Novel Research on Applications of Surface Energy Analysis

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Hello everyone and thank you for joining us for today's online workshop. Today's session has been hosted as a part of IGCSEA Week 2022, a five day online festival celebrating the inverse gas chromatography technique and and the onus from TATION ICCSEA developed by Surface Measurement Systems. We thank you all for joining us. And for anyone who hasn't yet had an opportunity, the first day of ICC SEA Week released a useful Application Note Pack which contains all of our recent application notes, technical notes and case studies which you can currently download on our website. So if you didn't get a chance to download that yet, you can just go to our website@surface measurementsystems.com select the banner in the top right corner and you'll be able to download that pack on that page free of charge. So thank you all for joining us for today's workshop exploring novel research on applications of surface energy analysis. We're very lucky to have with us here today Dr. Daniel J. Burnett and Professor Darrell Williams of Surface Measurement Systems to give two differing presentations to explore recent case studies and research into the applications of IGC in the surface energy analysis area. As with all of our presentations, we'll be offering a live Q and A session at the end of each presentation with the speakers themselves. So we strongly advise you to submit questions or raise your hand to take part in these and get involved. We want it to be nice and interactive with you. So just to explain quickly how this takes place, you can either submit your question in writing, which is where you would find the questions panel in the webinar control panel on your right and submit your question in writing there. And then I will submit your question to the speaker during the live Q and A or alternatively if you have a slightly longer question or a two part, three part question you would like to discuss directly with the speaker, just raise your hand using the hand raising icon and then when it comes to your turn to ask, I will unmute your microphone. You can unmute it yourself as well and then you can engage the speaker directly to ask your questions. So once again in the live Q and A, simply submit your question in writing in the questions panel or raise your hand and we'll let you know when you can unmute your microphone. Our first session today we are joined by Dr. Daniel J. Burnett to explore the importance of surface energy and wettability in biomaterials. Before I pass over to Daniel, I just wanted to give a quick intro to his background. For anyone who is unaware Dr. Burnett is the Vice President of Surface Chemistry Systems North America and he's located at our North American headquarters in Allentown, Pennsylvania. His team works on research studies and science applications for many prominent companies across the North American market. He received his Bachelor's Degree in Professional Chemistry from Eastern Michigan University in 1997 and his PhD degree in chemical Engineering from the University of Michigan in 2001. Dr. Burnett has authored and co authored over 25 papers in peer reviewed journals and presented at numerous national and international conferences. So without further ado, I would like to now hand over to Daniel to begin his presentation.

