Hi everyone and welcome. My name is Saskia Keita and I will serve as your moderator today. Thank you for joining us for today's webinar strategies and enabling technologies for an for enhancing API servability. As your moderator, it is my role to ensure that we make the most of your time with us. I am here today with Thomas Breen and Marcus Lupta. Thomas is a strategic marketing manager and responsible for a broad portfolio of excipients for liquid formulation, and he has more than six years experience in the farm and biopharma industry with different positions in the field of pharmaceutical formulation. Thomas holds a PhD in biology from the Technical University of Munich and in parallel to his PhD and industry roles, Thomas acquired a bachelor's degree in economics with focus on marketing. Marcus holds a pH. D in bio and chemistry from the Technical University of Darmstadt and is by academical education a biomolecular engineer. He joined the company six years ago and is responsible for the strategic development and positioning of an exhibit portfolio for oral solid dosage form applications with the focus on identifying engineered particles. To enhance solubility and bioavailability, 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 presentations, topics, or anything that stands out. All the widgets are resizable, movable, so feel free to move them around to get the most out of your desktop space. You can expand your slide area or maximize it to full screen by clicking on the arrows in the top right corner. 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And lastly, attendees who wish to receive a webinar certification will need to fulfill the criteria, the criteria of minimum 45 minutes of fume time and completing 3 poor questions within the duration of this webinar. So that's it from my side and it's my pleasure to turn things over to Thomas and Marcus. Saskia, thank you very much for this nice and kind introduction. My name is Marcus and I will start with the first part of the presentation and then we'll hand over to Thomas. So a warm welcome to all of you. Good morning, good afternoon or good evening wherever you are on the globe. But with this being said, let's dive into the today's topic, which is called strategies and enabling technologies for enhancing API solubility. We will cover multiple topics today. Here you see the agenda. First of all, we will introduce you the DEVELOPABILITY classification system, which is actually based on the biopharmaceutical classification system and actually. Works for formulation scientists really suitable and really well. Then secondly, we will talk about strategies to enhance the solubility of DCS class 28 molecules. In the third section, we will cover strategies for the DCS class 2B section. And last but not least, we will wrap up with the summary. If you have not heard about the DEVELOPABILITY classification system before, this is no pity and I hope by the end of today's presentation. You will know how to actually work around with this strategy approach if you look at drug exposure and how you actually come to understand API and how APIs are within the systemic circulation. You need to understand the exposure of drugs in the bloodstream and it is essential for the physiological effect. Therefore you need to. Think about the latme. You need to speed up the liberation, you need to increase the absorption, you need to influence the distribution, you need to reduce the metabolism and postpone the elimination. By this it is really important to think about increasing the absorption. By increasing the absorption you can think about solubility, permeability and also other aspects. For solubility, a chemical approach is really essential. For physical approach there's also a way to enhance the solubility. Then additionally for permeability you need to think about the administration routes, permeation enhancers and also API lipophylicity overall. If you think about absorption of an API from the intestinal tract to systemic circulation, it is really important to have solubility and permeability in mind. With this being said, we dive into solubility of APIs in the development pipeline. If you look at poor soluble molecules, those are actually becoming more and more prevalent. By looking at the left hand side you can see a breakdown. Of the biopharmaceutical classification system in permeability and solubility, within class one and three you can see the molecules which actually have really good solubility. And with the class two and four you can see the APIs which actually suffer from poor solubility by looking at the right hand side and by looking at the pie chart on the the left pie chart on the right hand side, you can see the distribution of marketed drug substances from today. And with 10% and roughly 30 to 40% within Class 4 and Class 2, you can see that overall about 40% of the API suffer from poor solubility. By looking on the right hand side for the distribution of pipeline drug substances in the future, you can see that about 10 to 20% will be classified in the category four and about 60 to 70% will be classified as. Molecules within the Class 2, so overall 7080 or even up to 90% of the APIs will suffer from poor solubility. So poor solubility is on the rise and can lead to low and variable absorption, which is a pity in the end. So what is the BCS and what it is used for? The BCS is based on solubility and permeability and is originated in the 1990s for an in vitro to in vivo performance essay. Thereby it is adopted by regulatory authority. So it was used by the FDA by so-called biowaver application to reduce unnecessary additional in vivo studies for bioavailability and bioequivalence. With this being said. You need to just have in mind that it's a regulatory tool, which is really, really helpful by filing a drug product in the very end, but maybe not for formulation development. So for formulation scientists, actually the developability classification system, which is in place now for about 12 to 13 years is way more accurate tool to work for formulation enhancement. Thereby the Dcs is based on the BCS and can be used to optimize formulations of poorly soluble molecules. Let me walk you through this diagram. You can see the predicted permeation in humans and you can also see the dose solubility ratio. And the dose solubility ratio goes from left to right from the molecules which are actually having high permeability and solubility to the molecules which are actually having low solubility. So the Dcs is based on the BCS but has slightly differences the BCS. Uses aqueous buffer systems to understand the solubility. The DCS uses facet media. Facet stands for fasted state simulated intestinal fluid and with this intestinal fluid simulation you understand a really accurate picture what is taking place in the body while having solubility in place due to this. By relevant media and this accurate picture, we can be less conservative by our framework. So we can shift the dose solubility ratio from 250 to 500 so it is easier to be classified as a soluble molecule within the DCS than in the BCS system. And last but not least, we come to the most critical change. We subdivide the category two in two classes by the Slat line. The slat line is the solubility limited. Absorbable dose line and we categorize the class 2IN molecules which are two a so dissolution rate limited molecules and the class 2B which are solubility limited molecules. It is really important to pinpoint the exact and true reason why you actually suffer from poor solubility because if your API. Actually has poor solubility. It doesn't help to increase the dissolution rate and also vice versa. It is a little bit tricky. The last slide for the DCS is about the general approach. Thereby you can understand how to determine the solubility and also the permeability. The solubility is a thermodynamic solubility equilibrium. Thereby it is described as the maximum saturation concentration and like I mentioned before, it is measured in Fasif media. It is described by the dose solubility ratio which is the minimum amount of solvent which is required to dissolve the maximum amount of API per dose. For the permeability assessment, which actually describes the flux through the cell membrane, you can either do Coco 2 cell monolayer assays or you can use predicted. Software like Gastro Plus to understand the permeability and with both the solubility and permeability you can determine the DCS class which you want to have and therefore you also need to understand the