Everyone and welcome. My name is Naima Speron and I will serve as your moderator today. Thank you for joining us for today's webinar unleashing the Potential for Poly vinyl alcohol in spray drying for oral solid dosage forms. 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 Marchek and Marcus Lupta. Lena is a pharmacist by training and focused on material characterization for solid oral dosage forms in her PhD work in pharmaceutical technology. A senior scientist in a team that concentrates on the development and application of functional excipients for oral delivery. She is responsible for the oral delivery of large molecules, permeability enhancers as well as predicting processability for oral oral solid dosage forms. Marcos holds a PhD in Bio and Chemistry from the Technical University of Darmstadt in is by Academical Education. A biomolecular engineer. Marcos is responsible for the strategic development and positioning of an excipient portfolio for oral solid dosage forms 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. There you can also find our reaction button, indicated by the thumbs up emoji that allows you to give immediate feedback on the presentation topic or anything that stands out. All the widgets are resizable and movable, so feel free to move them around to get the most out of your desktop space. 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An on demand version of the webinar will be available after and can be accessed using the same link that was sent to you earlier. Lastly, attendees who wish to receive a webinar certification will need to fulfil the criteria of a minimum 30 minutes viewing time and completing 2 part questions with the duration of within the duration of this webinar. So that's it from my side. It's my pleasure to turn things over to Lena and Marcos. Naima, thank you very much for this kind introduction. I'm also warm welcome to my side. Like we already heard, today's topic is unleashing the potential for Poly vinyl alcohol in spray drying for oral solid dosage forms. Thereby I want to try to give you a really good and broad overview how you can use globally Poly vinyl alcohol and how it is the best solution for your solubility enhancement portfolio difficulties. And with this I guess we get it started. Here you see the agenda. First of all, we will talk about solubility challenges and about different formulation strategies. Then we will do a deep dive in solid dispersion technologies and how Poly VANA alcohol is a perfect fit for that. Then in Section #3 and Section #4 we will talk about partic MXP polymer which is a Poly VANA alcohol based polymer. Firstly was in solid dispersion technology which is spread dried for small molecules and then for novel modalities. And last but not least we will end up in the summary. So let's get this started. Solubility challenges and formulation strategies. Why is solubility important? Overall solubility of AP is in the development phase is really critical and important because if you have oral solid dosage forms which is taken orally by the GI tract, it needs to be fully dissolved in the GI tract or in the small intestine to have a therapeutic effect. If that is not done place taken place at a certain time, it will go right through the body into the dump. So it doesn't achieve A therapeutic effect. And this is of course something what you don't want to have. If you look at the Biopharmaceutical classification system which you can see here on the left hand side, this is classified by the permeability and solubility and thereby we have the Class 2 and the class 4 which are the AP is which are falling into the class of poor soluble molecules and overall poorly soluble molecules are becoming more prevalent. How and why is something what we will talk about today and how to solve it is even more critical. If you look at the pie chart in the middle here you can see the distribution of marketed drug substance and if you see in orange and in pink that about 40%. This is quite conservative data off the market. The drug substances today have poor solubility. If you look now into the future pipeline, so maybe 10 or 15 years from now, we will talk about 7080, maybe even up to 90% of the AP is will suffer from poor solubility and poor solubility can lead to low and variable absorption. And this is of course something what you don't want to have to have a therapeutic effect. Why is the biopharmaceutical classification important? On the left hand side, you can see that the biopharmaceutical classification system, so the BCS is a framework of permeability and solubility. It is in place now more than for 30 years. It is a really great tool and it is used by the FDA by so-called bio vivo application to reduce the unnecessary additional in vivo studies for bioavailability and bio equivalence. So overall it is a regulatory tool which is really good, which is really great. But what it is doesn't do is basically giving formulation scientists to to support what they maybe would need sometimes and this is where the overall gap is and how can we close this gap. We can close this gap with the Developability classification system. So short the DCS and the DCS is based on the same framework like the Biopharmaceutical classification system, but it has three critical changes which I will talk about today. You can see that here there is the predicted human permeability and also the dose solubility ratio. This is really important and this is really good. But how and where are now the differences between the BCS and the DCS? First of all the DCS is based on fossil media. So first difference BCS is aqueous buffer systems. The DCS is fossil media fossil stands for fasted state in simulated intestinal fluid. So it gives you a really reliable