Okay, thanks John. Good morning, good afternoon, and good evening to everybody in attendance. Thank you for taking the time to participate in our IGCSEA week and in particular taking time out of your busy day to listen to the talks from myself and Professor Williams who will follow me. So without further ado, I will get started and as John mentioned, please we welcome any questions or comments or anything via the chat Q and A or raise your hand as John had mentioned, so today I'll be talking about focusing on surface energy and its role in wettability in relation to biomaterials. So for those of you not familiar with surface energy, it is probably the most commonly measured property by inverse gas chromatography. It is analogous to surface tension of a liquid. So if you think about surface tension, surface energy is kind of the analogy for the solid phase and it's basically defined as the excess free energy at the surface relative to the bulk of the sample. What is important is that it is directly related to the thermodynamic work of adhesion. So anything you have interfacial interactions between two powders, a powder and a liquid, a powder and a vapor, any solid materials, the initial interactions will be driven by the surface properties of the different materials. Commonly, surface energy is divided into two components, a dispersive component. So this is also called the London van der Waals interactions. This is also sometimes called nonpolar contribution to the surface energy. And then there's a Lewis acid base component, which is also sometimes called the polar contribution to the surface energy. I'll typically use dispersive or gamma D and then gamma AB for the acid base component to the surface energy. Although in the literature this might be called gamma LW and then this might be called gamma P for polar contribution. Why do we measure the surface energy? As I mentioned, it can be one of the main driving forces for adhesion and cohesion phenomena. This is important for things like drug excipient interactions, composite interactions, powder mixing Powder flow, powder segregation, powder agglomeration, static charge, in particular to the acid base. Contribution of surface energy. Whenever we do some sort of mechanical or chemical process to a material, whether that be milling or grinding, typically you're doing that to get desired particle size or other attributes. But that can also induce some surface changes as we subject the material to these high energy processes. And so we need a way to track or monitor or determine if we made any changes to the surface as we do some of these other unit operations. Batch to batch variability, you could have impurities or just different levels of disorder or of amorphous content or subtle variations. And if those variations are dominated by the surface of the material, inverse gc and a particular surface energy by inverse GC is very sensitive to pick up those differences and then just general material characterization and material properties. If you want to look at the functionality of surfaces, if you want to look at how I've coated or surface modified something, monitoring and tracking and determining the surface energy can be important for those formulation challenges. So basically in these cartoons here, we've just shown a graphical way of things that as we change the surface energy, for instance, if I have this surface and I increase the surface energy, I can often increase the wettability. If I think of a powder or a fine particle, and if I increase the surface energy, keeping everything else the same, that'll typically increase the cohesive forces and lead to things like agglomeration or segregation. If I am milling or grinding or plasma treating or doing some sort of mechanical or oxidative or some other process, very often, although I may make the surface more rough, and surface energy by itself is independent of roughness or surface area. But I'm often going to expose buried interfaces, open up different crystal planes, make surface amorphous, and I very often will increase the surface energy of the material as well. And then if we think about a composite or a multi component system, if we let's say we have these larger particles and these smaller particles, and if I keep everything else the same and I do some surface modification to increase the surface energy, I could overcome the cohesive forces of the smaller molecule particles and increase adhesion. So all of these things can be affected by the surface energy, and that's why it's important to measure that. And as I mentioned, it is directly related to the thermodynamic work of adhesion, which is the interaction of two dissimilar surfaces, and the thermodynamic work of cohesion, which is the interaction of two like surfaces. So very Often it's a balance. When I have a composite or a blend or some sort of multi component system is that I and if I want that to be a uniform blend or I want to get good adhesion or make a good composite, very often I would want the work of cohesion to be similar to the work of adhesion. If I have one particular material that's very high surface energy relative to the other materials in that formulation, the very high work of cohesion would mean that those particles would like to stick to themselves rather than stick to something else that might be in your formulation. So it's very often a balance between adhesion and cohesion forces is what we're looking at. When we're looking at multi component systems, just to transition a little bit, that's just surface energy in general. Now we're how we measure surface energy and in particular to inverse gas chromatography and where this kind of plays in your material characterization toolbox. And this is how I break it down. There's other techniques that won't be covered by this, but in general you can use energy as a probe. That's X rays, spectroscopy, light. You can use heat as a probe looking at heat gain, heat loss, heat transfer. In particular, inverse gas chromatography and other surface energy techniques and other absorption techniques use molecules of the probe. So we're going to use how a molecule interacts with either the surface or the bulk of a material, and how those molecules either adsorb or absorb and then how they desorb can determine a lot of both physical, chemical, structural and bulk information about the material of interest. So we're using how a molecule interacts with the surface to learn about the surface of the material. And specifically to inverse gas chromatography. It is a technique that has been around for quite some time. It is a little bit lesser known technique than some of the other chromatographic techniques that are used for more analytical information. But it is essentially where we revert the role of the stationary and mobile phase. So in an analytical gc, you'll use it to a known solid phase material that you're going to use to separate and then identify and quantify the gas or vapor phase species. In inverse gas chromatography, your sample is the column per se. And then we inject a single molecule of a known molecule with known physical chemical properties. And then the retention time, how long it takes that molecule to interact with that material, can then determine and give us information about the solid phase that we're trying to investigate. So essentially instead of an analytical tool, we can use it as a physicochemical property tool to characterize solid materials. As I mentioned, inverse GC has been around for quite a while. And this is just a histogram plot. If you did a Google Scholar search of the phrase inverse gas chromatography and took a number of references per year, you can see it has been around for quite a while. And in particular the last 20 to 25 years it has seen significant growth. And just as a point of reference, in about 1999, surface measurement systems came out with our first commercial inverse gas chromatography system. And right around 2009, 2010, we came out with our next generation inverse gas chromatography SEA instrument. And not, you know, surprisingly or not by coincidence, this does seem to trend. With the ability of a commercial grade turnkey instrument, the number of publications has increased significantly in the last 20 years. So in inverse GC it's the most important thing is to look at the relative change in retention time. There's lots of factors that can change. Absolute retention time in inverse GC is typically how that retention time changes as we change some other variable. That variable could be temperature, could be flow rate, could be concentration, or it could be in this case molecular cross section or size, shape or chemical nature of the material of the of the vapor. So this is looking at octane, heptane and hexane. And as you change that molecule, you see a decrease in retention time. And then all of the molecules are referenced from an internal standard, which is typically methane. And this essentially acts as a reference point for all the other molecules. And this has an advantage that this will normalize any packing irregularities or void spaces that may be from column to column or operator to operator. So this is fundamental is to make sure you have a reference molecule, most cases that is methane. And just a schematic of the SMS inverse gas chromatography SCA instrument. It is either helium or nitrogen. Just to make a note, we do offer nitrogen as the scarcity of helium becomes more and more of a problem. Most of our customers do use nitrogen if they're just starting out with inverse gc. If you're an existing customer and helium is a rate limiting step, then we can switch your system to nitrogen. So you want to contact your local representative and they could give you information about converting your system from a helium carrier gas system to a nitrogen carrier gas system. So just an aside, there's a carrier gas that constantly flows through the system and then we inject different molecules at different temperatures or flow rates or concentrations. All of that is controlled by a PC that basically does all the work for you. The only thing you have to do is pack a column. The columns are typically a 30 centimeter glass column. And to pack a column, you simply place a small amount of glass wool at one end, load the sample with your sample of interest. This could be a fiber, could be a granule, could be powders, could be films, and a small amount of glass will to hold it in place. We have a range of column diameters of different sizes to accommodate a range of both volumes and sizes of particles or powders or fibers. Typically you maybe want to put in between 10 and 500 milligrams of sample. The amount of sample will typically depend on how active that surface is and how much surface area is available. But normally it takes about five or ten minutes to pack a column, load it into the system and the instrument does all the measurements from there. And just to highlight, I won't go into details, but we often get questions and when I show data later on, you'll ask, you know, what's the reproducibility? And this is a large reproducibility study that we have done with the igcsea. And you can see that the standard deviations in both surface area measured by inverse GC were quite low. And so we can see we get extremely good reproducibility surface areas below 0.1 meter squared per gram on the standard deviation and very. And then also this is on a different study looking at 10 successive runs on one column. Again we can get quite a good reproducibility. So if you ever have any questions on reproducibility of the instrument itself, we can provide a technical note that will detail all this information. This was, there's two different technical notes, one on some different types of materials that can give you that information. So moving on to actual the. The interesting bit of the talk, hopefully is actually looking at surface energy on some biomaterials and how we might apply that to, to a range of different materials. Before I get to that point, just as a reminder for those not familiar on measuring surface energy by inverse gas chromatography is we typically use a series of straight chain alkanes, nonane octane, heptane, decane, and there's a couple different approaches in the literature, but essentially you inject a few non polar molecules or dispersive molecules and you get the dispersive component of the surface energy, this gamma D, and then you use some Lewis acid base molecules and Again, there are different acid base series. We won't go into all of them, but essentially from these Lewis acid base, we can get the acid base contribution to the surface energy. So we inject a few dispersive molecules, then a few acid base molecules, and that can give us the dispersive and acid base contributions. And that gives us the total surface energy of whatever material you're trying to study. So moving on to a study we have done here. This was done in collaboration with Dr. Jerry Hang's group at the London Imperial College. We were looking at some glycine oligomers and we wanted to look at the effect of two effects. We wanted to look at the effect of the chain length of the glycine. So we went from glycine, we also ran diglycine, I don't have it on the chart here, but triglycine, tetraglycine and pentaglycine. So we wanted to see how changing the chain length of the glycine affected the surface energy. And we can see that here. So this was done. We did that at 0% relative humidity. And that's what we see here. We see the dispersive contribution in the red shaded box, the acid base contribution in the blue shaded box, and we did that again for the glycine oligomers, and then we did the same thing as a function of background relative humidity. So we wanted to see what the difference was between a dry sample and a partially hydrated or different moisture contents and how moisture or water would affect these materials. And we can see here from the glycine, as we go from 0 to 50% relative humidity, basically no change, water does not interact very strongly with this material and we see almost no change or no measurable change in the surface energy of that material. However, as we increase the chain length of the glycine, we can see that moisture has a stronger and stronger effect on the surface energy. And I did forget to note is that's not surprising because as we go from the glycine to the triglycine to the tetra to the penta, we can see that the acid base contribution, or sometimes called the polar contribution to the surface energy increases as we increase this chain length. So the surfaces are getting more and more polar as we go up in glycine chain length. And this increased surface polarity is then showing a much stronger dependence on the relative humidity. So water is playing a major role in the surface properties of these materials when they become more and more polar. And this is just showing, just as a summary, this is the Acid base contribution to the surface energy as a function of the glycine chain length. And as we, again, we go from glycine to pentaglycine, we see a very strong dependence on the acid base contribution to the surface energy. And basically, we see an increase in the polar peptide bonds as we go from glycine up to pentaglycine. So some initial modeling was done to try to look at the structure of these different materials. And we have it for diglycine and triglycine, the full structure here. And the modeling suggests that there's an increase in available hydrogen bonding sites and the major habit faces and the increasing chain link glycines make these surfaces more attractive to water molecules. The different chain lengths would suggest a different dominant site that's at the surface and available to the water molecules. So the information that I showed previously was what's often called infinite dilution surface energy. We can also look at the heterogeneity of the surface by doing a range of experiments over a range of concentrations. And this will allow us to look at a surface energy heterogeneity. And we do that by doing experiments over a range of concentrations. So if I have a little cartoon, and this is obviously just some, just for visual information, not actually how it would look, but these two surfaces might look fairly similar at infinite dilution because they're going to be dominated by the most energetic sites. But if we can do a range of concentrations, we can then get a much broader and diverse picture and a fuller picture of the surface. And so this is kind of like shining a flashlight at one spot. This would be, you know, shining a floodlight across the entire surface. But we can tailor this and structure the vapor to surface ratio to build up essentially a profile of surface energy as a function of surface coverage. And by surface coverage, we mean the number of moles that were injected divided by the number of moles that would be required to cover a monolayer of the surface. This does require knowing the BET surface area of the material. I won't talk about that. I know Darrell's presentation later will touch on measuring surface area by inverse gc. But if we know the surface area of the material, we know the cross sectional area of the probe molecules, then we can determine this surface coverage. And what then that allows us to do is we can get the surface energy as we see on the Y axis, as a function of surface coverage. So when we're all the way off to the left, the surface energy values that we measure are going to be biased by the Most energetic sites. And then as we cover more and more in the surface and wet a larger fraction of the surface, we get more of an average surface energy value. So this has two benefits. Number one, it helps us get a fuller picture of the energetic situation on the surface and allows us to distinguish surfaces that may look similar by other techniques. If I only measured it at high concentrations, these two surfaces might look quite similar. And this would be similar to like contact angle, where I measure the. I wet the entire surface. Here we can control that surface to probe molecule ratio. And we can see these are two solid dispersions. This is solid dispersion here, just with the drug and a binder. And this is the solid dispersion with a drug, a binder plus a protein. So we can see maybe this protein is coating some of it or covering some surface groups that are there and that could help stabilize something in the cell dispersion. Because now this API or this drug may not be exposed to water or other things like that. We can see that the protein is likely coating the drug because this protein added solid dispersion. We can see a much lower surface energy, which would suggest an increased stability for that material. Again, as important with most biological materials, water can play a massive role in how they behave. So we wanted to look at this as a function of relative humidity as well. So we can see here this is at zero. We took the a single value, I believe at 0.05, surface coverage, and looking at the polarity or the relative polarity, which is when we take the acid base contribution divided by the total contribution to surface energy, and that gives an indication of surface polarity or surface wettability. So we can see that we do see some changes as we go from 0% relative humidity to a 70% relative humidity. And we can see that we do see a strong dependence on that. Not shown here is that some of the moisture absorption Data taken by DVS does indicate there might be a phase change above 70% RH for the PPZ sample, which is the one that included the protein, which may include some other restructuring of the protein.