DCS class to A and to B molecules are divided by the solubility limited absorbable dose line. With this being said and with this in place I will hand over to Thomas who will. Guide you through the dissolution rate limitation and also the solubility limitation. Thank you very much Marcos and welcome to the audience. Also from my side, my name is Thomas Wheel and as Marcos already indicated, I would like to deep dive now into increasing dissolution rate of APIs. And here I would like to start with physical modification and in particular particle size reduction. By micronization. So what is micronization all about? So as a general rule of thumb we can say that dissolution rate of a truck particle is related to its surface area and this means the larger the surface area the higher the dissolution rate of a truck. And this means we would aim at having smaller particle sizes as this is in the end increases surface area and also increases dissolution rate. And this is exactly what MICRONIZATION aims at. So it's reducing the particle size and as the name already indicates, to the micrometer range. However, there are of course no generally defined orders so where micronization starts and in which particle size range it takes place. So this also of course very much depends on the exact methods that you are using. The most frequently used methods, however, are mechanical milling. So you can say that this would result in what cost particles and tread milling on the other side, which generally produces more fine particles. So having a closer look at both techniques. So mechanical milling would usually produce particle sizes very roughly in the range of 50 to 75 micrometers and it is also a very established. And let's say quite easy to handle and rather cheap technique. However it involves moving and or rotating parts. And this also means there could be mechanical wear or it is generally mechanical wear involved here. And this could also mean that there is abrasion of machinery parts. So let's say contamination with traces of metals is here therefore possible and therefore one of the. Few downsides of this technique. And also there is limited control of the particle size distribution possible, which means that in the end you often have a rather broader range of particle size. On the other hand, when it comes to check milling here particle size is down to approximately 1 micrometer is possible. So in general we can say much smaller than compared to mechanical milling and. Treadmilling employs pressurized gas which is expanded at usually more than Sonic speed and this is exactly the force that is then utilized to melt down the particles of the API to this small size. The beauty of this technique is that there are no moving parts and this means no or potentially even no mechanical wear, and this also means there is no or very limited contamination risk. When it comes to operation of methods, there is also a higher control of particle size distribution possible. So you would have one narrow size distribution compared to mechanical milling. Another technique in this regard I would like to present to you here is in C2 micronization. And why? Because this is let's say rather new technique which also does not. Require any mechanical equipment so it's different and C2S name already indicates takes place during production of the final API. And here the truck is precipitated and during precipitation those small micronized particles are formed. So how does it work in detail so the truck is precipitated with a non solvent? Then followed by drying. So for poorly water soluble drugs this means that you would solubilize it with an organic solvent and an aqueous solvent is then used as the precipitator. And this precipitator usually also includes stabilizing agents to prevent re aggregation events. And stabilizing agents here in this case are usually different kinds of polymers. So one could use for example polyethylene glycol, Poly, vinyl alcohol, PvP, different celluloses. But those are of course all API dependent and it needs to be evaluated which stabilizer is best suited for your specific API. The upside is that particle size is down to approximately 1 micrometers are possible and also it involves a much tighter particle size distribution. And also the truck amount in the preparation is generally very high. Also there's an additional benefit to it. So as you use stabilizers, the surface of the API is then polymer hydroponized and this further increases the dissolution of the final truck. So if you would like to further go down in particle size, there are also other techniques possible to be used. And here I would also like to go into more detail about the technique of nano milling. So nano milling is also a very well established procedure to enhance the solution and again focusing on strongly increasing the truck surface area by. Decreasing particle size and as the name already indicates so we are talking here going about below 1 micrometer and typical into the 100 nanometer range and milling is here in this case performed using a medium with beads made of ceramics or highly cross link polystyrene. You can also see it on the schematic view on the right hand side. So this is in a schematic way Nado Miller so you would. Put in the crystalline API into the milling chamber and within the milling chamber you have then the milling beads and the API and outcome is in the end a non suspension comprised of water stabilizers and the API. And this non suspension by the way can be converted into diverse dosage forms. So you are not limited here. You can still go with liquid formulation, so for oral. Projectables or aerosols, but also to solid formulations into capsules or tablets. The benefits of nano milling are that it is very well established. There's by the way no chemical modification taking place and as already mentioned, no limitation for the final dosage form. Of course it also comes with some challenges, so there is of course mechanical stress to the API. Re aggregation can occur as well, so for those two points stabilizers are needed. There are very many trucks already marketed and available in Nano mill form. We have trust listed some of those to give you an impression. In the upper table on the left hand side and on the left hand lower side you will find a table with commonly used stabilizers. That are used and also required here to prevent re aggregation events. So those are mainly proloximal, polyethylene glycol, Poly, venule, alcohol and also tween. And with this I would like to hand over to Marcos to provide more insights on promoting the dissolution perfect. Thank you very much, Thomas for giving us insight how to promote the dissolution rate with physical modification, with MICRONIZATION and also with nano milling. Now you can see that we will talk about how to promote the dissolution rate with disintegration first and then we will cover a few more topics on that end as well. So how to accelerate the disintegration? And the promote the dissolution. The disintegrands are really important for the dissolution rate and thereby you can use super Disintegrands or disintegrands. This is really important for oral formulation, dosage forms, for odts, for bucal, for sublingual formulations. So really a broad topic and if you look for disintegrands and their features you need to have good hydration. Capacity, capacity. And with this good hydration capacity, the downfall comes often into play. That would be Hydroscopic hydro cost, hydro cost, cost, hydrophobicity. So basically that material actually draws water really bad. And this is something what you don't want to have. You want to have good hydration capacity, but not in too much detail or significant end. Additionally you also need a good surface structure. With a good surface structure often a compressibility comes into play and also a good compatibility for enabling technologies for the future. And with all those features and also multiple other ones you can have a fast disintegration. Like I already mentioned, there can be disintegrants like monitol or there can be super disintegrants like cross Carmel. Sodium CCS. If you look at a tablet plant, which you can see here, a simple formulation can be withdrawn. So you can add disintegrands. You can add your API and also other excipients in your tablet. If you add then water to your tablet, what actually happens in the gastrointestinal tract? The particle, so the disintegrands actually starts to swell and a disintegration. Takes place, thereby the tablet explodes and the API is ready