picture what is taking place in the body and due to this more reliable picture what is taking place in the body, we can shift from 250 to 500 the dose solubility ratio and this is something which is good and the more conservativity is also totally fine. So basically the biopharmaceutical classification system is less is more conservative than the developability classification system. So in the DCS it is easier to be categorized as DCS one and three molecule which is totally fine due to this more accurate picture what you have from the body. Then lastly we come to the most critical change and that would be the subdivision of the Class 2 and the division by the SLAT line, the solubility, solubility limited, absorbable dose line. We have those molecules which fall into the framework of dissolution rate limited molecules which you can see here as DCS 2A molecules and we have the two and QM true fundamental difficulty of silly solubility of the DCS to be molecule. And with this slide line, it is really important to understand why we need to pinpoint the true and exact reason of your solubility ratio difficulty or of your solubility limited difficulty. Because the dissolution rate molecules can be addressed way easier than the solubility limited molecules and vice versa. You always need to fine tune and understand the formulation approach. How can you now determine the formulation to approach? If you look at this framework, you can see enhancing solubility. First of all, you can tackle the dissolution rate limited compounds with promote dissolution or physical modification. This is something which we are not talking about today. If you want to learn more about that check out our website or you can also get in contact with me and I will tell you more about this. What we will talk today about is solubility limitations and the develop ability classification system approach for DCS to be molecules and enabling formulations thereby solid dispersion technology and solid dispersion technology tackled with hot melt extrusion is a possible point to interact this then also for spray drying and also for drug carrier system. Overall, it is really important to fine tune dependent on the DCS class your formulation strategy. With this we come to the second agenda point, solid dispersion technologies and solubility enhancement with Poly vanna alcohol. How does it help us now? So if you look at solid dispersion technology, you can see that here is the crystalline solid form. The crystal in solid form is thermodynamically a really stable form. The individual drug molecules which you can see here in pink, they are held together with crystal lattice energy. And this crystal lattice energy is something which is really helpful from point of view of stability but not if you think about solubility enhancement. So first of all you need to break up the the the bonding so the crystal lattice and this can be done within the body within the dissolve dissolution process. If you think about that then you have individual drug molecules, so the amorphous solid-state. The amorphous solid-state is something which tends to re crystallize and this is something what you don't want to have because the amorphous solid-state basically helps the API to go faster in solution and then just the salvation energy is needed. So it comes down to the physical chemical nature of the overall API how fast it goes in solution. So amorphous solid-state already mentioned it's tends to re crystallize, so it is not stable and how can we stabilize this. Now you can see here that we can prevent a re crystallization with a spray drying process, with a hot melt extrusion process or with drug carrier systems. All of those three options are really great to leverage the overall solubility enhancement process. The most common amorphous formulation are polymeric matrix formulation and amorphous solid dispersions with a polymeric matrix. How can we produce this? On the left hand side? You can see that an API and the polymer can either go by the higher route. By this dissolving in a solvent then doing a spray drying process then you achieve the STD and overall you achieve an amorphous solid dispersion which you can see here on the right hand side. So you have individual drug molecules within the amorphous state and those are actually embedded in a polymeric matrix. Another way would be if you look on the left hand side again about API polymer, you mix and melt everything in HME equipment, so hot melt extrusion equipment and then you also achieve an amorphous solid dispersion. Today we will focus on spray drying, so the upper part of this course and why is this important? It is really important to have the goal in mind and the goal would be a homogeneously dispersed drug in a polymeric matrix, so embedded in this matrix, so Poly vinyl alcohol to have this API embedded in the amorphous solid form. Overall Poly vinyl alcohol is a synthetic and chemically defined polymer and it is produced your problemization step of Poly acetate which you can see on the left hand side and this is then polymerized to Poly vinyl alcohol. So you have subsequently partial hydrolysis grades and units. So on the upper lower part you can see we have hydrophilic molecules which are actually the hydroxy groups and we have hydrophobic groups which are the acetate groups. And depending how many of the carbons you hydrolyze you, you define tune the amphiphilic nature of this Poly venal alcohol. Why is this important and how can this help us now? Overall the synthetic and chemically defined polymer gives a really good batch to batch consistency. Overall Poly venal alcohol had been used for decades. It is multi compendial excipient with a grass status and it is really safe to use in the pharma industry. With