Oops.

Okay. In another study, this was a paper that was published by a group at Ethicon where we were involved in measuring the surface energy of different aggregates that are used as a blood clotting agents. And these are basically, you know, either starch base or other, you know, hemostats that can affect blood coagulation and blood clotting for a wound care. And you can see here that there is a significant difference in the performance in particularly, you can see that the sample 5, the aggregates with a high sphericity, were the best performers. You can see here you get a good separation and you definitely have clotted the blood. Whereas the control sample, you can see that is completely free flowing. And the starch base spheres did not a very good job of that. So this is the end performance. So we want to look at the surface energy values of these materials and it's a little bit busy. If you want the full details, you can see here is the reference for this paper. But again we can see for these starch based spheres, we can see if we look at the total surface energy and the acid base surface energy that the acid base contribution is much higher. So these are very hydrophilic. Whereas when we go to the other samples, in particular the samples with the high sphericity, we see a lower acid base contribution, meaning that these might be more lipophilic. Then we look at this wettability. This is the acid base divided by the total ratio. We can see that these hemostat samples that do a good job of interacting and coagulating the blood do a better job, are more hydrophobic or maybe more lipophilic, which is more applicable, more attractive to the blood. Whereas these very hydrophilic materials are probably more attracted to the water and they don't do, they don't attract the blood cells and they don't coagulate. And this is just showing this work of adhesion. What we did is we found a representative value for the. There are tabulated and known values for the surface tension of blood. And if we know the surface tension of blood and we know the surface energy of the powder, we can calculate a work of adhesion to cohesion ratio. And the closer this ratio is to one, the better you would expect that the aggregates or the coagulants would interact with the blood. And we do see that here we can see the starch based spheres which if we go back here, do a poor job, show a much lower adhesion to cohesion ratio. It's much further away from one. And when we see that the spherical ones, which were the best, had the closest value to one, and that means that the surface energy of the coagulants is very similar to the surface tension of blood. And that means they'll want to interact with each other as opposed to segregate and not interact, which is what we see with the starch based spheres. I've gotten to about the end of my time. I've only highlighted A very few applications that SMS has worked with with some other partners. Here are just some very quick scan of some other studies where surface energy measured by inverse gas chromatography was used to look at some other biomaterials. There's other applications looking at bone cements, biomaterials, bioglass, dental cements. All those things are interacted and controlled and have a strong dependence on the surface energy and how those materials behave as, as a composite, let's say, in a bone or a teeth or the bioavailability of materials as well is all related to their surface energy and their wet ability. So without further ado, I would like to thank colleagues at sms, both past and present, who have now, at other places, who contributed to some of this work over the years. This is not done in a vacuum and not done by me alone. So it's a team effort from a lot of people over a lot of years. So this was just a kind of a summary of some recent work related to wettability of biomaterials. So, John, I will pass it on to you. If there's questions or if we need to move on to Darrell's presentation, I will let you take the floor.

Yes, and I believe we have a few, a few minutes of questions and we have a few waiting here. So just a reminder to our audience, if you would like to ask a question, submit it in the questions panel or raise your hand and we'll come around to you. So the first question Dan asks, what is the surface area limit for the ITC Sea?

That's a very good question. I would say on the low end, around maybe 0.05 to 0.1 meter squared per gram. So it's really a function of can I get enough surface in the column? You may have to go to very larger columns if your surface areas are below 0.1 meters squared per gram. Typically I just simply can't get enough material in the column to measure it accurately. But if you add one of our wider columns, we do have columns that can have up to a 1cm diameter, you could get below 0.1 meter squared per gram. But I would say for our standard system, in my experience, around a 0.05 to 0.1 meter squared per gram is kind of the limit on the low end. On the high end, I would say it's not a technique that's for measuring surface areas above 200 meters squared per gram. In that case, we simply, because it's a discontinuous pulse method, we simply, simply cannot get to high enough concentrations to get in the BET range. So for some zeolites or some activated carbons or some molecular sieves or some other materials, I would say in a pulse method, if you use a frontal method, you could get those higher surface areas, but typically between 0.1 and 200 meters squared per gram. Excuse me. Assuming you can outgass it properly as well. Sometimes higher surface area materials need to go to vacuum and high temperature, which we don't typically do. So I hope that answers your question.

Thank you. Another question is what happens if the column when packed, has gaps in the particulate samples?

Sure. I mean, it's okay if there's gaps in the samples. And that's one of the reasons why every column and every experiment, and in fact, in our method, it automatically does two methane injections at the beginning of the experiment and two methane injections at the end of the experiment. And that'll take, that'll normalize out any gaps or packing irregularities or void spaces. The only thing is, you typically don't want that to change during the experiment. So what we do is we typically have a preconditioning step where we'll flow over gas for 30 minutes, an hour, two hours. And that will normalize the column. If it does repack, it'll do that in that first 30 minutes to hour. And that conditions the column. And there's actually a check. So that's why we do injections at the beginning and at the end of the experiment. And you can check to make sure that your dead volume hasn't changed during your experiment. So it's a very good question, but we have it covered by using our tracer or our dead time molecule. We do dead time measurements before and after the experiment to make sure it hasn't changed during the experiment.