for being dissolved in the gustrointestinal track. On the next slide I brought you a video where you can actually see how CCS can be used, so I hope you enjoy watching that. After an explosion took place, you can actually really enhance the dissolution rate by using Super Disintegrants or in generally disintegrants. Now shifting gears a little bit and how to promote dissolution. You can promote dissolution by replacing hydrophobic lubricants with hydrophilic lubricants in your tablet blend. So. How can this be done? In there is a multifunctional excipient. What actually can do? Both. You can have a hydrophilic lubricant and you can also additionally promote the dissolution enhancement effect. So therefore polyximer 188, which is actually a block copolymer of polyethylene oxide and polypropylene oxide can be used. It is a functional excipient like I already mentioned, and it can either or it can. Enhance the dissolution rate and can act as a dissolution rate enhancer or has an additional function of acting as a hydrophilic lubricant and can replace hydrophobic lubricants. It is compatible for direct compression for continuous manufacturing. Multiple future perspectives as well and also 3D printing if you look at. Pollock summer 188 or our product partec PLX 188, we recommend to use dissolution enhancers or if you want to use it as a dissolution enhancer between one and 15% and if you want to have it just for lubrication effects we recommend to use between 2 and 5% so you have one excipient. You have multiple functionalities and you can improve the efficacy and unlock future manufacturing capacities for the benefits. So poloximer 188 and how it can act as a hydrophilic lubricant. It is an effective lubricant and achieves even. When combined with brittle deforming fillers, a really good effect. On the left hand side you can see a formulation which has monito as a filler in place and by adding at least 2% of poloximer 188 in your tablet band you can see a really good ejection forces and good contability for direct compression. On the right hand side you can see a formulation which actually has lactose as a filler. Lactose has a downfall to it that if you use magnesium steer rate, which is a hydrophobic lubricant, that lactose is notoriously incompatible with this and you can see that by using polyximero 188 by 1. 2 and 5% you can actually have a good ejection force compatible and we recommend to use at least 2% of POLYXIMER 188 to actually have a good and perfect solution for direct compression and a simple formulation enhancement and a hydrophilic lubricant. Now shifting gears a little bit. By looking at the dissolution enhancement and this is a path forward to promote the dissolution. I already explained to you how Poloxima 188 has multiple functions and one function is to act as a dissolution. Enhancement and dissolution is enhanced. We are increased wetting and micelle formation. If you look at a tablet plant on the right hand side, we added 5% of POLOXIMA 188 to the tablet plant and we have. Phenofibrate phenofibrate is a Dcs to a molecule and therefore it is important to distinguish between DCS class to a molecules and DCS class to B molecules because on the left hand side you can see how phenofibrate acts. If you have crystalline phenofibrate you can see a really really poor dissolution profile by adding 5%. Off poloximer 188 to the tablet blend you can see really good dissolution enhancement effect and this can be done by an easy and fast solution by just adding one extra excipient to your formulation blend. So to enhance the dissolution right and to promote the dissolution can be tackled quite easy if you distinguish that your API is within the Dcs to a category how does your. Poloximer 188 actually do this. If you look at the chemical structure you can see that Poloximer 188 has hydrophobic and hydrophilic parts to it. And those two parts actually bind an API and bind aqueous environment. And with this you can actually see really good that the API is bind to the hydrophobic part and the accurate inverse environment is bind to the hydrophilic parts and. Thereby pollocks my 188, drags the API in contact with the aqueous environment and you enhance the dissolution rate. With this we come now to Saskia and the Paul questions. So we now have our first Paul question and we would like to get your answers here. So which abroad do you typically choose for dissolution enhancement? So you also have more options to choose. So let's give us another few seconds more. So thank you very much for your responses. This looks quite interesting. And yeah, now we come to Thomas, who's yeah, going to present the next. Topic thank you Saskia and I would like to proceed with giving you more insights how to increase sole ability of the drugs. And here I would like to start with chemical modification of the APIs. The first point by the way is not directly a chemical modification but definitely identification and selection of 1. Yes, performing chemical form, and this is in this case the polymorph screening. So what is polymorph screening all about? So polymorphism means in general that trucks can have several crystalline forms, and this is quite often the case. So it is true for more than 50% of all currently market APIs. And polymer screening is by the way mandatory due to safety reasons. So for example regarding thermodynamic stability and also toxicity and therefore is also part of the ICH Q68 guideline. Polymorphs can also be considerably different regarding diverse properties, trust to mention some here, so solability and dissolution rate, but also biological activity. Karmacodynamics and melting points and also different others, so all of them can be very specific to the respective polymorph. Therefore finding out which polymorphs an API has and especially the one with the best characteristics this year of definitely high importance. And also by the way, different polymorphic forms are considered to be different chemical entities by the regulatory bodies. And also this is of course important with for some other topics as well. And here I would like to mention also IP protection. So different polymorphs are here very important when it comes to developing new drugs. Innovators would therefore screen and identify as many polymorphs as possible in order to. Protect the related IP and this of course then prevents generics entering the market with the same molecule. On the other hand if we take the view of a generic company, so they would of course aim at non protected but still of course viable polymorphic forms. And with those unprotected ones they could then therefore enter the markets earlier, so we see already that different polymorphic forms. Can play a crucial role only also when it comes to entering the respective markets and securing these market shares here as well for polymer screening, very often solvents are used as a process chemicals and here the most often ones are also shown in the table below. I won't go through all of them but for example formic acid deal through ether, methanol. Acetic acid and many more so those are very frequently used solvents here for polymer screen. Further techniques for chemical modification are for example soil formation and also others. I would like to start with soil formation here because this is also a technique which is in general very well known and also very well established. And why? Because more than 50% of all currently marketed trucks are installed from, so this is definitely a lot. This also means that this techniques has been employed since several decades already and it's not new. But still, as said, it is one of the still most often used techniques to increase solubility of the final truck product. And how does it work or what is the principle behind? So it aims at ionizing the API with the aid of a counter ion. And for a counter ion usually you would need an asset or a base and this would then lead in positively or negatively charged API and then it is in its solid form, therefore higher solability is achieved. And the important thing here is also that typically during that process proton transfer is taking place, the ratio of assets and basis can be seen in the lower right craft. So those show here all FDA approved small molecule APIs on the market and you see already at the plants that. Well, roughly 13% of those approved small molecule drugs are in acid form and roughly 39% are in their basic form and the rest, so a little bit less than 50% are non salts. So why should one go with salts. So the opportunity here is