Hi everyone and welcome. My name is Zia Park and I will service your moderator today. Thank you for joining us for today's webinar How to Improve API Solability by Sultan Crystal Formation. As your moderator, it is my role to ensure that we make the most of your time with us. I am here today with Doctor David, Doctor David, Principal Scientist at Solid Formulation and Doctor Thomas, Strategic Marketing Manager at Sapiens Liquid Application. Thomas is Strategic Marketing Manager at Mark and responsible for our growth portfolio of experience for liquid formulation. He has more than 10 years experience in the pharma and biopharma industry, with different positions in the field of pharmaceutical formulation. Doctor David, Principal Scientist at Merck Germany, Germany, working in the solid formulation R&D group, supporting the development of Noble experience. He has more than six years of industry experience in the Pharmaceutical industry, focusing on the characterization of active compounds and stabilization techniques for solid or dosage formulation. While you will also have the opportunity to participate in a couple of quick poll questions throughout the session, I will encourage you to take part in this surveys. If you are watching this webinar on demand, you can still submit poll response. 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. So let's see from my side. It's my pleasure to turn this over to our experts. Can you please start? Yes, thank you very much, Saya, and welcome to the audience. Also from my side, let me start with today's agenda. So we will start with an introduction into the topic, then we will give an overview about two techniques, store formation and Co crystal formation and provide you some backgrounds and information on methods and challenges. And also especially here for the Co crystal part, also provide insights about regulatory implications. And we will close this webinar with a summary and Q&A. So let me directly start and Trump into the topic. So what is it all about Solubility of AP is, isn't the key to success. So this is the leading question of today and to put the answer here, but the first slide already, yes, definitely. And let me come to the different points why this is the case. So I think everybody is well aware and we can all agree on that developing new AP is is very lengthy and cost intensive process. Therefore, the pharmaceutical company developing a new API would definitely want to avoid any risk that comes along with developing of AP is. And here solubility is definitely one key aspect. And why is this the case? Because sufficient solubility here is extremely important for the API to be absorbed by the body. So it does not matter if it's a solid formulation in the end or a liquid formulation, at a certain point it needs to be absorbed, therefore needs to be dissolved and solubilized. And therefore solubility strongly influences the track product efficacy and needs to be sufficient and potentially even as high as possible. And to put it the other way around, so insoluble AP is can hardly pass the GUST. For instance, Tylen membrane therefore cannot enter the systemic circulation in sufficient quantity and therefore this needs to be avoided and can need to have certain suitability. Parental solutions and highly concentration. Concentrated formulations are to more specific areas or topics where solubility is of even higher importance. So for parental solutions they need to be free of visible particles. So everything needs to be solubilized and dissolved. And for highly concentrated formulations, I think it is obvious. So in order to achieve an S high concentration as possible, solubility needs to be increased, potentially even higher than in usual formulations. So this is a potentially even more challenging field where solubility take takes place a key role. And on the right side, you'll see the BCS classification system with which you are potentially already familiar with. So we have 4 different classes and today we are talking about the right side. So BCS class two and four and both have no solubility. So this would be the AP is to be addressed. So take together we can say that low solubility increases the risk for candidate compounds to fail during drug development. Therefore, this needs to be avoided and suitability needs to be addressed. But first of all, let me come to the question. So why is that this the case? Why is suitability becoming more and more of an issue? This is mainly due to the fact that today's high throughput screening and target oriented truck discovery often results in challenging poorly water suitable AP is and you see on the bottom the current situation. So the current distribution of marketed drop substances classified here with the PCs system. And you see that as of today we are talking about roughly 10% PCs class, 430% PCs Class 2. So this is already 40% of marketed drop substances classified as hardly soluble. But if you will take a look at the right side and this is really the point which makes it very clear at one glance that this needs to be worked on and needs to have focus in the in the future and even today. So this shows the pipeline and the classification of the truck truck product pipeline. And here we can say that roughly 10 to 20% will be as will be PCs class 4 and 60 to 70% PCs Class 2. So taken together, we are talking here about 70 to up to 90% of trucks currently under development being poorly water soluble. Therefore, addressing this challenge becomes increasingly important and how can it be addressed? So as you might already know, so there are