this being said, you have a good consistency in quality of this excipient and this supports the quality by design and this helps you in the end to minimize the risks in development and manufacturing processes. Talking about Poly venal alcohol, we have a 2 figure nomenclature which you can see here on the right hand side. So normally you see Poly venal alcohol followed by two digit code first of all. So in this case the four stands for the viscosity of a 4% solution at 20°C And the second number, and this is really important for fine tuning and optimization processes, you see here an 88 and this stands for the degree of hydrolysis. So if you come back to the left hand side you can see how many of the carbons are hydrolyzed, so how many hydroxy groups you actually do have and how hydrophilic your overall polymer is. So the second number describes the hydrophilicity of that coming to partech MXP polymer for spray drying. So Poly venal alcohol which can be used for different processes and here for spray drying What are the benefits of partech MXP. So of Poly venal alcohol you can enhance solubility and you can achieve hydraulic loadings. With an amorphous solid dispersions you can have stable amorphous solid dispersions. You have an unfulfilling nature. This is something already mentioned and depending on the Poly, vinyl, alcohol, alcohol grade. This is really great and can be optimized ideally to your needs. It is applicable for a broad range of APIs. Then second last, you can modify really the dissolution kinetics. So depending on which excipients you add to your formulation blend, this actually gives a good modification process and you can really modify the dissolution kinetics on that end and it is optimized to its hydrolyzers grade and this is something I already mentioned. How is it now optimized? If you look at Partec MXP 488, Partec MXP 488 and MXP, what does it stand for and where does it come into place? If you think about Partec, Partec stands for particle technology, so particle engineering for a specific purpose. Partake MXP was designed for the purpose of hot melt extrusion, so optimized within the particle size distribution for hot melt extrusion. And what you can see how the name implies melt extrusion, Poly vinyl alcohol. You might now have the question how does it help me within the spray drying process. That is no harm that the particle size distribution is optimized for the HME process. But of course Poly vinyl alcohol can be also used for spray drying processes and how does it help me now? Overall, if you look at the specifics of Partec MXP 488, you have a good thermal stable polymer. So you have and you can achieve a really broad range of APIs and this is really really beneficial specifically for different approaches which you want to do. Secondly, if you think about Partech MXP 382, this has improved hydrophobic interactions and the 82 is something which is really important. So 18% of hydrophobic units and the improved hydrophobic interactions give you a good prolongation of super saturation and also a really good precipitation inhibition, which comes to a really great performance in the variant optimized hydrolysis degree. This is something what I already mentioned before, but I want to show you in an example how that helps you. If you think about the drug polymer interactions and optimized hydrophobicity, hydrophobicity is something which you want to have to stabilize the API in the amorphous form. So on the right hand side you can see Partik MXP 38282 again is hydrophilic units. This hydrophilic units translate then in 18% of hydrophobic units, so. 18% of acetate groups, those 18% of acetate groups are really good from an interaction point of view from drug to polymer with hydrophilic units of 82%. You also might ask the question specifically with an amphithilic nature of the molecule. You might have the question what about the hydroscopicity of the overall polymer. On the left hand side you can see the dynamic vapor absorption and thereby you can see the desorption and sorption of the overall Poly vinyl alcohol grades. And in this specific case case of Partick MXP 382 and a good desorption and sorption process takes place. So it can take up water, but it also can release water really well and this throughout 0 until 100% relative humidity. So the balance of hydrophilic and hydrophobic groups in Partech MXP 382 ensures optimal stability and precipitation inhibition for perfect performance. So you have one polymer which is really a high performer. I already mentioned this in the beginning. This is suitable for multiple technologies. It can be used for hot melt extrusion and this is how we optimize the particle size distribution to it. Then the achieved amorphous solid dispersion which you can see here on the right hand side. After the HME equipment can be produced into a powder and then put in a tablet. You can also palletize the amorphous solid dispersion. You can also achieve ODFS out of that, so oral dispersible films. Or you can also do direct shape tablets, so really versatile within the space of hot melt extrusion. Additionally extrusion based systems. So 3D printing is really suitable to to the optimized particle size distribution as well. But we optimized of course also the properties of the fiscal of the polymer and this where it comes into play for spray drying. So it is really suitable also for the spray drying process and this is something what we will talk and focus about today. So Amalfa solid dispersion and the advantages of spray dried dispersions, you can enhance the solubility and bioavailability, you can have low API amounts. So this is really where the benefit comes into play of of spray drying. If you have low API amounts this is the option you should