clearly to. Achieve the optimized solid-state properties of the final truck product. And of course you would aim at having good bioavailability, so let's say highest solubility and also dissolution rate. But beyond that it can also have additional benefits. It can for example result in increased API purity, better physical and chemical stability, manufacturability, particle size. And also flowability, so definitely many parameters that can be positively influenced. If you go with salt, a typical process flow is as follows. So you'll see it here in the middle of the slide. So you would usually start with a product salt screening. So that means identifying which counter ions could be used for your API in due respective dissolution studies to find out if the dissolution has changed. In the intended way with a smaller set or the the top combinations let's say you would then do stability studies, then identify the best combination of your API and counter ion and then in the end do a scale up of the process and of course formulation and pharmax cokinetics. Then still can and have to take place and are usually the last step of development. So taken together, benefits of soil formation is that it is very well established, it is relatively simple, let's say, and also cost effective and it has very high regulatory acceptance. Why? Because more than 50% of all marketed APIs are exactly in soil form. So this is absolutely a standard, let's say, for regulatory bodies. There are of course also some challenges that come along with it. So for example the API needs to be ionizable and this is not the case for all APIs. So this means not all APIs can form salts. Also there can be common ion effects, disproportionation and also increase high cross complicity. And all of these three effects in the end can then lower again solability and this is something that of course is not to be achieved here with this technique. And should be avoided. I said so. More than 50% of all trucks are in soil form. However, to give you some impression and insights here we listed a handful of those here in the upper table also with the respective counter iron to give you a feeling what combinations are out there. Common soil form salt farmers or counter irons are also listed in the table below. These are mainly very well known assets, so fumaric acid, formic acid, citric acid and many more are very commonly used and also broadly applicable to a broad range of different kinds of APIs. Another technique that I would like to present to you today in this regard is corcrest information. And why would you go with core crystal formation? Because it can be an alternative if for example soil formation does not work. So as I already mentioned, so for soil formation the API needs to be ionizable and if it's not, then core crystal formation can definitely be a very beneficial technique to go with. And this technique is by the way relatively new and relatively means. It is known since several decades already, but as you see here also from the craft below, which by the way shows the references for core crystals in the formulas database, you'll see here that the peak is rather in the last five to 10 years. So this means more and more trucks or publications about trucks in core crystal form are coming up. But as you know, there is a lonely time from development to market. So, so far only a handful of drugs have really hit the market already. So we are talking about here less than 10 marketed APIs which are currently in Co crystal form, but those roughly 10 are of course approved by regulatory bodies. So regulatory bodies are well aware of this. Technique and it is possible therefore to go with the core crystal to market. However it is not the the standard by today. So most companies would still start with soil formation and many only look into core crystal formation as alternative if this does not work. But we also recognize that in the in the past so this changed this paradigm so. Co crystal formation is definitely something which more and more comes into focus during truck development. By the way, what is the principle of Co crystal formation? So the API and Co former here interact by different forces and therefore build 1 joint crystal letters and you see it also here in the schematic view on the lower left side. So you have your API, you have your Co crystal former and in the end. This will lead to 1 crystal letters with both both parts inside. Yeah, when it comes to opportunities of core crystals, it's mainly of course the same as soils. So I would not go into detail here. Again, when it comes to a typical process flow, you'll see it again here in the middle of the slide. Usually you would start with core former screening of course. But often this is also done in silico because one would want to find out which is the best core former, but potentially and also as many do not have a 2 prod experience currently with soil with a corpus information. And there are also several in silico tools which could help you and which could very much already narrow down which core formers could be suitable. With those of course there would be a toxic evaluation necessary and with those which are suitable for your API you would then do a product Co crystal screening and afterwards dissolution study and with the top combinations of course stability study and again the scale up of the process for the one combination that you want to go with. And again and that is of course the same As for salt formation formulation and pharmacokinetics are then still taking place. So taken together the benefits of core crystals are clearly that it is an alternative if the API is non ionizable. And also by the way no common ion effect is taking place, notice proportionation effects are taking place or this is very beneficial and also core crystals are less prone to microscopicity. There are of course also some challenges that come along with it. So for example, pro forma selection is quite challenging or can be quite challenging if you lack the necessary experience. As said, however, in silico tools can help the crystallization process control is also challenging and regulatory acceptance can at least be hurdle. And I would want to go into more detail about that also on the following slides. But first of all, there are diverse techniques out there for corpus deformation. We don't have the time today to go into detail here, but to mention just the most important ones. So slurrying and grinding are definitely the probably most often used ones, but there's also solvent. Exploration, sublimation and Hotmail extrusion which can be used for corpus formation. As already mentioned, computational and silico tools for Co former screening are very promising. There are already some services out there, but this is also something which is broadly currently being developed. In the end it definitely can save time and of course also resources if you think about. The API itself. Usually you would only have limited amounts available if you start development and here. If you can narrow down potential core formats by computational tools, this could be definitely of benefit as there are only a few marketed core crystal trucks currently. Some have been listed here in the upper left table. And Common Core crystal formas are listed here in the table below. Some more words on the regulatory implication of core crystals. So as I already mentioned, it is rather new. Therefore also this has some implications from a regulatory perspective. There are some reflections and guidance from both the EMA and the FDA and I would like. To provide some of their statements here on the slide starting with the e-mail. So they brought out a reflection paper on call crystals in 2015 and here they stated that there is no strict borderline between the soil formation in the one end with complete proton transfer and call crystals on the other hand with no proton transfer. Co, crystal and soil share many conceptual similarities and therefore also similar principles for documentation should be applied. So taken together, Co crystals and soils are put here together very closely from a regulatory perspective by the Emma when it comes to the FDA. So they brought out a guidance on Co crystals for the industry in 2018. And they stated something different and they said that core crystals are distinguished from soils because unlike soils the components that coexist in the crystal letters interact non ionically. The core crystal with the pharmaceutically acceptable core pharma can be considered to be a