Thank you.

We have a hand raised by Peter Kelly. So, Peter, if you would like to unmute your microphone, you can ask.

Hi, Dr. Burnett, thank you for the talk. I'm a graduate student at the University of Maine working on your SCA system.

I'm curious about this work of adhesion versus work of cohesion ratio that you discussed.

I'm doing surface heterogeneity measurements as well. What coverage would you suggest looking at that ratio for, say, a composite system? I mean, the, the calculations will do it for all the coverages. So if you have the software, it will do it for all of the coverages. But you know, I would typically, when I'm trying to boil it down to a single value, I typically try to go out to maybe like 0.1 N over NM. So that way it's maybe a little bit more representative for the entire surface. However, with that being said, it's sometimes those high energy sites that really drive adhesion and agglomeration and segregation. But it is difficult to. When I have maybe 10 different coverages and I want to compare it to some other orthogonal measurement, whether it be some other performance measurement. So when I'm doing it, I might look at something where they. Now, if they plateau out at different levels, I would say maybe around 0.1 N over Nm. But the software will give you values at every surface coverage if you wanted to.

Okay, wonderful.

Thank you so much.

Thank you, Peter. And the last question before we move on to our next presentation, Dan, could you elaborate a bit more about how to get the polarity of materials?

Sure.

I mean, this is just. It is a function of the software and it's really just a mathematical way to look at the surface energy in a different way. What the way we approach it is, it is, it takes the gamma ab. So let me see.

I think it's.

So it takes the gamma AB divided by gamma total, and that is just a way. So it takes the acid. So if I was going to. Let me go back here and just show, let's say, surface energy, it takes the, let's say the dispersive or the acid base portion divided by the total portion. It's not a different measurement. You get it from the surface energy data. But what it allows you to do is maybe it could help you distinguish two surfaces. I might have two surfaces where the total surface energy might be the same. So maybe if I was to go to, let's say, this example, I know this isn't probably perfect, but, you know, let's say I added up this glycine sample and maybe the total surface energy is around 50, but is dominated by the dispersive component, where I might have another sample. Now, this isn't the case, but if I added these two together, it might be 50. But 20% of that surface is from the acid base contribution. So all it does, it takes the acid base contribution divided by the total contribution of the surface energy. And we call it surface wettability, surface polarity. It's just a way to help distinguish surfaces a bit more relative to their chemical nature rather than just the total surface energy. So I hope that helps.

Thank you so much, Dan. Yes. I believe now we will move on to our next presentation. So once again, thank you so much, Dan, for being with us today and for Sharing your presentation with us.

All right, thank you, John.

So, moving on to our next presentation now, we are very fortunate to have with us Professor Darrell Williams of Imperial College London and he is of course the founder and Managing Director of Surface Measurement Systems. He will be exploring the topic surface energy and surface area studies on pharmaceutical powders using invasion inverse gas cryptography. Just before we dive in, I'll give everyone a quick reminder of Darrell's background. Professor Williams graduated with a Bachelor's Honours in Physical Chemistry from the University of Melbourne, Australia and a Master's in Polymer Science from Lehigh University, USA before coming to Imperial College London to complete his PhD. He is the Founder and Managing Director of Surface Measurement System and the professor of Particle Science in the Department of Chemical Engineering at Imperial College. He's published over 100 papers in reference journals and has been granted five international patents. His research interests include the surface of bulk characterization of complex organic solids, including especially biopharmaceuticals, foods, pharmaceuticals and polymers, as well as their manufacturer using spray drying, crystallization, freeze drying, milling and granulation. The Surface and Particle Engineering Laboratory Imperial College that he leads has four postdoctoral research fellows and 11 PhD students. Professor Williams, he's invented one of and has led the commercialization of two standard techniques for materials characterization, one of which is inverse gas chromatography. This work being conducted via surface measuring systems and his work has been recognized by by Imperial College with the President's Medal in 2017, the EEF's Future Manufacturing Award in Innovation for 2018 and the Institution of Chemical Engineers Geldart Medal in 201819 for his major contribution to particle technology. So I hope you'll join me in thanking once again Professor Williams for being with us here today. And without further ado, I will hand over to Dan.