plenty of opportunities out there on the right side. Here we see some examples, but there's even watered, of course, on the formulation side. So you could address it with solid lipid Nitin particles, lycosomes, solid dispersion, cyclotextrins and also other excipients. So this is on the formulation part, but there's also more to it on the left side here. In this case, API processing. API processing is earlier in the drug development process. I will come to this also on the next slides. And here are also plenty of possibilities during which solubility can be addressed. Where if you mentioned 4. But solubility can really be addressed here by diverse processing techniques. Today, of course, we want to talk about salt formation and cocrystal formation. So why should you want to go with one of these options? So because API processing addresses the solubility very early during API development and let's say it eliminates surprises at an early stage. So formulation is quite late in the truck product development process. And if you rely on solving solubility issues with the final formulation, you might find out quite late or even too late that formulation alone is not sufficient to increase the solubility to a sufficient extent. Therefore starting to work on that issue as early as possible here really key and the aim of the API processing is to find an optimal solid-state form. And this is also strongly dependent on the specific API and usually it requires prod screening, so it is not something which is very quick. So you really need to work on that. And the most common solid-state forms employed are polymorph, different polymorphs, soils, hydrates or soil weights and Co crystals. And as already mentioned today, we want to have a closer look here on soil formation and Co crystal formation. And how would you usually start doing that? So you start with your parent compound and you would then do a PKA evaluation. And if that PKA value is higher or equal than five, and this is only very rough guidelines here, then you would probably go with the soil screening. If it's lower than three, you will probably go with the Cocos screening. But today we see more and more than that both is done in parallel by pharmaceutical companies. So that also Cocos screening in parallel to soil screening is done especially, of course, if the PKA value is between 3:00 and 5:00. And it's, yeah, from a chemical point of view not very obvious which route to go with. Then you would definitely go screening both in parallel and then deciding what's the best way to go is. And if one or both is feasible. You would then decide of course on either option and then scale up the process that you have found and developed. And in the end then comes a formulation development. So formulations of course still necessary and possible. I think that is clear to potentially even further increase the solubility entry would also to format Co kinetic state studies as well. And after this introduction, we have the first point question for you. Please participate in our first poll question, just the answer you think is the best and I will give you 30 seconds. The question is which options do you typically pursue to increase API solubility? Please choose your answer. You have 20 minutes, 20 seconds left. You have 10 seconds left and I will go with the answers. Thank you for participating in the poll. It looks like a lot of audience have chosen option B and the last one, physical modification and or formulation. So let's return to the presentation. Hello, yeah and welcome everybody sponsor from my side. So salt formation, what it is about salt formation is a well established technique employed for several decades already and currently marketed drugs are predominantly in salt form, more than or about 50% and still with an increasing trend. The principle is that the APIs are active pharmaceutical ingredient is ionized with the age of counter ion meaning an acid or a base and it involves typically a proton transfer. This approach is of course just suitable for ionizable drugs, meaning drugs having a functional groups that can be ionized. And yeah, it can result in in anionic or cationic or even spitterionic species. And it's also shown here on the bottom left that the API and the counter ion crystallize actually in the same crystal lattice. If you look at the form of the FDA approved molecules of APIs, you can see that about really 50% or 13% have been formulated as assets. 39% are basis of the APIs and it's really that about 50% are in small form. Yeah. Why should you opt for salts? Yeah, salts renders the opportunity to influence the solid-state properties. They enhance the bioavailability in terms of solubility and also distribution rate can be altered. It may result in a beneficial impact on the API purity and you can use it for API isolation, even to crystallize a salt as a solid out of the solution. You can alter the crystallinity when you do this. Yeah. It has also certainly an effect on physical and chemical stability. Manufacturability can be influenced in terms of the crystal habit, particle size of flowability. And the procedure is usually that you go for salt screening, you do a dissolution study, you make a stability study, you scale up and then you go into formulation. So that's a high level overview. And summing up, the benefits of salts are it's a well established technique, simple and cost effective, high regulatory acceptance also. And the challenges are the API needs to be ionizable and you have some effects that may also influence actually the stability of the salt like disproportionation