be a tween, can be a polyethylene glycol, can be a triacetine, you name it. Overall, plasticizers are low molecular weight compounds which are added to the polymers to improve its flexibility and mechanical property. Plasticizers reduce the stiffness of the whole system and PVA is a rather stiff polymer and thereby here you can see an electron microscopical image and partake MXP 488 ODF which contain plasticizers. So we did try multiple different plasticizers which you saw before and I want to point out four of them. On the left hand side you can see that we added tween 20 and also pack 400 with 10%. And in the front view in the picture you can see that we still have unmelted material and we also have in homogeneity. This is something what you don't want to have. And also in the cross section you can see nicely or yeah, well nicely but not nicely that they're still unmelted material and this is something what you don't want to have. So the plastic size is 20 and PEC are not really compatible with MXP 488. But looking at the right hand side by adding 10% of triacetine and 10% of Partech SI which would be a sorbitol and overall poliol performed really well with Partech MXP you can see on the front view that we have really nice no unmelted material, homogeneous material. And on the cross section you can see really well that we have a nice tier line and the tier line stands for the strength of the overall ODF which is really good and helpful for the performance film mechanical properties. As an evaluation here you can see four different columns. First of all you can see Partik MXP 488 and for the in columns 2-3 and four we incorporated 10% of plasticizer into the formulation. What you can see is that the process parameters are kept the same, but the mechanical properties did vary depending on which plasticizer was used. So we have as a mechanical properties the Young's modulus which is standing for the solid stiffness or the resistance to the elastic deformation. Then we also have the tensile strength. Tensile strength is the maximum load that the material can support without fracturing or rupturing. And then we also have the elongation and what is really important to balance out the process parameters and the mechanical properties. And what you can see here is specifically for triacetine that the Young modulus is reduced, also the tensile strength is reduced and the elongation goes up by incorporating triacetine in the formulation. So triacetine helps to reduce the film stiffness and improve the film ductility and by also ensuring enough strengths of the overall film. So you have a really well balanced and partake MXP 488 in combination with Triacetine has really good film forming ability and really good process. So now looking at the different and last case study, we have Loratadine as a Class 2 compound and this is used for the treatment of allergies. So we have an ODF formulation. Which helps for a. Better therapeutic benefit and we incorporated Loratadine was 5% in that Loratadine has is a small molecule, has about 400 Dalton and the melting point of 140°C and a really good degradation temperature which makes it as an excellent case study for an ODF study. Here you can see that we did try 180°C and 200 up to 200°C and we achieved really good disintegration times. We achieved also really nice films down here which are translucent, so a smooth film appearance, good film mechanical properties and a fastest integration time. So really nicely done for that. And this makes also sure that Laura Tadim could be taken by a handicapped person or maybe also by kids or older people as well. So a good process, ability and film properties achieved. With this, we come to the last poll question. Yeah, thank you Marcos. Are you using PVA for one of the technologies? Select all that, Apply a wet granulation, B spray drying, C hot melt extrusion, D tablet film coating or E3D printing. Yeah, and we're coming nearly to the end of the baby now. And we still have a great participation, participation with responses. I give it a couple of more seconds because there are so many still replying. Yeah, thank you very much, very interesting. And with this I give back to Marcos. Thank you, Naima and I guess I'll bring us home. So the very last two comprehensive slides formulation development with Poly vinyl alcohol, really dependent on the Poly vinyl alcohol great and type. You can fine tune to the application area, you can have liquid application, semi solid and solid application and really depending on the different all event alcohol grates and we have 11 of them, you can fine tune it to their application area. They all are within our improved essential envelope and here you can see the article numbers and all that. If you want to check it out, I recommend you to go to our solid formulation that page from sigmaaldridge.com. You can check it out later by going through the slides. So covering at a glance how do you discover Poly vinyl alcohol and its versatility. So depending on which excipient grade Poly vinyl alcohol you use, you can use multiple different technologies more like classical technologies like tableting or red granulation, solubility in technologies like spray drying HME or more the emerging technologies like 3D printing or ADF. We have multi compendial material and all of our polyvinocal grades go within OR along with our improved documentation and we have a good batch to batch consistency which I want to outline here on. This is supporting reliable reproducibility of quality and performance in the final track formulation if you need support. We are more than happy to give you formulation development support and we are also really happy to give you guidance with our technical experts on an application servers or anything like that. Check it out. More than happy to give you any kind of support which would be needed. Thank you very much for the attention and thank you very much for your time. Feel free to reach out to me, feel free to reach out to Lena and biggest thank you goes to the contribution of our whole team behind this. Just to name a few people. I think the the sheet was not big enough to name all of them, but there would be almost Funda Bradley, then also Gautrin