Well, thanks everybody for coming along to hear the presentation. Today I'm going to be focusing on pharmaceutical materials overall and the predominant area of activity. My presentation will be surface energy, but I will spend a few minutes talking about surface area because from time to time surface area is quite a useful information set you can get using inverse gas chromatography. So that's the overall plan for today. The structure is some overlap with what Dan introduced before around igc, but we're going to focus in the latter part on service energy and three or four applications around milled powders, powder flow, powder granulation. So we're going to be particularly exploring the question, which is really quite simple. If I measure surface energy, so what, what am I going to do with information? Why would I care and we're going to show three or four problems where we've been able to demonstrate that the surface energy of powder allowed us to predict performance of powder ensembles, whether it's flow or. Or whether it's a solution, a range of factors. So we're going to try to explain today why surface energy is a useful property, and surface energy is a way which we can understand some of the more subtle ways complex organic materials behave. I think you probably had introduction to IGC from Dan. I won't spend too much time on that. His short answer is it's a very powerful physiochemical method for characterizing powders, fibers and physical films, as well as semi solids and particulates. And today we'll focus on particularly on powders. And we'll talk a little bit about fibers on the way through. It's not a new technique, although it's only been commercially available now for probably about 20 years now. And SMS has been involved in the commercialization of technique for quite a long time. One of the important parts about the technique is that we're going to use molecules to probe our materials. Whether we are probing the surface properties in terms of surface energy or surface area. It turns out that molecules, organic molecules, whether that's octane, ethanol, hexane, those are very useful molecules for probing surface properties. And the logic as to why it's important is quite simple. We're often interested in the way powders behave. So we might be interested in powder caking or powder flow or powder solution. So what we're actually interested in is how powder interacts with other matter. Could be a liquid, could be a gas, could be another solid. So it turns out if we're interested in the interaction that the surfaces of particles have with other particles or the walls of vessels, it actually is not. It's quite logical to use another molecule to probe the surface properties. So it turns out that using molecules such as hexane or octane or methanol, they're the naturally relevant ways of probing the surface properties of particles. And therefore it gives us data sets that's quite interesting as far as understanding the performance of these materials in complex powder flow configurations. And we'll see some applications a bit later on today. The IGC method, I'm sure, has been described before, but if you just joined this particular presentation, just in summary, we're going to pack unknown powder into a column here. We're going to elute through it a carrier gas containing some specific solid molecules that will interact with the solid state. We're Going to measure the time of flight as these molecules pass through the column. We're going to compute typically isotherms and then we're going to convert those into some physiochemical descriptors. And today the descriptors are surface energy and surface area. They're the two. There's a very wide range of properties we can measure. We're only going to talk about a couple today. We're going to talk about a little bit about heterogeneity mapping, a bit about dispersive surface energies, and a bit about bet surface areas. But there's a range of different properties we could determine using these vapor phase molecules interacting with our material once we've packed it into a column. So as I said, we're going to go on to surface energy in a few minutes. But I just want to talk to you a bit about surface area. It's one of those properties that everybody measures, but sometimes the measures get a bit tricky. There are two reasons why measuring surface area can be challenging. I'll just remind you what they are. Firstly, if I've got very low surface area materials less than a meter squared per gram, we're going to discover that nitrogen Bt is not great rate. Also, if I've got a material that interacts with water vapor, that is also a complication because the techniques that typically used to measure surface area require the sample to be fully dried. In some cases, that could destroy the material. Let's imagine you've got a dihydrate, it's a powder. You want to measure the surface area, but as soon as you put it under vacuum, you dehydrate it and you lose the structure. Now, the surface area you've measured is totally irrelevant. So it turns out with IGC we can do two particular sorts of surface area experiments. Imaging, we can do low surface areas and we can also do surface areas at different communities. I will show briefly an example of those. So here's a very useful table that summarizes the techniques that are out there at the moment. And what you can see here we've highlighted. Let me just turn on the pen here. That's right, laser pointer. So for nitrogen techniques for surface areas, about 1 meter square per gram up to, you know, typically about 140 up to 1400, I should say. Nitrogen absorption is the go to method. But once we get down to a few meters squared per gram and certainly one, the errors become quite large. Typically a 10% error would not be uncommon common. So for some people that could be a bit of a problem. So if we look at materials such as pharmaceuticals, fibers, excipients, it's quite common for a lot of materials to be in this 0.1 to maybe 5 meters squared per gram area. That's an area where nitrogen is not very accurate. So it turns out the good news is that IGC is actually very accurate from about 100 meters squared down to about 0.1, maybe a bit less. If you're careful, you can measure areas with typically about a 1% error. So it's much more superior. You also do the experiment at room temperature. There's no vacuum required. And rather than use nitrogen or krypton, use organic molecules such as hexane, octanol, whatever. And these give us a lot more chemistry. We learn a bit more about the material using those sorts of vapours. So just to remind you, there's an international standard out there for measuring the surface area using bet, and that does not preclude the use of techniques like igc. It defines a whole raft of molecules you can use for doing adsorption. And you'll see there that water molecules, heptane, octane, benzene. So there's a range of molecules that can be used, not just nitrogen. So don't think when I'm doing your nitrogen BT I have to use nitrogen, you don't. There's a range of other molecules that are sanctioned by international standards, including octane and heptane, for example. And we'll be using those sort of molecules today. So just to sort of give you a bit of a feeling for the technique, so here is some experiments done using a standard reference material. This is a CRM170 standard BET reference material. And we can study that using our IGC method. Pre treatment at 100 degrees for 6 hours, experimental done at 30 degrees, large sample, 500 milligrams. We've done it with octane. Okay. And you can see the octane isotherm is shown here. This is the raw data. This is PP naught. This is the amount absorbed. I take the BET model, I linearize it, and here's my BET analysis. And I get a result of about 1.02 meters squared per gram. And the official result is 1.05. So within experimental error, I'm getting the same result using octane at 30 degrees as I would get using nitrogen at 77 kelvin. So that's something which is nice to know, but of course, so what happens if you want to do some low surface areas? So here's some data at low surface areas, it's A single column repeated 10 times, it's 0.28 meters squared per gram. Pretty low. Doing this on nitrogen would be really quite a problem indeed would be probably rather unsuccessful. We can get errors of about 1 to 2% for very low surface areas, which is really quite a nice thing. This particular material is paracetamol, the standard crystalline pharmaceutical material. But here's another material. This is the surface area of cotton fibers. And what's interesting about this, of course, is that we're doing the surface area at different humidities. Now that is not possible using nitrogen or krypton. You cannot do this volumetrically. So what you can see here, at low humidities, the actual surface area is constant at about 0.9 meters squared per gram. But as I increase the humidity, the fibres are effectively swelling and the surface area is increased by about 12%. So I can use my IGC approach to determine the actual surface area of a swollen hygroscopic material. So if you're working on materials such as cotton or silos or any other semi amorphous materials that swell in the presence of water, we can actually use this as a way of monitoring the swelling process. So I want to introduce those topics on surface area. But let's move on now to the main topic. The main topic is surface energy. As you've heard before, it's analogous to the surface tension of a liquid and it tells us really around the thermodynamic state of the surface. And we're particularly interested in intermolecular forces that work on surfaces. And we're particularly interested in two types of surface forces. We're interested in what are called dispersive long range forces. So we'll talk about the dispersive component of the surface energy. They'll typically be described as gamma D and it relates to the long range van der Waals forces. So these are forces exhibited by all materials. And we're also interested in the acid base forces. These are short range chemical forces. Sometimes they might be described as polar forces, sometimes they use the word hydrogen bonding, sometimes acid base. But they are all in common. Short range molecular interactions. Some molecules, some materials exhibit them, some