or hyproscopicity. And there's also the common ion effect. So salt formation, it's in general aph dependent problem as shown here at the bottom on the right. The two solid phases like the salt and the freebase, they coexist actually in equilibrium in a saturated solution. And addition of small amount of an acid or base will actually not affect the pH or the concentration of the drug in solution until enough is added so that only a single phase is yielded here in solid form. And yeah, this concentration is actually called the pH Max. It's reached X at the pH Max and it is is a point of maximum solubility because both the salt and the free base contribute to total solubility as shown here on the left hand side. Actually you see that it is also dependent on different counter ions, so they result in a different pH marks, while as a PKA of the drug molecule logically remains constant here. It's noted here at 5:00. And yeah. However, what you can also see is that salts having an increase solubility also result in a smaller range of pH exposure to be thermodynamically favored over the free base. Meaning here actually for a it's hydrochloride having like the highest solubility versus torsolate having rather low solubility. But yeah, brought pH tolerance. Sorry, I went backwards. In addition to this, this, this this this pH dependence, there's also the common ion effect, the equilibrium shown here on the bottom left side. It may be influenced by the addition of common ions such as sodium chloride or protons which actually can acidify the the drugs environment and shift the equilibrium according to Le Chatelier's principle to solve formation of the hydrochloride salt of basic compound and in production. For instance, evolution of hydrochloride gas or sublimation of the free base may shift the reaction in favor of the free base. So that goes here actually. And this can be a big disadvantage because in case of extrinsic counter ion addition, reducing the solubility of the IAPI is is as there's a lot of HTL and HTL stored in the gastrointestinal fluids and also in bio relevant media which are typically utilized for development now. And this effect is known as the common ion effect. And other problem of sorts is so-called disproportionation. It's a major problem with respect to the physical stability. And this reaction involves actually the dissociation of the ionic solid into its neutral or weakly basic compound and acidic form. Of its counter iron leading to an intrinsically less soluble form of the active pharmaceutical as shown here in this in this equilibrium so this dissociation the pH value on of the micro environment also known as surface pH of the drug relative to its pH Max value would determine whether the disproportionation of yours. As we have seen on the graphic on the previous slide, the pH Max of a weak basic compound is typically lower than its PTA value and more soluble salts results in smaller range of pH exposure to be a thermodynamically favored over the free form. So this is something we have seen here in this graphic. And yeah, so and this may actually cause issues concerning excipient incompatibility. For instance, if you look here at this at this HIV drug telaviridine during development at exposure of 40° and and 75% relative humidity for a week, it's undergoes actually a solid-state reaction to the free form. I think here's a they use the mesolate salt and the pH Max of the salt is about four, which is then less than the pH micro of most excipients in tablet formulations. And they're actually listed here, for instance, in this table, the common pH of of these surface pH of these excipients. And this causes then spontaneous disproportionation. For instance, in this case here it was I think sodium Costa was used having a surface pH of five to seven, so which is quite close to four. So the solubility of the salt is about then 2000 times higher than for the free base. And this also indicates actually a big driving force, free energy gap, meaning a big driving force for this reaction. And yeah, this this is actually also the reason why at Merck we do not formulate drugs with the PKA lower than five assaults, since the pH Max is typically about two to three pH units lower the PKA or below the PKA value of the drug, which is too acidic for common formulations. Yeah, on on this page here you can find commonly marketed examples of of drugs formulated as salts. And yeah, just for your information at Mercury offer portfolio, not only limited to the Co format shown here in high quality and quantity. And yeah, with this, I would like to close the discussion on salts and come to our next topic, which is core crystals. But I think there will still be a core question here. So we have the second poll question. The question is, from your perspective, what are the biggest hurdles when it comes to API core Crystal development? So that I will give you one minute to choose your answers. Please choose the answer. Your thing is the best 30 seconds left. Well, I'd like to give you an additional 20 seconds. 