pharmaceutical core crystal and has a regulatory classification similar to that of a polymorph of the API. And this is again very interesting as. They clearly state that soils are distinguished from core crystals and that core crystals are more closely, from a regulatory perspective to be seen as a polymorph. And as a summary, we can state that the reflections on core crystals currently still strongly defer between the FDA and the EMA, and this could potentially also come along with some herders. So if you discuss your combination. Term of Co forma and API or to go with the Co crystal at all with the different regulatory bodies, they could potentially see several things differently. And for the future, it would be beneficial of course to have further alignment here in that space by the way, when it comes to the Co forma itself. So there's also currently very little guidance from both regulatory agencies. And therefore not much material is here which can be stated here in that regard when it comes to chemical modification, I would also like to touch another potential route to go with and this is pro truck formation, so White Pro truck formation. So pro trucks are molecularly modified APIs with. Improved physiochemical characteristics and the important thing about it is that they have very low or even no at all activity until they are converted. And this is usually done at the side of action in vivo. And this means that before they come to the place of action usually they don't have an activity and this also comes with additional benefits as well. In the past by the way, they were often regarded as strategy of last resort. So which means if nothing else works then one tries to have that high effort to form a pro truck to get that solved. But this has very much changed in the last years. So today Pro trucks are quite often used and also the rise opportunities here arise beyond trust increasing solability. By the way, currently approximately 10% of all marketer trucks are pro trucks and this is also currently with increasing trend as well. So having a look at the schematic view here on the lower left side, so there are mainly 2 big routes you can go with a pro truck. So one is the carrier link Pro truck and this one is activated by the removal of the carrier at the side of action. And the other one is bio precursors. And here bio precursors are activated by meta polarization at the site of action. And both routes in the end have several objectives as I already mentioned. So improved solubility can be 1 objective and also improved membrane permeability. But also and this refers to the fact that the. The activity starts at the point of action, so targeted release here is definitely one big benefit and therefore also reduced side effects. Going more into detail about Carrier linked pro trucks, so common carriers are for example different kinds of polymers. One could mention polyethylene glycols, but also proteins and antibodies can be carriers. And linkage of the carrier and the truck is possible by diverse covalent binding type. So for example amides, carbon mites, carbonates and so on. So there are different bindings that you could think of. Just to mention one example of the Carrier link Pro truck, here we chose exosome and this has the indication of multiple myeloma and is a reversible proteasome inhibitor. And this pro truck is hydrolyzed under physiological conditions to its active form and this can be also seen here on the right hand side. So you would start with the Pro Truck Excel Summit side trade and this side trade residue is then at this side of action cleaved or hydrolyzed and the remaining truck is then the active form Excel summit. When it comes to bioprecursor, so as I already mentioned, they do not have carriers or linkers. So the precursor acts as a substrate to enzymatic activation and this activation is usually done by diverse or can be done by diverse chemical modifications, for example reductive or oxidative activation, phosphorylation, decarboxylation and also others. One example here for a bio precursor is causal clear and here it is converted from its inactive to its active form, here also at the site of action by an and somatic activation. So taken together here the benefits of pro trucks. It is a very versatile approach and it also can improve diverse properties, not trust solability but also many others. And it can also be an alternative if other strategies are not feasible. But in any case, due to the high benefits, it is definitely beneficial to take a look at this option. However, the challenge is also that is a very demanding development, so you need the right combination of carrier and your truck of course, and also the cleaved crew. So let's say the carrier that is then cleaved away from the pro truck. Must be safe as well because this is then of course also released at the site of action. And with this we would like to come to our next poll question. Yeah, from your perspective, what are the biggest hurdles when it comes to chemical modification of APIs? As mentioned before, you can select multiple answers, so first would be insufficient knowledge and the different techniques in general. Second, lack of technical process knowledge or identification of suitable processing chemicals, for example coformers. Next, sourcing of processing chemicals in right quality and quantity, regulatory challenges, other or I do not see any hurdles, give us another more seconds. All right, then this looks quite interesting. Thank you very much for your participation in our question and I think we can move on. Thank you very much, saska. And also thank you very much, Thomas, for the last topic. I will finish up the topic of DCS to B molecules with enabling formulations and like you could already see by looking at the base and looking at the dissolution rate limited DCS to a molecules you can. To a physical modification and to promote the dissolution. This works quite easy by going for solubility limited molecules for chemical modification and also for enabling formulations which we will talk about. You see it is a little bit more tricky and you need to put more efforts in it and This is why it is important to distinguish between those two categories. If you think about enabling formulations, you need to understand how. To handle solid-state modification and what solid dispersion technologies are solubility of DCS to be molecules can be enhanced via the amorphous form. By looking at the left hand side you can see the crystalline solid-state. The crystalline solid-state is that individual drug molecules are holed together by lattice interaction and this lattice interaction is really strong thermodynamically. It is a really comfortable state to be in. But it is important to break up the interactions to actually get your individual drug molecules into solutions. So it is a matter of fact how crystal lattice energy needs to be broken up. Then you have individual drug molecules and those individual drug molecules then can go with salvation energy by creating a cavity in solution in solution. So with this. You need to understand and you need to figure out that amorphous solid and amorphous solid dispersion can enhance the solubility due to the fact that individual drug molecules are not hold together with lattice interaction. The one downfall to this is that amorphous solid tends to re crystallize to the crystalline solid-state. So you need to somehow build. Amorphous solid dispersions, and this can be done by putting a matrix around the amorphous solid and the amorphous solid-state can be leveraged to enhance the solubility of DCS to be molecules. Then how can you actually build such a matrix? So the amorphous solid dispersion can be actually built by taking an API and the polymer and the most common amorphous formulations are actually polymeric matrix formulations. You have two ways or multiple ways of building this. Two ways would be you have your API polymer mixture, you dissolve it in a solvent which is suitable for spray drying. You have then a spray dry dispersion and you actually achieve an amorphous solid dispersion on the right hand side. Another way would be that you take your API your polymer. You mix and melt it together via hot melt extrusion processes and you have your amorphous solid dispersion achieved via an HME process. The overall goal is homogeneously dispersed drug in the polymeric matrix. With this we will talk about now solid dispersion technologies and how hot melt extrusion can deal with this. So the advantages of an HME process, if