don't. But measuring those is quite important in terms of understanding the surface properties of mine materials. However, today we will predominantly be talking about dispersive long range van der Waals forces. They're the ones we'll be focusing on today. So let's for a moment talk about the surface energy. Now, there are lots of ways to measure surface energy. I've used them all over the years. And here I'm just giving a little summary as to. Did I lose the slide then? Hang on, that's still clear there, is it, Don? Yep, yep, we can see. Thank you. So there are four techniques out there that you can use to measure the surface energy of solids. The first one on the right is a common technique, as is the one on the right. The wetting balance method is quite a simple method. You take a material, could be a fiber or a flat film, you hang it from a balance and you essentially force it to make contact with the liquid of interest, and you measure the wetting force. It's not suitable for particulars, although I know people will try to tell you otherwise. Experience that people have done that is not a happy story. Surfaces that have got roughness or surfaces dissolve, there's a whole range of surfaces that is not going to be suitable. And there aren't many liquid you can use for the experiments. But for a flat material and for some polymer films or some silicon wafers, that could be, well, could be good. The most common technique is to do contact angles, sessile drop. Put a drop of liquid on a surface in question, measure the advancing and the receding angles. That's a very, very common, very simple. And for flat surfaces, it's a great technique. But if you got a particular material, if it swells, if there's hysteresis, dissolves, if it's rough, there are a range of complications, making it pretty tricky. And final, but becoming more popular is atomic force microscope. Again, if the surface is flat, this can also be quite good. You can use the tip of the AFM to measure an attractive force between the substrate and the actual tip. And potentially you can map the surface energy of material doing that. The theory requires a bit of care. You need to know the radius of the tip. There's a few things you've got to do. It's quite laborious, but it can be done, particularly for flatty surfaces. However, if I've got a flat surface, I've got three or three techniques. What if I've got a paler, If I've got a powder or a very rough surface, none of those techniques on the right are going to help us. If I've got a powder or a rough surface, I need inverse gas chromatography for particular materials. It's excellent, it's repeatable, no hysteresis, there's no roughness effects. I can use a very wide range of solids. I can map heterogeneity. I can also determine isotherm so there's a lot of things I can do using IGC that I can't do. The technique. So for particular materials for measuring surface energy, it's the go to method. Of course we've heard before if I measure the surface energy of material cohesion sorption, we I can get an understanding of those phenomena by measuring the absorption properties of my surface using igc. As far as pharmaceutical materials, why do I care? Well, here are a dozen reasons why you might want to measure the certainty of your pharmaceuticals. You might be interested in drug excipient powder interactions. You might be interested in how the powders adhere or bond, including attachment to walls of vessels. You could very much be interested in powder mixing, segregation, powder flow or static charge, which sometimes happen for many powders. If I'm grinding, milling or commuting my powders, or micronizing them, then I want to know about the process induced disorder on the surface. I can get that from IGC data sets. I want to be more about product stability, how amorphous versus crystalline is my material. Again get it from igc. And also I can get a pretty good measure of the heterogeneity of my surface. Is the surface homogeneous, it heterogeneous? If so, how much? I can also do very basic things. Can I compare the batch to batch variability of three or four different manufacturing materials? The answer is yes I can. And also I can determine intrinsic properties, surface acidity, basin surface energy, surface area modified, non modified, and also look at stability. So there's a lot of things I can do with IGC as a tool which is relevant to the that fact pharmaceutical industry. So things that you know are relevant to our discussion today. I think you've seen this before, I won't go through it again. But this watches simply describes how you change the surface energy, wettability, powder cohesion, process disorder and adhesion between particles changes. So just a cartoon that you see I think earlier today from Dan. So one of these that comes up quite often is people say to us well aren't my materials homogeneous? Well, the truth is most pharmaceutical materials in our experience are not homogeneous. And actually when you look at what's going on, it would be a bit of a shock if they were homogeneous. We've got the presence of contaminants and impurities. We've got different crystal planes, different crystal facets which have different chemistries with different degrees of morphicity. There are polymorphs, hydrates, solvates forming, There are surface groups, there's sometimes different variations in the extent of modification, there are defect sites, edges, surface pores, crystal steps. There's irregularities in the lattice, there's pore sizes. There's a real large range of crystalline anamorphous properties, defects and chains that can actually affect why my material is not homogeneous. So in my eyes, if I've got a crystalline material or indeed an amorphous material, the chances are it's going to be to some extent heterogeneous. Question is, how much? So I just want to take you back to how we're going to do the IGC experiments. Coming up in a moment. So what I've just put in front of you here is a model isotherm. So we've got on the X axis the concentration of, of the molecules that we're going to use to interrogate the surface. And on the Y axis, we're going to have the amount absorbed. So traditional IGC is carried out at very low concentrations down here. But it turns out if we want to probe the heterogeneity, we need to go to a bit higher surface coverages. So typically we're working in the region up here. So on this, sort of the start of what's called finite dilution or finite concentration. So in other words, we have relatively high surface coverages. So the molecules are going to sample anywhere between 5 and maybe 30% of the surface. So that's the extent of coverage of the surface we're going to be aiming for in these experiments. When we do the experiments, and I think the heterogeneity method Dan described earlier today to you, essentially we have a couple of typical examples. A cartoon which gives you an example. So the surface here, this one, which is pink, okay? This pink material has less defects, okay? And because it's got less defects, it's a more homogeneous. The surface energy doesn't vary very much. Whereas my blue sample has got a lot of different heterogeneities. Whether these are pits or other chemical heterogeneity doesn't matter. So when I look here at my heterogeneity data, differences like this, firstly, for the red surface, the pink surface, I've got a very narrow distribution, potentially low energies, whereas the blue one, I have a wide distribution. But some of the energy is also quite high, and that's shown here. So here I've got the blue curve shows a much bigger variation in the energy from the high to low. It varies a lot more. And the one that's pink's got less defects. It's not homogeneous. If it was that it would be a horizontal line. But you can see the degree of homogeneity is greater in the red sample. And we can define some other properties as gamma 50 is median energies where 50% of them above or below a particular surface energy for the material. So let's talk about the work. So the study I'm going to talk about today really focuses on the use of D Mannitol. So we're going to see two main types of mannitol here, an as received demonitol, which is basically as provided by the manufacturer. So it's a very high crystalline mannitol material. And we're going to have a cyanized D Manitol, as we'll see in a moment. D mannitol has three different crystal faces and they're all slightly different chemically, but we can change those in a moment. And we're going to actually make the mannitols all hydrophobic by cyanizing them. Now, the initial work, we're going to look at two different substrates we're going to do. We're going to grow some large crystals and we're going to look at the surface properties using condon angles. Then we're going to take some powders of the same material and characterize them using surface energy on igc. So large crystals and powders, large crystals using the contact angle measurements, the powders using igc, compare them and see, hey, are they the same? So just to remind you, there's a structure of D mannitol and what you can see is a lot of hydroxyl groups. So here is the crystal that Raymundo grew many years ago. And you can see the 011010 and the 1-20-crystall faces. And we'll see later on, that crystal is about 7 millimeters across and it's about a couple of centimeters long. It's big enough for me to put a drop of a kind of dangle liquid on each crystal face. And what you're going to discover is that the data is different for different crystal faces because of different concentrations of hydoxyl groups. So here we go. This is the contact angle measurement at the moment on D mannitol crystals. So we've got the crystals here. And you can see here, this is diodomethane. This is my hydrophobic liquid. It's measuring the van der Waals interactions. And this here is water. It's measuring the acid base or polar interactions. So what I'd like you to notice the following, that the diodomethane ones for 010 and 120 are fairly similar, but for 011 quite different. Bit more hydrophobic at the end here. If I look at the water here, you can see here the water has conant angles of 56 on this surface, 46 here, but on this facet, 12. So in other words, for that to be true, there must be a lot more hydroxyl groups on the this facet. Okay. Because