go to and not go for HME equipments or something like that because the API amounts needed for spray drying are way lower if you have a heat sensitive API. Also spray drying processes something which is really beneficial if you think about upscaling and high throughput. Since it is in place for decades. There's a lot of knowledge from formulation scientists how to upscale really well and also about high throughput performance. Then it is a continuous technology. And last but not least, you can fine tune the particles really well to your needs after the spray drying process or how you fine tune the spray drying process. How does the spray drying process look like? So you come from a liquid to an amorphous solids in just milliseconds. This is divided in three sections. First of all we have the liquid feed and the liquid feed can be either done by A2 fluid nozzle, so you have a single solvent where you have polymer and API mixed into each other, or it can be fed into the whole system with polymer and API in individual individual suitable solvents. So A3 fluid nozzle. Then the liquid feed is coming to a drying chamber. So you have droplets containing the API and the polymer on there. They form at the tip of the nozzle, smart tiny itty bitty droplets and they evaporate in just milliseconds through a gas stream and then an amorphous solid dispersion is produced. So basically you have your API, you have your polymer and the ASD is produced here in just milliseconds and this is then moved into the collection vessel via cyclone and there you can have your final product, the amorphous solid dispersion. Last slide from my end Poly vinyl alcohol for the overall spray drying process. If you think about the spray drying process, viscosity is really important and the viscosity related behaviour is needed and needs to be ensured for a processing range and a good high drug loading capacity. So if you look here at the framework of viscosity into the concentration of the polymer, this is something which we looked into. So if you look in pink and turquoise you can see here partake MXP one time MXP 382 and MXP 488 and we have the concentration from zero to 15% polymer and the viscosity of the overall solution in yellow and in green. We can see other polymers which are used and what you can see here is basically that all polymers increased with increased concentration, so the viscosity increases with increasing concentration. What pink and turquoise apartic MXP do they increase not as much as yellow and green, specifically around 5 and 10% concentration inside the solution. You can see that the viscosity increases drastically at different concentrations. So on the right hand side you can see SEM images and the SEMSEM images show how partake MXP 382 actually has looks like after it is manufactured with 15% in the solution. So you have really good nice homogeneously morphology of the of the particles which are actually really good for further processes for flow ability and other aspects. On the right hand side you can see HPMCAS which is one of the gold standards which can be used for spray during processes as well. And there you can see that filaments are generated. Those filaments don't give you a good flow ability. This can maybe lead to a bad performance. Compressibility, it's also not not that great after that. So overall the morphology is something which is critical and which is not as ideal. This being said, for the introduction from spray drying over amorphous solid dispersions and how you can overall do the process With this, I first of all hand over to Naima for a poll question and then to Lena. Thank you, Marcus. Coming to our first poll question, do you use a three fluid nozzle for the spray drying process? A We don't have a spray dryer. B. Yes, we only use a three fluid nozzle. C Yes, we also use a three fluid nozzle. Do you know we don't use a three fluid nozzle or EI have never heard about a three fluid nozzle before And we really appreciate all your answers. Looking forward to your participation on this first pulp question we have. Yeah, I give you a couple of more time to choose your answers before we move on to the next slides and have a look at the results of this poll question. Thank you very much for your participation. This is really interesting to see. And with this, I pass on to Lena, who continues with the presentation. Thank you Naima and thank you Marcus for this great introduction into spray drying with Poly vinyl alcohol. So now we want to dive a bit deeper and show you how spray drying with Poly vinyl alcohol enabled solubility enhancement of poorly soluble small molecules as well as poorly soluble novel modalities such as protects. Here you can see the dissolution behavior of indomethacin. It's a model drug with a low solubility in the gastric environment. In the X-ray powder diffract grams you can see on the right the NEAT API is shown as well as sprayed red dispersions with 30% drug load with different polymers such as two of our Poly vinyl alcohols 382 and 488 as well as HPMCASPVP and a grafted copolymer. The need API shown in pink is crystalline based on the crystalline peaks, whereas the St. DS, the sprayed right dispersions are all amorphous for all of the polymers with the exception of PV PK30. On the left you can see the dissolution of the sprayed right dispersions and the NEED API in simulated gastric fluid and almost no dissolution of the need indomethacin is shown. Thus almost no API would be solubilized for absorption in the body. However, by spray drying, especially with the Pvas in yellow and blue, you can see that here we have a strong solubility enhancement effect and we see a very fast onset in the dissolution and a long lasting stabilization of the solubalized material