you take an API, a crystalline API, and your matrix polymer, you melt and mix both together as a homogeneously dispersion. In the end, you cool it down and you have your amorphous solid dispersion. What are the advantages of the HME process? You have enhanced solubility and bioavailability. You have overall really stable and high drop loadings of your API in the metrics. You can control your release profile and modify the release kinetics. You can have a continuous effective process for future manufacturing processes. Additionally, what I think is the best and most important part are solvent free manufacturing processes. So. Thinking about sustainability, thinking about environmental friendly processes. It is a solvent free manufacturing process and last but not least it is supported by various dosage forms and it is really flexible in downstreaming. So mix, melt and overall perform with your API in your formulation after covering now the techniques of HME. You need to understand which polymers are actually suitable for the HME process. And there are multiple polymers which can be used. Either they are naturally derived like hpmc or they can be synthetic derived like copovidone or also polyvenal alcohol. Polyvenal alcohol short PVA is really really suitable for the HME process and one may ask a question why it is. The unphophilic molecule, you can see it has hydrophilic parts to it and it also has hydrophobic parts to it. And the combination of both and the unphophilic nature is really crucial and important for its mode of action within an HME process. Overall, polyvana alcohol can achieve stable and high drug loadings and. Thinking about polyvana alcohol, you can optimize the hydrolyzes. Great. How does this actually work? Thereby you need to understand how the nomenclature on the right hand side actually works. Of polyvana alcohol, you have two digit parts to it. So first of all you have a one single digit number which actually reflects the viscosity or the lengths of the polymer. And then after the minus you have a 2 digit part to it which actually is a hydro. The hydrophilicity of the polymer. So basically 88% of the PVA 488 is actually having hydrophilic parts to it and for the three, 8218% are hydrophobic parts or 82% are hydrophilic parts. So this is how the nomenclature works on that. With PVA you have really flexible. Downstream process abilities and last but not least, you have various options to modify or release profile. On the next page we will talk about the flexibility in downstream process ability. If you look at hot melt extrusion, you can take an extradite strand of filament, you can pelletize this down, you can use those pellets, fill them into capsule and there you are really easy to go with. Preclinical studies and overall clinical studies in the very end as well. This can be technically also a final dosage form, but most in time usually formulation scientists put extra efforts in it to actually make a real formulation out of this. This can be done by taking an extra rate. Strand your filament and you mill it down to a white powder. This white powder can be then added with. Disintegrands with other excipients like fillers or binders into a tablet blend and this can be swallowed then by a patient. A more niche thing to do would be to direct shape a tablet out of your Hotmail extruder. Therefore you need a specifically device for your HME process. Also you need a specific device for film extrusion, which is really good for oral dispersable films, for bookle and sublingual administration to have a thin film which you actually administer via the oral route as well, there you need and specifically equipment attached to the HME process. Last but not least, future manufacturing processes, 3D printing reagents and 3D printing in general. Polyvana alcohol is really flexible and can be used with various different 3D printer technologies. So you have a versatile polymer extra date and this can be processed in various dosage form. Bottom line now thinking about polyvana alcohol for Hotmail to extrusion and the release profile. If you add different excipients to your tablet band you can really fine tune. Your release profile which you can see on the right hand side for idraconosol, I know this is a really busy slide, but actually you just need to look at the 3rd and 4th row and for the different tablet blends, you can see that for tablet blend one and two which was the blue and green one, sodium chloride had been added to a formulation and on the right hand side you can see that it actually has a really fast onset. For the dissolution profile for tablet three and four, you can see that potassium carbonate has been added to the tablet one, which actually prolong gates the overall dissolution profile. And by playing around also with fillers, binders, compression forces you can really fine tune and modify this so you have a single polymer. You have a single extra date but many options to modify the dissolution kinetics. Now jumping into more specifics and looking for different hydrolyses. Great and how to optimize the hydrolyses great. For polyvana alcohol you can use partik mxp for 88 so you have 88% of hydrophilic units. Thereby you have a really thermostable polymer for high melting point APIs. If you look at the right hand side, this is actually a breakdown of. There 67BCS2 and BCS4 compounds. So the compounds which are actually suffering from poor solubility and by looking at the tendency you cannot really see a trend for melting points of those API's. So they go from all the way from 100 degrees Celsius to all the way to up to 4-2 hundred 42150 degrees Celsius and which is quite. Tricky to handle are usually the molecules above 200 degrees Celsius, so the molecules which are actually pink and turquoise here, so about 30 to 40%, are actually really difficult to tackle for hot melt extrusion. On the left hand side you can see a breakdown of nine different API's and from ibuprofen which is actually quite easy to formulate which has. A melting point of 78 degrees Celsius all the way up to 260 degrees Celsius for telmosartan you can see that polyvano alcohol with a specification of 488 actually does a really good job by enhancing the solubility with this. So you have an polymer which is actually having a wide range of melting points which can be achieved. So good term of stability and a good match. For the overall portfolio for screening processes, now shifting gears a little bit and looking at hydrolysis optimization for polyvana alcohol and looking at the specifics for 382. By looking at Partick Mxp 382 you can see formulation, performance and prolongation of the Super saturation of kitaconosol. Why is this important if? You think about the specification of polyvana alcohol and the 382, you can see that 18% are actually having hydrophobic units of the polymer. Those hydrophobic units are really, really important to stabilize hydrophobic DCS class 2B molecules within solution, but also within the solid dispersion for shelf life on the left hand side you can see a GI tract dissolution profile. So going from. PH1 after two hours to pH 6.8 and you can see by using different polymers which are actually on the market that all polymers have difficulties by stabilizing the API in dissolution within the pH of 6.8. So the API crashes out in solution. What you can also see by using polyvana alcohol with a specification of 382 that you can prolong gate. Your dissolution profile by 3040 or even 50 minutes. So this gives you way more chance that the API can permeate through the intestinal membrane. So what does that mean and how can you translate the area under the curve from this to the right hand side? You can take the area under the curve and you can see that by using polyvana alcohol 382 that you can have a twofold increase. Of solubilization and you have improved hydrophobicity which actually leads to a superior super saturation maintenance via a precipitation effect inhibition effect and also this prolongates the release profile. So really beneficial. We did test this for multiple APIs and we could always enhance the dissolution profile by at least twofold most of the time even for two to threefold. So this being set for hot melt extrusion now we will talk about solid dispersion technologies and spray drying. This is a more short section but we will touch base on that as well. And then last but not least, we will also wrap up with some other formal amorphous solid dispersion technologies, so spray dried. Formulation and the advantages. What are the