10 seconds left. Please choose your answer. Yeah. And that's it. Well, thank you for participating in the second poll. It looks like a lot of audience have chose identification of suitable core formers and the next one is lack of technical process knowledge. And let's return to the presentation. Thank you, Zaya. So yeah, core crystal formation, what is this about? In the pharmaceutical context, it's a relatively new approach compared at least to salts. So Co crystals say render an alternative for non ionizable compounds as nearly all kinds of APIs can form Co crystals. And the principle is that the API and the Co former interact by yeah, certain forces, which are obviously non ionic, meaning Van der Waals forces or basically hydrogen bonding interaction. And they also crystallize in one joint crystal letters. And here's also a search I did in formulas database recently. And you can see from the number of patent applications that come up when you search for the term Co crystal that it's an increasing interest in, in, in, in this kind of materials. To date, however, they are just less than 10 marketed API as Co crystals. And yeah, that's typically it. It always takes some time until such trends reach the market. Why should you develop Co crystals? Co crystals, say, also render the opportunity to influence solid-state properties. Similar to salts, you can enhance bioavailability such as solubility and dissolution. Late may also result in beneficial impact on API purity. You can use it for isolation and improving crystallinity. Potentially. It has typically also positive impact on on physical or chemical stability. Manufacturability can be also an issue in terms of habit, particle size and probability. And as the the issue with Co crystals is just it's it's difficult to find the Co formas. So at Merck here we trip typically screen for Co formas using an in silico screening methods. Yeah, in addition then there is a Co format tox evaluation because you can choose a lot of different molecules and it's it's not a well established technique yet. So we, we do this tox evaluation then as the the experimental screening starts, yeah, followed by a dissolution study, a stability study, potentially scale up and formulation. So summing up the benefits of corpuses, they are an alternative on if non ionizable drugs. For non ionizable drugs, there's no common ion effect, no disproportionation effects, less prone to icoscopicity challenges, conforma selection, crystallization, process control. Yeah, if you crystallize them from the liquid and then you need to make sure that they have the same solubility. And also there is less regulatory acceptance because it's yeah, compared to salt doesn't exist for multiple decades. Yeah. How do you actually screen for cocrystals extra mentally? So let's say exists different screening techniques for cocrystal formations such as solvent evaporation, solvent assisted solid grinding. You can also use sublimation, slurring or even in the DC you can screen for them. I think the most common approaches are marked in fat here and are both and Yeah, pro forma selection is an API specific task, so it's dependent certainly on the purity of the API, also on structural features of the API. You you should have some functional groups in there at least increases your chance of finding what corpus will substantially. The physical properties of the API are also important. Now I just mentioned for instance, solubility if you try it from solution, thermal stability and yeah and so on. And the screening should be as comprehensive as possible. It's also interesting for yeah, generic companies or in general for farmer industry in terms of IT protection of their new chemical entities. And yeah, experimental screening is, is challenging in, in case of limited API availability. It's also off the case in the early stage of the development and that's why your computational screening is promising approach to save time and resources. Of course, when you screen for salt, you can be reassured that you find some if you try certain counter ions. However, for Co crystals this is more challenging and that's why it makes sense to use here the computational screening. Yeah. And since this is more challenging, we have also developed actually a tool for Co crystal screening and in silica tool harnessing AI for Co forma selection. So yeah, we maximize here success and minimize the effort using our AI. Our AI based tool can predict actually potential compatible Co formas and its employed data set covers a large chemical space and its model was actually trained with an active learning approach. And yeah, I have developed this model with with the team. And I would like to highlight here as well that it really consists of consistent data, which is really crucial when you develop such an AI. And using this active learning approach, we could also actually with reasonable resource effort developed a very well performing AI, which also actually combines the advantages of quantum mechanics or so we need to calculations and data science to to find corpus that's here. And we can increase the chance of finding the right Co former by around 3-4 compared to random digital testing. And yeah, so far the tool seems to be superior compared to what is that's on the market. Hence we have a much higher and faster chance of finding a good Co crystal to take into development. Yeah, summing up here, there is still a list of marketed Co crystal drugs. And yeah, similar to the salt case, we also offer Co farmers at Merck. Yeah. Maybe it's worth mentioning that our and the local selection tool is certainly not limited to our portfolio. So that's something we did not do. And with this, I would like to hand over to Thomas. Yes, thank you very much. I would like to close the session with the last topic. So regulatory implications of Co crystal formation, currently they are not too many marketed truck products in Co crystal form out there. So we are roughly talking about maybe about the number of 10. So but this is strongly evolving. There will be much more in the future. But as you have already seen, so many different kinds of Co