by the polymers. Especially the PVA 382 displays strong spring and parachute effect. This is what is aimed for in amorphous solid dispersions and we see a high dissolution enhancement compared to the other polymers. Here is shown the dissolution behaviour of ketoconazole, another model drag with low solubility, however here mainly in the intestinal environment. Again the crystallinity and the dissolution is compared between the NEAT API and the spray dry dispersion with 30% drug load. Again we use here different polymers for the spray drying process. In the X-ray diffractrocam you can see again that the API is a crystalline material whereas the spray drying led to amorphization for all of the spray dry dispersions with the exception of PV PK30 Again and on the left you can see the dissolution now in fasted state simulated intestinal fluid and again we see a strong improvement of the solubility by spray drying. Again, we have this fast onset for all the polymers and the stabilization of the Super saturated state. The dissolution enhancement is strongly seen for the PDAs as well as the grafted Co polymer and mostly pronounced in HPMCAS. Thus, it looks like that HPMCAS leads to the strongest dissolution enhancement effect here in the intestinal pH. However, when we now look closer into what is really happening with it, the drug in the body and we mimic the transition from gastric to the intestinal environment by doing APA shift pH shift from PH1 to pH 6.8. We see that in the acidic medium only PVA leads to an improved solubility of the drug and HPMCAS leads to a lower dissolution as the API on its own. So after the shift to pH 6.8 Q, we see that only the PVA 382 leads to crystallization inhibition which is not shown after pH shift which with HPMCAS. And should be noted that the PVA led to similar dissolution enhancement in the festive we've seen before as also here in the pH shift experiments. So now that we've seen how PVA enabled the solubility enhancement of model drugs ketoconazole and indomethacin, we also had a closer look into marketed drugs such as ritonavir. And to test the amorphous stability, high drug loadings from 40 to 70% ritonavir were sprayed right with PVA 382. As all sprayed right dispersions are fully amorphous, in the X-rayed fractogram we see a high amorphous stability and due to the low viscosity of the Pvas we are able to load high drug loadings of up to 70%. Here in the spray rat dispersions you can see the dissolution behaviour of Ritonavia in spray rat dispersions ranging from 30 up to 70% drug load in fasted state simulated intestinal fluid and by spray drying with PVA at all drug loads we've seen an improved dissolution profile compared to the crystalline drug itself. The highest dissolution enhancement here is seen at 40% drug load which is when we compare it to marketed drug formulations acquired high drug load and we've seen that with higher drug loads we have a slight decrease in the in the enhancement of the dissolution. However, we still see an enhancement in dissolution and see that it's possible to produce sprayed rat dispersions with up to 60 or 70% drug load. And that is very impressive. A comparison between the dissolution and simulated intestinal fluid of the API market to drug formulation of Ritonavia and a sprayed rat dispersion with the Poly vinyl alcohol using all the same drug amount demonstrated that the spray dried dispersions can outperform the marketed drug in the aspect of solubility as we see very fast onset for both the spray dried dispersion as well as the marketed formulation. However, we only see in the spray dried dispersion a prolongation and long term stabilization of the solubility of the ritonavir in fasive and this is due to the spray drying process. So we now have looked only into ritonavir with PVA 382. But here you can see the comparison of the braid rat dispersions with 30% of ritonavir and different polymers. So the X-ray diffractograms confirms that the amorphous embedding is also possible for ritonavir with PVA 488HP MCASPVP or also the graphic copolymer. However, in the dissolution profiles, we see a very strong dissolution enhancement of ritonavir in fasive, in the spray dried dispersions with the Pbas in blue and in yellow, but also seen for the HPMCAS. And although we have the highest solution enhancement here for the HPMCAS, we have other aspects in the manufacturing that need to be considered such as the process yield. And especially when formulating APIs where only low amounts are available or that are very cost intensive. We here see that with HPMCAS only 1% of process yield is achieved after spray drying with HPMCAS. However, after using Pvas we have a yield of 404554 and 28% and we have seen in the beginning that up to 70% drag load where possible in PVA 382. But here we can see that amorphous embedding of high drug loads would also be possible in other polymers. However, when we compare now the dissolution of these high drug loaded sprayed red dispersions, we see here now that in contrast to the 30% drug load we see the strongest dissolution enhancement with spray drying was now seen for the PVA 488 and 382. And thus we see that at high drug loadings PVA leads to superior dissolution enhancement compared to the other polymers. And now that we've seen the benefits of spray drying with Poly vinyl alcohol for poorly soluble small molecules, we could also investigate how novel modalities could benefit from spray drying with Poly vinyl alcohol. So one topic of novel modalities are Protex and Protex are currently a very hot topic as they hold the potential to target currently undruggable diseases. The Protex is short for proteolysis targeting chimeras and they are heterobifunctional molecules consisting of three different