the hydroxyl groups in the mannitol are what give us the actual small conund angles. In a moment we're going to compare this data with the data we get from igc. But from the Conant angle data we can determine the dispersive, which is van der Waals, and the polar, which is acid based interactions for each of those crystal faces. So if you didn't already know, what you can see here is that the different crystal phase at different surface energies and that reflects the fact that different functional groups on the surfaces. How do we know this? Well, actually what we do is we do xps. Okay. XPS allows us to look at the concentrations of hydroxyl groups in different crystal faces. So here's XPS data for showing the CLH groups for 1, 2, 0 and for here 011. And you can see here the concentration of hydroxyl groups is probably four times higher. Okay. And that's because where the crystal facet is goes through the lattice, we end up with a lot more hydroxyl groups pointing out of the lattice structure on the 011 face. So the Connaught angles simply reflect the chemistry of the crystal faces, pure and simple. As I said, we wanted to make some actual hydrophobic material. So what we did was cyanation procedure here, dichloromethylsilane, trichloroethylene at 80 degrees reflux. And essentially we start with hydroxyl groups, we end up with methylized groups. Crystal structure hasn't changed, but the surface chemistry, as we'll see in a moment, has changed. Here is the surface energies for untreated and for treated. And you can see here that for the untreated materials, the solar energies varied a little bit, but once we treat them, they're all the same. Okay. They're all at the same height of vicinity now. So we now move away from looking at wettability on crystal crystals to now measuring IGC on the powders. Okay, so what you can see here is the IGC data. And this is, you can see here the treated material which is here is very homogeneous. Okay. Whereas the untreated Material is up here and it's clearly more heterogeneous because there are three different crystal faces. They all contribute to the overall energy we see. So, and if we go ahead now and we plot this is the continent angle data, this is the energy from continent angles. You can see within a couple of millijoules per meter squared. We have very good correlation between the continent angle data and the IGC data. So from our perspective, we're pretty confident that data has done what we said it would do. And the IGC data reflects the data we see on single crystals. So what we've got now that we've got the data from cyanized and as received D Manitol, we can calculate the works of cohesion. Okay. And of course, because the as received material's got a higher energy, it's got higher works of cohesion. So that's what we'd expect and that's a predicted result. So the first thing we're going to know is right here, so I've got these two powders. How do they behave? So the first thing we did was do a powder cohesion experiment using FT4 powderiometer. So I told you a moment ago that the blue powder here is a cyanoised one, has lower energies, so we would expect it would be easier to flow. And you can see here, here is the flow energy for the cyanoid material and it's much lower than the native adversary material. So essentially, once we cyanise the material, we're able to actually substantially change the flow behavior of the material. Okay. Particularly when the materials are aerated. So automatically, powder properties, using IGC powder flow mechanics, we start to see correlations and agreements. So let's move on to a slightly different topic now. We're moving away now from the Manitol. We're now moving on to some aspirin materials. So we're looking at the moment as a milled, unmilled aspirin materials. They were sieved at different particle fractions. The milling did not change the actual amorphicity. So the same crystallinity. What we can see here is the materials which have normally the same particle sizes. And so we've got some particles that were milled to 150, 100, we have some materials that were milled and some people that were grown natively to a certain crystal size. So we basically got a milled unmuled aspirin materials here. And you can see that the dissolution profiles for these materials is different depending on whether muled or not milled. And this relates to some extent to the surface energy of the materials. And here you can see the surface energies. So what you see here is that the red materials are unmilled. So these are native crystals that were grown, okay. So the red ones are unmilled. So they have had the slower solubility, the faster solubility comes with the milled materials. And the milled materials here also have the higher energies, so higher energies, faster dissolution rate. And that's something you can deduce from their IGC experiments. Okay. We've also had a look at the effect of surface energy and crystal habit. These materials were milled and they've the average size and what to be precise, as the aspect ratio was different. And we can see some relation between the aspect ratio of the materials and the actual habits we've got here and the sudden energy we determine. And here's an. Here's a bit more data on this. This is looking at the milling of mannitol. We can see here the different facets of different energies. But as we change the aspect ratio, so that means the ratio of N groups to side groups, effectively, we can see changes in the actual dispersive energy as we change. So the dispersive energy change with the aspect ratio. And that ties together. And we would expect that. So as we change the population of these species to that species, that's reflected in the actual surface area, surface energies we determine, so we can look at the aspect ratio change and the surface energy both linked together. The final example today I'm going to talk about is wet granulation. Wet granulation is a popular unit operation for consolidating materials. It involves us actually taking a liquid binder, spraying it onto a powder, and the formation of agglomerates. And these agglomerates are then typically dried and they're used in manufacturing operations. So in the study I'm going to talk to you about today, we are going to actually use a PVP solution as our binder. We're going to actually look at the particle size distribution as well as the Young's modulus of the granules we manufacture. And we're going to have both a hydrophobic mannitol component as well as the hydrophilic normal component. And we're in different ratios. So the idea is, as the hydrophobicity of the powder mixture changes, how does that affect granule properties? Do the granules get bigger or smaller or are they unchanged? And also does it affect the strength, the mechanical strength of the granules we make? So that's the Idea. So part of what we're going to do now is determine using the wettability information from the head, we're going to use our IGC data for the materials to understand should the PVP solutions wet or not wet our powders. Clearly, some powders are hydrophobic, some are hydrophilic. So we want to see which ones are going to wet, which ones are not going to wet. So the first thing we've got here is we determine the spreading coefficient. So this is using the wettability data for the powders and using the surface properties of the actual wetting solutions, we can predict whether or not the liquid will wet the surface or not wet the surface. Okay, so what we're looking at here is this is the spreading coefficient, and that tells us whether or not the liquid is going to spread. So the cyanised material here, where you would expect the liquid not to spread, and that corresponds to this spreading coefficient here. And these ones here, which are negative, that implies that the liquid will spread. So liquid spreads on the untreated man. Okay, it's a hydrophilic solution, so that's not unreasonable. And on a hydrophobic solution, it does not want to spread. So the first thing we've got here is the particle size. Okay, so this is granule size. And yes, you're quite right, there are some very big granules here. I do appreciate that. But what you can see here is that this material here, the black squares, is 100% cyanide. So that's my most hydrophobic material. My most hydrophobic material is actually making the smallest particles. Okay. And if I look at here, which is the as received materials, which are the diamonds, they're over here. So those are larger. So in other words, the particle size distribution does depend quite substantially on how hydrophobic or hydrophilic the powder is and whether or not the binder can wet out the material. Oh, okay. I don't see. We also, there's. We've also don't know where the mechanics went for that. Let me just see. Oh, okay. But. And I can also tell you that the mechanical. I'm missing a slide. I apologize. That I can also tell you that the mechanical properties of the materials also changed based on the wettability. So not only did the particle size distributions change, but the mechanical properties of the individual granules was different for the cyanized versus the unsalinised materials. So not just is the particle size changing, but the mechanical properties were also dependent on the wettability of the material. So conclusions here, IGC can be used to measure surface energies of surface areas of low materials. Using the BET model, we can map surface energy variations of powders using an ICT based approach. The IGC surface energies agree well with single crystal wetting studies. We can look at how the Surny effects as it relates to milling behavior and changes in the crystal facets that are present in a powder system. The Surny relates to powder flow and surface property. Powders directly influences granular particle size distributions and the compressive mechanics of wet granulated powders and hydrophilic powders give smaller granules compared to the hydrophobic ones. So just some of the teams involved with the work and the main work I spoke today was some work done by Raimundo who's been at Abbey for a few years now, and George Wang was also involved in some of those studies. I think that's just about my time. I'm happy to stop and answer any questions you might have. Thank you for your time and attention.