crystal formas can be taken into consideration might be a good Co crystal forma. But you might wonder, OK, which one to go with not only from the chemical point of view, but also from the regulatory point of view. And we would like to go a bit more into detail what the two regulatory agencies, the EMA in Europe and the FDA in the US stated about these topics so far. And it has been some years until since the the last statements on these topics. And I would like to cite some of the sentences that they brought out. I think these are the OR one of the key sentences which might shed a bit light on how they see the difference. Yeah, regulatory components of focus to formation. So starting with the EMA, so they brought out a reflection on Co crystal several years ago and Dan has said that there is no strict borderline between the salt formation and the one end with complete proton transfer and Co crystal formation in the other end with no proton transfer. And here might already wonder, OK, so we have heard today that this is one big differentiator between Co crystal formation and soil formation. Yes, we will come to that also on the next slide when we see what the FDA has to say about it. EMA clearly says there's no strict borderline and they say that ultimately the reciting material properties are the critical factors that determine the suitability of developed solid-state form for the designated purpose regardless of the molecular bonding involved. And one of the reasons is that the solution of such different forms of truck substance in the stomach or intestinal canal will lead to the release of the same substance. So let's put it that way. It doesn't matter if you start with a cochrus or salt, they say the substance being released is the same. So they say there is not that much of a difference and they say that Cochrus and salt from many conceptual similarities and therefore also similar principles for documentation should be applied for the Co forma itself. There's not too much information so far regarding the guidance. What's the EMA says here trust As for any other component of additional product each exhibience or counter ions Co formas must be pharmaceutically acceptable. So safety and quality must be assured, and if not previously used in additional products, they should be justified. This may be documented in the same way As for a novel exhibit. So let's interpret here. So the EMA puts the pro formas very close to the status of an exhibit. And if you have a new pro forma, it should be treated similar as a novel exhibit. So let's come to what the FDA stated about it. So they brought out the guidance on coal crystals for the industry several years ago. And here they said coal crystals are distinguished from salts. And here it already becomes very interesting because this is not fully in line what the EM EE MA said. So FDA says coal crystals are distinguished because unlike salts the components that coexist in the Co crystal letters interact non ionically. And to further refine that they said if both API and Co forma have ionizable functional groups so that means it could ionize be ionized. The conclusion that a component API and Co forma coexis in the Co crystal which interact non ionically. So that means you have to show that or how the interaction takes place. So if you find out that there is ionic interaction it is. So if you find out that it's really non ionically then you have a Co crystal and a further say a Co crystal with a pharmaceutical acceptable Co forma. That means the above conditions can be considered the pharmaceutical Co crystal and has a regulatory classification to that of a polymorph of the API. Here again it becomes very interesting. The FDA does not put it very close to excipients like the EMAFDA says it has to be treated like a polyworm and further they say truck products that are designated to contain a new Co crystal are considered analogous to a new polyworm. So what do they say about the Co format itself? Unfortunately also not that did not went too much into detail. They stated you're a component that interacts non ironically with the API in the crystal letters that is not a solvent and is typically non volatile. Then it's Co crystal former and there needs to be assurance that substantial dissociation of the API from its Co crystal form across before reaching the site of pharmacological activity important statements, but also not too much of A guidance what the core former in the end could be. So it leaves it relatively open. And with these insights, we would like to come to the last point question as of today. Thank you. Please participate in our last poll question. The question is how do you typically identify the most suitable conformance? You have the options and please choose the answer you think is the best. And before I check the answers of our poll question, I would like to remind that you can send us your questions whenever you want using the Q&A widget. And I would like to give you a mini. Please choose your answer. 30 seconds left. Well, I would like to give you an additional 30 seconds in order to everyone can join. Please choose your answer. 20 seconds left, 10 seconds left. And now let's see what is the most selected answer. Well, it looks like most of you have chosen return to search and publish data. Thank you for joining our poll question, and let's return to the presentation. Yes, thank you for answering these questions. I would like to come to the summary of today's webinar. So we have learned that API processing in general can address API solability early on during development. And we have looked here at two specific methods, solid formation and Cocos information. So when we went into detail, we saw that soil formation is a very well established method and has many different upsides. 