regions. First of all, the ligand that binds onto the protein of interest that shall be degraded. Then in the second part is the ligand for the E3 ligase which activates the proteosomal degradation of the protein of interest and they are both connected with a linker region. And the interesting part is that the ligand for the protein of interest does not have to bind in the active centre, but can bind anywhere at the protein of interest. Because the E3 ligase ligand leads the E3 ligase in close proximity of the protein which then leads to ubiquitination of their protein and subsequently to degradation of the protein. And therefore protechs have the potential to address undruggable targets in oncology, immunology and neurodegenerative diseases. And in addition, after a protein is degraded, the protech is then recycled and can target another protein. Thus only very low concentrations are needed for them to be effective. But due to the hetero bifunctionality, they have a molecular size around 502,500 Daltons and thus they are on the verge between small and large molecules. And this often leads to quite unfavorable properties such as low solubility or low permeability. And therefore technologies and excipients are needed to enable the oral delivery by enhancing solubility or permeability and for solubility enhancement. Here spray drying with Poly vinyl alcohol can be applied. So the first Protag I want to show you includes the Protag AVINOS 110 and this compound is a proteolysis targeting chimera addressing the degradation of the androgen receptor protein And this is used in castration resistant prostate cancer and is currently in clinical phase study one and two. And this compound was chosen as a model protect for us as it is an orally bioavailable candidate already in clinical testing. However, it still displays a very low solubility in water. The solubility enhancement methods can be well investigated. With this compound and by enhancing the solubility via spray drying with Poly vinyl alcohol, the oral bioavailability could be further enhanced and the overall drug amount needed in the truck product could be reduced for the patients. Avenas 110 was sprayed right with 30% drug load in PVA 382 and compared to the need crystalline material as well as a physical mixture of PVA and the pro tech in the X-rated fractograms it can be seen. The spray dyeing led to successful amorphous embedding of the compound and this amorphization is still stable after four weeks when stored at 5°C but also at accelerated conditions of 25°C and 6060% relative humidity. On the left you can see the dissolution and phosphate buffer pH 6.8. We can see here that the knit Havanas compound shows no to limited dissolution in the media. However the physical mixture with 30% drug load already see here slightly enhanced the solution which shows that already only the presence of Poly vinyl alcohol enables the dissolution enhancement. But the strongest effect and the strongest dissolution enhancement is seen in the spray dry dispersion with Poly vinyl alcohol. Here we see again a very fast onset within the first few minutes and then a very stable parachute effect by the PVA, which is also seen after storage of four weeks at 5°C, but also the accelerated conditions. The behaviour of the sprayed rat dispersion was further analyzed in by irrelevant media mimicking the GI tract environment. So the samples were given into 37° WORM simulated gastric fluid and then transferred over a peristaltic pump into fasted state simulated intestinal fluid. Thus we're mimicking the transport from the gastric into the intestinal environment and by that we can investigate how the material or the formulation would behave in the transport from the gastric to the intestinal medium. And what we see here is that in accordance to the phosphate buffer results we saw before, we see again a low solubility for the knee pro tag, slightly enhanced solubility for the mixture of PVA with the pro tag, but a strong solubility enhancement with spring and parachute effect for the sprayed red dispersion with PVA 382. That's solubility enhancement by production of amorphous solid dispersions is often based on the stabilization of the energetically higher amorphous state of a crystalline material in a polymer matrix, and this is what Marcus has explained in the beginning. However, opposed to the crystalline protech I just showed in the few slides before, many of the currently developed protags already display an amorphous solid-state initially. Thus another aspect here was to investigate if stabilizing an already and nearly amorphous protag in the polymeric matrix by spray drying with PVA would nevertheless lead to solubility enhancement of this poorly soluble protect. Therefore Zeldec 51 was used as a second protect. Now Zeldec 51 is a protect that is synthesized by the two dumpschat to degrade the FK five O 6 binding protein 51 and this is an essential regulator in the cuckoo corticuid receptor and is therefore believed to highly contribute to stress related depression, chronic pain or obesity. And Zelec 51 here was used as model compound due to its initial amorphous state as you can see in the X-ray diffractograms and its low aqueous solubility as you can see in the dissolution profile in phosphate buffer and pink. And after spray drying with 30% drug load in PVA 382 we see that we get an amorphous solid dispersion. We still have an amorphous material then after that, but when we look into the dissolution behaviour we can see that spray drying led to strongly increased solubility. Again, we again have a very fast onset and a very stable parachute effect of the PVA and this is seen also after one month of storage. And by that we could also show that spray drying with Poly vinyl