Berg and also Jenkin Lewis. Thank you very much for your contribution. Without you all the data could not be shown and would not be happening. With this, I guess we open up the Q&A session. Yes. Yeah, Thank you. Thank you. Just a really quick introduction to the Q&A. Thank you, Lena and Marcus for this great presentation. Yeah, now it's time to answer a few questions that have come in from the audience. But before we do though, I would like to remind you that it's not too late to send us your questions now using the Q&A budget. This also applied to on demand viewers. We will try to get through all of them, but if you run out of time we will respond to you individually. As a reminder, this webinar will be available on our website soon. All participants will receive an e-mail notification when it's available for viewing. Now back to Lena and Marcus, who will start answering questions that have come in. Thank you so much. So lots of questions have come in. Marcus, maybe you wanna take that one. Are all the different PVA grades pharma grades? Nice. So our PVL products are always in the excipient grades, so they're the classification. Pharma is maybe a little bit tricky, but for sure excipients grade which can be used in the Pharmaceutical industry and which are suitable for the mid risk application. Like I mentioned, we have multicompendial material which are at least within two pharmacopoeia, but depending on the product also listed in more than two pharmacopoeia up to four different pharmacopoeia maybe one word to the improve offering. So if you think about regulatory consideration, this really plays a big role. So the regulatory approval pathway is rigorous and time consuming, yeah pathway. So ensuring safety, efficacy, high quality standards is really important to achieve and success on that and to improve offering is an important feature which is supporting all the registration activities and thereby providing you high quality product documentation, comprehensive documentation and also really good support to facilitate the efforts on qualification on risk assessment and also on the process optimization to file your final track formulation. By checking out the different questions maybe I would hand it over to Lena and the high hydroscapacity of the formulation makes a formulation storage very challenging as its mechanical properties can change from day-to-day. What are your suggestions to solve this problem by having a limited resources? Thank you, Marcus. I think that's a good question and that came during the 3D printing part. So I think there are two different ways to tackle that challenge with high growth complicity. So one would be and maybe that's not for having limited resources, but of course it's the packaging. This is not something that we can address with excipients, but packaging is a is a big issue. You can use moisture resistant packaging for that. So blister foils that really don't let any water get through and you can also think of those foils over wrap that you can also use to close up the blisters as well. What can be used from excipient side is anything that absorbs moisture with which could be a silica for example. So this can be included as well. So we have the excipient strategy or the packaging strategy. Great. Since I could also have the time to read some more of the questions. By the way, thank you very much for all the questions. We get back to you with most of them I guess offline, but maybe handing one to me would be also please share successful commercial cases of Poly vinyl alcohol in HME and STD formulations. Thank you very much for that question. Thinking about the whole process of filing of product innovation of course always needs time and really depending on the region where we are targeting at the region where our products are used. You can see from the way from pre formulation or proof of concept screening to all the way down to regulatory submission stages. We really get great feedback on that. We also have a lot of scale up batches for bio equivalent studies which can be seen on that end. So it comes down to the customer side. Of course, I cannot name any specific comments on that. But so far we got really nice feedback that proving process works out really well with our improved documentation and also that it's nicely done and can be done with the quality of the product what we have. Great, Marcos. Thank you so much. And maybe we'll come to the last question with that. We have a question that came in. Have you attempted to use the PVA technology for biopharmaceutical molecules, for example, peptides or antibodies? And that is an excellent question. And I can only point out the webinar that's coming up 12th of March because you will see how we've used PVA in formulations using Protax. So we are getting there and it's going to be an exciting webinar. Yes, I'm really looking forward to that and this will be specifically addressed during that. So stay tuned by looking at the time. Maybe one more which I can also see, please share the application of Poly vinyl alcohol in bitter taste masking function. Can this polymer be used for this function? If you think about that taste optimization is really for ODF specifically important or also for coating and thereby PVA can be really nice combined with high intensity sweeteners like sucralose like neotam. We also have those in our portfolio. What you also can do and you can use the dual function of poliols which are already mentioned as plasticizers before. So you can add poliols which are also having a natural sweet taste to it and you can do a taste optimization with that aspect by incorporating this and also fine tune the overall process properties. So you basically hit two birds with one stone achievement with that? All right. Thank you very much for all the questions. If we did not get to your question, please feel free to e-mail our presenter directly to register for future webinars or to access our archive webinar library, please visit our website. I would like to thank Lena and Marcus for today's presentation and thank you to our audience for joining us. Have a great day. Bye, bye. _1732500399946

     

   

       

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