50% of all marketed truck products are in soil form. So it's very, very common. But it is only applicable for ionizable API. So that is one limitation. They are also also some downsides to it. So for example, stability risks when it comes to disproportionation, hydroscopicity or the common ion effect on the other side. So there are Co crystals, this is rather new but strongly emerging. So we will see more and more Co crystals coming to the market in the future. The big benefits here is that it is possible for nearly every API. So nearly every API can form a Co crystal and you can avoid several issues that might come along with source. Challenging here is potentially still finding out what is the best Co format for your specific API. So did this, this is on the 1:00 and also experience that's one code select, but it is also the lack of a suitable screening tools or prediction tools. This is something and this is also what David's introduced. We are also working on and we have prediction tool in place which can also be offered for assisting finding out the best Co formats for specific AP is the specific point. Also here is the regulatory implication of formation of Co crystals. So it is also the Co crystal as a whole but also the Co former which needs some regulatory guidance and SPF trust show to you. So the reflections on the on Co crystals currently still strongly differ between the FDA and the EMA. And to go a bit more into detail again, so the EMA sees Co crystals quite similar as soils and then more put a focus here on efficacy and safety, which is from their opinion the main concern which has to be met. FDA on the other side refers to corpuses more like polymorphs and they really focus here on the ionic interaction. One needs to find out if it's ionical or non ionical and then clearly decide, OK, do I have a Co crystal or does that count as a sort. So in general, we can say that both the FDA and the EMA provides currently still little guidance regarding the Co forma itself and in general still like some alignment. And so we are clearly hope that also in the future there will be more to come from these agencies with an aligned approach probably and also with more a clear guidance regarding the Co formats. And with that, I would like to thank you for listening. And now we have AQ and a session and are happy to answer your questions. Thank you for this great presentation. It's time to answer questions that have come in from my our audience. But before we do, I'd like to remind you that it's not too late to send us your questions now using the can a widget and after this webinar, please join the feedback survey with top right corner widget. You can also ask for for the presentation follow through the survey. We will try to get through all of them questions, but if we run out of time we will respond to you individually. First question is when is the PKA too low to be considered ionizable? Yeah, So good question. So in general the PKA difference between the base, so the drug and the typically the drug is the base and the Co format should be about equal or or greater than three to to have like successful salt formation. And yeah, this is the rule of thumb at Merck. As we mentioned earlier, we do not formulate salts having a PKA lower than five due to the discuss disproportionation issue regarding the pH Max of the surface pH of most excipients. Now I hope that answers the question. Thank you for the answer. Next one is Eastern on ex PNS causing a lot of disproportionation reactions. Yes, I mean in general it's really depends on on this relationship which we had discussed in in this webinar between pH Max and and micro MPH of the exhibience. But in the past we had, I can tell we had a lot of, I personally, I experienced a lot of issues with magnesium steroid. So yeah, if you have issues with your formulation and with respect to disproportionation and there's magnesium stirate in it, Yeah, I would look for that first. Thank you. And the new question is coming in Which is the most efficient screening technique for coal crystals? Yeah, that's a ghost question. So from my perspective, in order to find new Co crystal solvent assisted solid grinding is is the best technique because the advantage is just that, yeah. With regard to completely liquid based techniques where you dissolve the the API and the Co former completely, you need to have equal solubility of both compounds because otherwise you have the risk that you crystallize just a single component and not Co crystal. And for solvent assisted solid grinding, it's really a solid reaction that that happens just with a few drops of adding certain solvents that can actually mobilize. Yeah, both phases a bit. And then this reaction happens just in in this environment. And if you grind it, then you introduce more mechanical energy that can actually be sufficient driving force to find your Co crystals. And that's a very successful technique. Also discuss this with with CRO's and they were of the same opinion. And our that's why also our AI is based on on this technique. But yeah, so also slurring is an is is a good technique. If if you're slurry for a longer time, for instance at elevated temperatures, you can also have good chance. Yeah, always depends on the API certainly. But I would say if you don't know anything then go for solvent assisted solid grinding. Thank you for the answer. And the next