alcohol would also lead to strong solubility enhancement even with already amorphous protects. And in addition, it was carefully tested if the spray drying process with PVA could negatively impact the activity or the binding activities of the Protect. So western bloods were made and it was shown that degradation of the protein of interest after 24 hours was similar for the neat Zeldec 51 protect or the spray dried formulation. And further the binding of the protect onto the E3 ligase was tested. And here we all could also show that this is negative is not negatively impacted by physical mixing or the spray drying process with PVA. And thus we could see that our spray drying process does not has any negative impact on the activity and degradation ability of the protag. And before now we come to our summary and conclusion, we already have a last poll question for you. Yeah. Thank you, Lena. And our second and last poll question is, is your group working on oral delivery of molecules smaller than 500,000 AES B? Yes, and we would like to learn more C not at the moment, but will be in the future. And D no, Yeah, we can see that there are still answers submitted. So we give it a bit more time. So everyone who wants to reply has a chance to do so. And also coming back to the question, this is of course higher than 500 Dalton. Yeah, answers are coming slowly to an end, so we can move on and have a look at the replies. Thank you so much. That looks very interesting. And with this I give back to Lena. Thank you, Naima. So today we have heard in detail how we can tackle solubility issues with spray drying with Poly vinyl alcohol. Let's summarize that a bit. So we've learned today that spray drying with Poly vinyl alcohol can overcome solubility issues and it can be applied very flexibly for broad range of molecules such as small molecules as well as novel modalities and larger molecules such as protects, but also different processes such as spray drying but also hot melt extrusion. For example, Patek MXP 382 was especially designed to be used in prod concentration ranges due to its low viscosity and it is suitable for Hydra clothing, especially in spray drying. We've seen strong solubility enhancement as well as a long stability of these amorphous salt dispersants created for poorly soluble small molecules but also for novel modalities such as Protax. And due to the improved hydrophobic integrations in the Poly vinyl alcohol, we have excellent precipitation inhibition properties and a strong parachute effect. Further. Our Pvas are high quality milk materials for pharmaceutical applications and thus the improv dossiers are available. And with that, we want to conclude and thank you very much for joining us today. Thank you, Lena and Marcus for this great presentation. Now it is time to answer a few questions that have come in from our audience. But before we do, I would like to remind you that it is not too late to send us your questions now using the Q&A widget. This also applied to on demand viewers. We will try to get through all of them, but if we 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 is available for viewing. Now back to Lena and Marcos, who will start to answering questions that have come in. Thank you, Naima. So let's dive right into the questions and I think it's the first question here we have. PVA is typically difficult to use for spray drying applications due to its lowest solubility in organic solvents. Do your new grades of PVA overcome this issue or have you also assessed Hotmail extrusion as an alternative method of ASD preparation? Marcus, do you want to answer that one? Yeah, sure. So if you think about Poly venal alcohol and specifically our two grades of Poly venal alcohol, we actually designed this specifically for the HME space and for the HME space, it's specifically important to optimize the particle size distribution for spray drying. The particle size distribution does not matter as much, but it's also nice to have. But for our Hmes this is really critical and an important so basically. Both partec. MXP are designed for the HME space, but Poly vinyl alcohol can be also additionally used for spray drying if you think about the MXP 488 and about the thermal. Stability which comes with it. This is actually. Really beneficial for HME and high melting point API but it can be also be used for for spray drying manners if you specifically think about the Partick MXP 382 and with this prolongation of the Super saturation and also the stabilization aspects within the amorphous solid dispersion that actually. Helps a lot. During the spray drying process as well and also the higher organic solvent solubility also helps a lot and therefore if you have to choose between those two, I would usually go with the MXP 382 first. If you think about spray drawing, I hope that answers that question. Let me double check what other questions we have. Maybe that one is for you Lena. What is the maximum concentration allowed for Poly vinyl alcohol within spray drying? Yeah, sure. So as Marcus has shown, maybe we can go to that slide before. We have seen that the Poly vinyl alcohol has a special advantage, which is that the change in the viscosity of the spray drying solution does not change a lot over the polymer concentrations. So maybe we can go back to that slide that Marcus has shown. Hope you can see that. So here we can see again that the advantage was that even at high polymer concentrations, the Poly vinyl alcohol viscosity of the solution did not change drastically and did not increase drastically compared to other polymers. And therefore we have the option to to load quite high polymer loadings in our solution. For example, here we see that 15% is absolutely no issue. We can definitely