advantages? You can use this for enhanced stability and bioavailability. It is really really good to use. If you have low API amounts during the development process then also it is good to use. If your API is really heat sensitive and degradates really fast. You can do a good upscaling and can achieve good and high throughput parameters. You have a future technology for continuous technology processes and by fine tuning the parameters you can actually fine tune the particle engineering part and the particle size of your final formulation of your amorphous solid dispersion. So you dissolve your API polymer mixture, you spray it and then you have a good performance. What does good performance? Look like and how can you actually achieve good performance with polyvana alcohol, in this case 382 and also 488 while using in the medicine. In the medicine you can see here the dissolution profile in pink and you can see how different polymers can actually work and stabilize the amorphous form and can actually extend a parachute effect and. Within turquoise and also within yellow you can see two polyvan alcohol grades which actually have a really fast spring. They have an extended parachute in the superior performance which is actually outstanding compared to some other grades on the market. So you have an excellent dissolution enhancement and also a great performance due to this. This being said for spray drying and. How to do solid dispersion technologies. With this we will talk about drug carrier systems now and for this we need to understand how mesoporous silica works. Mesoporous silica is a big mesoporous sponge with a lot of pores and it stabilizes the amorphous solid-state within those silica pores. Chemically speaking, it is silicon dioxide if you look at pharmacopias. Silicon dioxide has been used for decades within the pharmaceutical industries as a glidant. If you look at some key characteristics, you need to understand the particle size of silica. You need to understand the bulk density and most importantly the surface area and pore size. By looking at a pore size and a surface area, the surface area of 500 meters square per gram is really ideal. What does it actually mean I have here. Silica powder with me, which actually has the surface area of 500 meters square per gram. This means if you have 10 grams of silica, this is actually the surface area of a whole football field. This is really really a big surface area and this goes really well into play with the pore size of disorder pores, which are actually really small of 6 nanometers. So 6 nanometer pores can stabilize the amorphous form really well. And how do they do this? Misopore silica can be used and actually an API can be loaded onto the silica. So you take the suitable solvent, your dissolute your API in the solvent, you load then your solvent onto the misopore silica, then you need to evaporate the solvent and then your API is amorphously trapped directly in the pores. This is really good. Then you can take your loaded silica. Into a tablet, you swallow it in the gastrointestinal tract and the vice versa process takes place in the GI tract. So you have improved solubility, increased the solution and also improved absorption. 1 Downfall to this is that you need to stabilize via precipitation inhibition, so you need to use hpmcs or you need to use polyvender alcohol 382 to actually have a precipitation inhibitor. That it doesn't crash out in solution. How do you actually load mesoporous silica? You have different techniques to do this. Both are actually having no cost equipments. To it because you can use standard equipment with. Actually almost every lab has therefore no extra capital investment needed. You can do impregnation method or you can also do a suspension method. We always recommend to do use the impregnation method which is using a glass speaker. This glass speaker is actually surrounded by water bath. There you put your silica particles in and then you have a cannula and within this cannula. You can drop your API solution onto the silica powder. You need sweeping nitrogen to actually make sure that your solvent evaporates really good, and then by slowly dropping drop by drop your API solution onto the silica you can achieve good amorphous solid dispersions. So. Now if you have the amorphous form on your silica, you need to understand how it actually acts for dissolution profiling. You can see on the left hand side in restro dissolution profiling and you can see a reference capsule where we actually took phenofibrate and you can see a really poor dissolution profile of phenofibrate. By loading phenofibrate onto silica and putting this in a capsule or in a suspension, you can actually see that it actually enhances. The solubility what you can also see that it matches the in vivo performance of fasted pigs and by looking at the plasma concentration you can see that it actually permeated also in the systemic circulation and that it matches the performance of BI relevant in vitro data. So now coming to this graph again and that you can do a spray drying and hot melt extrusion to form amorphous solid dispersants some. Molecules tend to re crystallize and this is something what you don't want to have. No face separation is wants to be happen and also re crystallization is something what you don't want to have and glass forming ability and poor glass formal molecules actually tend to re crystallize and those. Poor glass former molecules, short GFI GFA 1 molecules tend to recrystallize and those are really difficult to handle. About 5 to 10% of the API's are those molecules and mesoporosilica is the best in class technologies to stabilize this API's. Last but not least about mesopore silica. Mesopore silica can be used as a platform technology to stabilize. Unstable amorphous APIs. So therefore you have a uniformity and consistency in particle size, in flow ability, in tablet hardness and also in friability. On the left hand side you can see that I brought you an example flow flow ability and you can see in purple the flow ability of silica and you can see in pink loaded silica and how the flow ability. Is somehow consistent and by having the API within the light pink version you can see that the flow ability is unconsistent. So uniformity and consistency and particle size flow ability, tablet hardness and friability to de risk unexpected polymorphic changes and challenges during the drop development process and to use it as a one-size-fits-all platform technology approach. With this, I will hand over to Thomas who will finish up the whole section. Thank you Marcos, and let me please take the last topic of today, API complexation by CYCLODEXTRINS. So what are cyclodextrins? They are cyclic oligosarides derived from natural starch and you can see it also in a schematic. View here on the lower right side it contains several subunits, and the subunits also. The number of subunits that say define also which kind of cyclotextron it is. There is Cyclotextron Alpha, beta and gamma. So Alpha has 6, beta has seven and gamma has 8 subunits and those subunits by the way also. In a 3D model, so to say, form a hollow cone. You can see it here in this schematic view. And this hollow cone has a hydrophilic exterior and hydrophobic cavity. And this is exactly what defines the mode of action of cyclodextrins. So an API which is very hydrophobic on the outside has therefore the chance to go inside this hydrophobic cavity. And gets let's say complexed with cyclodextrin, and as this cavity has a hydrophilic exterior, then the API can overall have a much higher solubility than without being complex with cyclodextrins. Benefits of cyclodextrins are therefore of course increased solubility, but also higher stability as also the API. Is sort of shielded from the surrounding media and therefore potentially also more stable. It's also overall enhances the bioavailability and also cyclotextran can mask orders and tastes. And by the way it is not only applicable to small molecules, so it can also reduce aggregation behavior of biologics, depends of course also on the size of cyclotextrans that you use. Gamma is therefore the largest one. It has larger cavity, so potentially also larger proteins could go here. Inside Alpha is usually typically quite small and only a smaller portion of molecules could here be complexed with this cyclotextrin. But they are not only the three variants alphabeta and gamma, but. Very interesting for the solability rate is there there for the different kinds of derivatives that are out there. So let's