question is how promising is the application of machine learning techniques to Co crystal screening? Yeah, I think there are a lot of publications out there. We also wrote a review about this topic one or two years ago. If you Google progress screening, assessment of latest advances or assessment of latest approaches, you will find it. It's yeah, it discusses all those machine learning techniques that have been applied because they have come up a lot of publications in recent years. And yeah, it I think they have quite some potential. I mean, we have developed our own AI. The issue with these literature approaches is always Even so if they are published in high impact journals that the data which has been used is, is typically from different sources. Also you have this issue with negative data. There's no negative data published, so it really depends on the data you used. And that's why we also went for, yeah, going generating our own data or consistent data sets where we really know what it is. We generated more than 1000 experiments using an active learning approach. So really an intelligent UE that you can use when you have already a model architecture in mind. And with this, this has quite some potential. But yeah, I wouldn't just rely on everything that's published out there using literature data from various. Sources. Thank you. Next one is what is missing with respect to regulatory guidance from the health authorities. Yeah, that's a good question. I mean, Thomas just pointed out the the regulatory statements here that exist, just some from the FDA and from the EMA and they're both treated differently I think from NMTD, there is no guidance at all yet. So I think it would be best to have like from my perspective, like, yeah. And homogenized guidance so that you really know what what you can do. Also in terms of exceedance, there's not a lot of guidance for, for this kind of material class. Don't know Thomas, if you want to add something please feel free. Yeah, I think you perfectly touched it. So I think the alignment is here still missing. They did not state something so far which is blocking. Let's say there are several Co crystals on the market already. So definitely is it is accepted by the authorities, but I think it would be even more, you know, frequently used or brought to the market if the companies would know in in a bit more detail what's the regulatory bodies expect. And as David pointed out, an aligned approach would be good. So if you think about bringing out your final truck product in several regions of the world, we have then to deal with several opinions how a Coke research should ideally look like or what to take into account. And that makes it more complicated compared to having an aligned approach between all major regions here. And that is what would be good to see in the future. Well, thank you for the great answers. Next one, does method of Co crystal formation can affect the successful formation of Co crystal or is it? Is it the critical thing? Only the intermolecular reaction between the API and conformer? For example, our DCC show there is no solid solid interaction between the conformer and API. Is it still possible for us to form Co crystal using that combination? OK. Yeah, that's also a good and very precise question. So, yeah, certainly the method of the Co crystal formation influences the success. So as just pointed out, for instance, solvent assisted solid grinding is a very good method to find coke crystals to screen for coke crystals. But yeah, it's not a given. You should always try several methods like slurring or or you can also try crystallization from the melt. So if you for instance just looked into DSC and then I would also look for other methods to prepare a coke crystal. If you just tried to to see interactions from the DSC, meaning I, I, I think you would try to look at the melting point shift and and that does not necessarily need to be there if you find a core crystal. So in theory, ideally you have an excipient that has a certain melting point, then you have a Co crystal that has a certain melting point and the melting point of, and then you have an API having a certain melting point and the Co crystal typically has a melting point in between, but it can also be higher or lower depending on the nature of the Co crystal. To answer the part is, is it a critical thing that there's only intermolecular interaction between API and pro forma? I would say no because there's also the lattice energy contribution. So it can also be that's that there's not a lot of interaction between the Co crystal and the Co former. However, it really fits well in the crystal, the lattice that they both form together and then there's not a lot of interaction. But in terms of lattice energy, there it is they they fit well or of the crystal lattice. And yeah. So to answer your question, if you should also, is it possible that the form also corpus to using that combination? Yes, I I would try also the other techniques mentioned. Thank you and thank you very much for all the questions. If they did not get to your question, please feel free to reach out to us. The survey, we said that you have top right corner on the screen. You can also request the presentation file for the survey. And to register for future webinars or to access our archived webinar library, please visit our website. And I would like to thank you, Doctor David and Doctor Thomas for today's presentation and thank you to our audience for joining us. Have a great day. Thank you. _1732286176953

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