Thank you very much Darryl. It was a great presentation. Yes, we have a few questions submitted so let me just draw those up. So our first query, they've asked for just a bit of a clarification or a comment on your conclusions. They say regarding the surface energy hemorrhagic of the silicone treated man, it makes sense that the silicone treated with OH groups has resulted in homogeneous acid based structure energy, but they have difficulty understanding why the dispersive energy became homogeneous as well. Assuming the long range longer dispersion forces will always be existing. Do you have any comments or thoughts on that?

So let's talk about heterogeneity. So the hydroxyl groups, there are different hydroxyl group populations on each of the crystal facets. So each facet, although they all have hydroxyl groups, they've got different orientations and therefore they have different activity levels in terms of the other groups in the actual molecule. So the three different crystal facets, they all have hydroxyl groups, but not all hydroxyl groups are equal. When we react them with the cyanine groups we basically methylate those and we basically take away the active hydroxyl groups with a passive methyl group. And those methyl groups, they, their lability, their reactivity is less dependent on structure and orientation than in the case hydroxyl groups. I hope that answers the question, but do feel free to come back with a subsidiary question if you like.

Yes, please do. If you have any follow up questions, please just enter it in the panel. Another question we have here, they ask is there a Correlation between surface energy and amorphous content.

Amorphous content. Well, certainly there will be a connect. They are connected. Yes. I think if you wanted to actually use surf energy to determine amorphous content, you'd have to be fairly careful about how you develop the method. It could be possible. Dan, if. Do you know if we've done anything where we used certain energy to determine amorphous content? I can't remember. We have, yeah.

I mean just, just to make it clear is that we would be measuring the surface amorphous content. So the amount of the surface that's amorphous, that can be quite different from the bulk amorphous content. So something could be 10% amorphous by bulk. But you know, 80 to 90% surface is amorphous. So we have done those studies. You basically normalize it by surface area. There's a way to do it with binary mixtures. You basically assume that the crystalline phase is component one and the amorphous space is component two. So yes, you can quantify amorphous content. Not as sensitive as you can with DBS. It's probably plus or minus, you know, 3, 4%. So it's a bit more qualitative. But just to. It would be biased to only the amorphous content on the surface of the materials. But yes, it's possible. There's been a few papers published on that. GSK published a paper with us several years on looking at surface amorphous content by igc.

Okay, thanks very much Dan for that. Next question please.

The next question, what impact, if any, does humidity have on surface energy?

Let me make an initial comment. Dan can make a comment. Look, clearly once you introduce humidity, the humidity will compete for sites on the surface. So it does get a bit more complex in terms of what's happened with humidity. Generally I would expect surface energy would go down as we start to passivate the surface with water molecules. Dan, would you like to comment on that question? Because you might a bit more experience with doing that.

Yeah, that's a great question. I would say if moisture is not changing the surface. So if it's a, let's say a hydrophobic surface, you add water, you're going to get very little change. You might just see like, like Darrell said, a small decrease in the surface energy. However, for a lot of real world materials, moisture changes the properties of material, could open up different functional groups. It could cause an amorphous to crystalline transformation, could cause a moisture induced plasticization or phase change. A protein could unfold or restructure. So it's not a monolithic answer to say, you know, humidity is going to affect it in a certain way. It really depends on how water. If water changes the material, you'll clearly get a different surface energy. But if it's just water available, typically water would maybe stick or coat maybe the higher energy sites preferentially. So at low moisture contents I might see a slight decrease in surface energy. Assuming water isn't actually changing the material.

Thank you. Okay, thank you.

The original question was asked by me, Lee and they would like to unmute themselves and just ask a quick follow up please.

Sure.

You can unmute yourself now.

Okay John, thank you. Can you hear me okay?

Yes.

Okay, so this is Melee from the University of Tennessee in US and thank you, Daniel. I just tried to follow up my question about the energy homogeneity of the clam treated mannitol. So understand when you treat that one you knock off the hydroxyl group. So I, I'm expecting the acid base surface energy is gone, becomes homogeneous. But I have difficulty to understand. Yeah, but I have difficulty to understand to see sort of surprising surprise to see the homogeneity of the total surface energy of there. Because to my understanding the dispersive surface energy should be always existing and all materialism might be heterogeneously not homogeneous. If you see what I'm saying. Does that make sense? So.

You'Re right. When, when you passivate the surface with the, with the methyl groups you are going to be left with pretty well van der Waals forces which will be homogeneous. So just give me the question again because I didn't quite. There's something subtle about that I didn't quite catch. I don't think.

Yeah, I was wondering why the component from the dispersive surface energy also becomes homogeneous out for a treatment?

Because the surface is now just all methyl groups entire. The entire surface of that material now is just all methyl groups and the methyl groups are giving us the van der Waals forces and so we're only seeing methyl groups effectively.

Oh, okay. So that doesn't generate London Forest at all.

But that studies don't that the method groups and are dominating the London forces.

Okay. Okay, got you. Thank you.

Okay, sure. Thank you.

Thank you.

And then I think we have just a last question here, darl. And they ask what could surface energy heterogeneity tell you about farmer powder other than flow ability?

And what was that powder.

Surface energy hydrogen tell you about fire powder other than flowability? So what can it tell you about the fire powder other Than other than.

Flowability, what else could it tell you?

Yeah, yeah, sure. Well, I mean it potentially is going to tell. I mean as Dan's indicated before, it might tell you about the surface disorder in the material. It is going to tell you information relating to the ability to granulate the material in terms of wet granulation processes. It's going to tell you about what else it tell you. It's a. To you. It's going to tell you about the. It's going to tell you a bit about the variation, the habit of the crystals. So is there, I did do three or four. I mean they're not, I mean there's, they're, they're difficult things to measure. Okay. I mean some of these things but certainly IGC gets you a handle on some of these properties around dissolution performance, around granulation performance, around powder mixing, powder flow. So I think it does give you. Is it the perfect tool? Absolutely not. But these are very tricky things to measure. Sometimes surface or more physically not easy to do. But it gives you an ins. It gives you a chance to get at those sort of measurements which otherwise would be very hard if not impossible to get at. Dan, what else would you add to that?

Maybe how powders might behave in a suspension with a particular liquid disposability. Are they going to be missable or not? So some of that stuff could be driven by that. So yeah, that's what I would add.

I think dispersibility of powders in different sorts of. And also flocculation aggregation behavior. If I disperse my powder solvent, is it going to aggregate or not? Is it going to be colloidally stable or not? I think that would be. I would expect that get that as well.

All the questions we have for this afternoon. So thank you again so much Dal for being with us here today and for sharing with us.

Thanks guys. Take care. Thanks for coming along today.

Thanks everyone for your time. Have a good day.

Now I just wanted to remind everyone that this workshop took place as part of IGCSEA Week. So there will be a bit of activity happening every day to celebrate and promote the ITC method. Tomorrow we will be releasing the ITC Scientific Bulletin which will be rounding up all of the studies published in the last six to seven months concerning the itcsea. So keep an eye on your inbox for that tomorrow. We have a very exciting webinar with Dr. Annette Condor on Thursday which will be exploring new applications using a brand new variation of the ICCSEA featuring a high temperature oven. So the first time we've revealed some of these findings in public. So really exciting webinar there. So be sure to go to the webpage you see in front of you there to sign up. And then on Friday we're releasing the latest in our Zortion Directory series, the ITC Zortian Science Directory. This is a historical glossary or collection if you will, of studies involving ITC and the itcsea, so for you to reference easily when you need resources or to look back for your future research. So that will be getting released on Friday as well. Before I conclude today, we've had a few queries about people asking for extended demonstrations or tutorials on igc. So for those of you that asked, we'll get back to you after the session. And if you would like to discuss IGC or the IDSA any further for a discussion of a demonstration or a look at how the science works, please do contact us at Marketing Surface Measurement Systems so I thank you all once again for joining us today. And please do remember to sign up for our next webinar on Thursday on the high temperature ITC applications. Once again, thank you and we will see you all again soon.