say the modification and you see it here also in this table below, beyond alphabet and gamma there is also randomly randomly methylated, better cyclodextrin, hydro hydroxylpropyle better cyclodextrin, solvable to ether, better cyclodextrin. And also for gamma there is also mainly hydroxy propylene. Of course, there are also many others as well. So you can think of way more modifications, but those listed here in this table are definitely the most relevant ones when it comes to pharmaceutical formulation. And also in this table you see the numbers of marketer trucks employing the respective cyclodextrin. So taking out one example for hydroxyl propurate better to the time of data collection, there were 38 products on the market employing a disrespective cyclodextrin and nineteen of these are for parental use in preckets are to that time the ones in clinical studies, so let's say in the pipeline. So this gives also a nice impression. Where the focus and development is. So it is definitely hypoxy procured better and sophoto is a better cyclodextrin. By the way, sophoto ether very much increased during the past year, so it's nearly doubled and also you'll see here on the table. So parental use here is definitely the main focus for this derivate. So why is this the case? Main reason might be because hydroxypropriate better and surfable to ether better have very good safety profiles. So they are both part of the FDA list of inactive ingredients. As said, marketer trucks exist for parental administration and also it is usually linearly excreted intact without any metabolization which also. Leads to very good safety behavior in the end and also their shielding effects can help minimize gastrointestinal irritation which adds to the safety benefits. And of course it can be very versatile use for liquid semisolid and also solid formulation. So there is no limitation in the recent years it's got quite prominent regarding COVID-19 pharmaceutics. So for example sophobutu ether beta cyclotextrin is part of the remd severe formulation and here most probably it is used to increase the solubility of the API. Whereas in the COVID-19 vaccine of tray and tray hydroxyl proprite better as part of the formulation and most probably to protect the proteins inside to give you. An overview of the potential of the solability enhancing effects, please have a look here at a craft on the right side. This is data that we obtained in our labs and here we formulated ibuprofen with hydroxy propyle beta cyclotextrin and dotted line is solability of ibuprofen alone. And you very nicely see that you are roughly let's say at 100 fold increase of solubility. If ibuprofen is complex with hydroxypropor better cyclotexture and does this become to our last question, so which enabling formulation technology do you typically use for solubility enhancement first hot Med extrusion spray drying track carrier system cyclodextrins? Other or I do not face solubility challenges, so let's give us another more seconds for you to answer the questions. So thank you very much for answering the questions. This looks also quite interesting for us. And with that we're almost at the end, yes. So let me share the last slide as an overview to sum up with what we have addressed today. So we have heard about diverse techniques for solability enhancement of APIs on the one side to enhance a dissolution rate. And here especially when it comes to physical modification, we heard about particle size reduction, micronization and nano milling. Also it can be addressed by promoting the dissolution by disintegration, acceleration, hydrophilic lubricants and dissolution enhance US. Also we have heard about Soleability limited APIs and how to increase soleability in that case focusing here first of all on chemical modification. There are diverse techniques which are frequently used in industry here to name polymorph screening, soil formation, Co crystal formation and pro truck formation. And also of course there are diverse enabling formulations out there. As I mentioned here, solid dispersion technologies like Hotmail, extrusion, spray drying and truck carriers. And also there's the option of API complexation for example with cyclodextrins. We hope that provided good and comprehensive overview over this quite complex topic of soleability enhancement and with this and we hope you stay some more minutes with us. You come to a small Q&A session to answer your questions and we will also answer further questions if the time is up after this session as well offline. Thank you. Yeah, thank you. First Thomas and Marcus for this great presentation. You already yeah, said the. Sentences I wanted yeah, to close. And yeah, as a reminder, this webinar will be available on our website soon and all participants will receive an e-mail notification when it is available for viewing. So let me quickly have a look at the chat and I think I have one question for you, Marcus. So. Question would be how much is the maximum truck load for silica formulations? OK, yeah, this of course depends really on the API. What we achieved usually was about 25 percent, 3035% of API loaded on the silica and we also achieved even up to 40 or 4550%. This is sometimes really tricky. And then you can take the silica particles in your formulation blend which with like 30-40 fifty percent of your silica. Therefore you need to do the math and depending on the API, you can have formulations which are actually having different percentages of API loadings on that. So really, really depending on the API, but 30% is quite easy to tackle by loading onto silica particles. OK, thank you very much. We have another one. So I think this could be for you Thomas. How does the structure of molecule and salt relates to the stability? Yeah, yeah, this is in general a very complex question and also there is not a one fits all answer but when a very generally I think we can say that it depends on the interaction strength of both ions. So that means the. Lettuce energy of the crystal letters that is formed. It is of course also important to know how prone the resulting compounds are towards environmental influence and especially water absorption. So typically salts are very hydroscopic and have hydration energy, which also explains they are they are higher solability than in the end but attracting more. Water could of course and also negatively influence the chemical stability. All right. Thank you for your answer. Then another one would be, will you also provide application services for solubility enhancement? I think this goes to you, Marcus. Yes, we do provide. For solubility enhancement Application service also for some other techniques like wet granulation and some other ones as well. So just reach out to us. We have multiple application sites and application service sites which are located in Mumbai, in Shanghai and also in Darmstadt. So I'm more than happy to provide you with any information. Yes, we do support you if you have any trouble and difficulty, great. And then I think we have time for one last question. It says is there an exhibit causing a lot of disproportionation reactions? I think this goes to Thomas. I think this many refers to salt formation and together used with diverse excipients. Yes, there are of course excipients. Which are more prone to cause this proportionation? Basically all excipients that have a higher micro environment. The mental pH compared to the maximum pH of the API, we have not gone too much into deep about the soil formations or pH. Max is the pH at which there is the maximum solubility of the API pH micro refers then. To the counter iron. So again if the pH micro is higher than the pH Max then this could potentially cause issues. Examples in this case are for it could be magnesium steroid but also sodium cross carmelos could potentially cause issues but again this is also absolutely depending on the combination with the respective API. OK. Yeah. Thank you very much for your answers and all the questions you put into the Q&A section. If we did not get to your questions, please feel free to e-mail our presenters directly to register for futures for future webinars or to access our archive webina library, please visit our website. And yeah, I would like to thank Thomas and Marcus for this great presentation. And also thank you to our audience for joining us. And yeah, have a great evening. Day. Yeah. See you soon. Thank you for listening to us. You have a great, wonderful day. Bye, bye. _1734829662208

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