use 15% of polymer here in the concentration and we've also seen that 20% is possible for placebo trials. However, here I would be a bit careful, especially when using an API. Here we have the risk of of nozzle clogging and therefore I would recommend that the highest concentration is around 15% of the polymer which is still comparably quite high. So I hope that answers that. And as another question here we have, could you share successful commercial cases of PVA in hot meal extrusion and spray dry dispersion formulations? Do you want to go with that? Yes, actually was the last webinar in January we had a really quite similar question. So happy to also answer that since it's apparently a really burning question for you all. So if you think about Poly vinyl alcohol that been had been classically be used for coating material and for coating material, Poly vinyl alcohol have been used for decades. If you think about PVA within the manners of amorphous solid dispersions, this is a rather new and innovative technique for or. The technique is rather medium old. But if you think about Poly vinyl alcohol, this is rather an innovative polymer to use for spray drying and also for HME. SO thereby it really comes down to that innovation takes time. So commercially to my knowledge there is no commercial available drug formulation. What actually has Poly vinyl alcohol was in a more of a solid dispersion incorporated in that I know from the people I interact with that we and they actually depending on the regions what we are talking about they actually have it in pre formulation concepts also in. Proof. Of concept status also in bioequivalent studies and different formulation development stages and really dependent on the region on the customer, we get quite good feedback and also that they are looking for scale UPS that they are looking into filing the drug formulation if all those potential aspects work out. So we get really good feedback on that. So I hope you can give it a try for Poly vinyl alcohol for either HME or like we already talked about for spray drying for today. Looking into the questions, I would do it alternative wise and looking by the a lot of questions. Thank you very much that all those came in but I would give it to Lena and that would be how does Poly vinyl alcohol relate to other known polymers used in spray drawing to? Improve overall the bioavailability. Yeah, that is a good question. Thanks. So I think. We've. Seen that the PDA compared to other polymers can be used for a broad range of different APIs as we've seen for the poorly soluble BCS class 2A and 2B. But also as we've shown for protects, which is of course will be an advantage of course as this is a growing field. And we've also seen that compared to other polymers such as HPMCAS for example, we have seen that that the PDA has a quite good process yield in the end. So this is an important factor especially when using APIs or drugs where you can only achieve low drug amounts overall or where the API is very cost intensive. So here we have a good process yield compared to other polymers and we've also seen that we're with the PVA are quite independent of the dissolution media we, we we're using. So we've seen that the solubility enhancement effect was similar in all the solution media such as the festive or phosphate buffer for example, and also in the pH shift we've we've done. So this is definitely an advantage compared to other polymers we've seen. And also I think it's important to note here that the PVA is suitable not only for the spray drying but also for other processes as Marcus has explained such as Hotmail extrusion, which is also quite beneficial for solubility enhancement to be able to use the same polymer in different technologies. I hope that answers that. Maybe. Let's come to our last question and Marcus, I think this one's for you. Have you investigated solubility enhancement of further protects or any other larger molecules by spray drying with Poly vinyl alcohol? So I think you could also answer that, but since you're already handsome handed over to me. So if you think about protects, if you think about larger molecules, we investigated multiple different protects, so also coming from university and also different commercially accessible protects. To my knowledge, I think we used four different ones which are either in the amorphous protect form or in the crystalline protect form and those we use. For. Solubility enhancement. And this had been done by spray drawing. HME is something we didn't look into, but due to the temperature, HME is also not the technology what we would go. For and what we also tried is a solvent film casting methods also with three I believe different protects and this was also done. Really, really well. Also within our application lab, they showed really good manners on the solubility enhancement effect and also on the stabilization in those thin films. So overall, we tried a lot of different protects and we also want to look into other novel modalities and also some other molecule entities which are higher than 500 Dalton. Yeah. With that, I hand it over to Naima. Thank you. Thank you very much for all the questions. If you have additional questions, please feel free to can contact our presenters directly. To register for future webinars or to access our archive webinar library, please visit our website. You can also register for our previous On Demand webinar on Poly Vinyl Alcohol One Polymer Multiple Solutions for Oral Solid Dosages by clicking on the register below. I would like to thank Lena and Marcos for today's presentation and thank you to our audience for joining us. Have a great day. _1731460735672

     

   

       

 

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