Webinar: Particle Engineering in Pharmaceutical Solids Processing

Hello everyone. Welcome to today's webinar Particle Engineering in Pharmaceutical Solids Processing Surface Energy considerations presented by Dr. Darrell Williams. Our webinar today will be Based on on one of Dr. Williams latest publications discussing surface energy as a key factor in understanding the performance of many particulate pharmaceutical products and processes. We will be reviewing the surface energy and surface energy heterogeneity of crystalline solids, methods for measurement of surface energy, paying special attention to inverse chromatographic techniques, effects of milling on powder, surface energy, adhesion and cohesion on powder mixtures, crystal habits and surface energy, powder granulation processes and surface energy. Our presenter is Dr. Darrell Williams. He graduated with a Bachelor's in Science with honors in Physical Chemistry from the University of Melbourne in Australia and a Master's in Polymer Science from Lehigh University in Pennsylvania in the United States. Before coming to Imperial College in London.

To start his PhD, Daryl has published.

Over 80 papers in refereed journals, been granted five international patents, and speaks regularly at international conferences and workshops. He has expertise in advanced materials characterization and is a world leader in advanced instrumental characterization of sol. He is also the founder of Surface Measurement Systems and inventor of the Dynamic vapor absorption method as well as a surface energy analyzer instrument now used in over 1,000 laboratories throughout the world. Surface Measurement Systems is the technological market leader in advanced vapor sorption instruments for materials characterization. During the presentation you may send your questions via chat or there's a Q and A section and at the end of the presentation Dr. Williams will answer questions according to time. At this time we're ready to start and I will pass it over to Dr. Williams.

Okay, good afternoon everybody. And good afternoon to people from all over the USA who are hopefully listening to this afternoon's webinar. So I'm pleased to talk to you about particle engineering, particularly in the area of pharmaceutical solids. And today's presentation will focus on the energy of particular materials. Indeed, I have an alternative presentation title which I also share with you, which is the following why should I care about the surface energy of my powders? And certainly a lot of people don't understand what surface energy is, therefore, not surprisingly, they don't care about it. But I hope by the end of the 40 minute presentation today that you'll have some appreciation as to why surface energy is indeed an important property of powders, particularly in the farmers industry. And indeed, the presentation I'm giving today is covered in a little more detail in our recently published review article in Current Pharmaceutical Design that is an open access journal which you can access free of charge Online. But if anybody's struggling doing that, do send me an email and I'll send you a copy of the presentation. So this is the outline of today's talk. I'll spend a few minutes at the start just reminding you about Servsengi, what it is, and also why it is important in terms of particulate materials. We'll spend a little bit of time looking at the general techniques available for characterizing certain energy of solids. And finally, we'll spend some time discussing one particular technique, which is known as inverse gas chromatography. We'll discuss the experimental method and how it works. Then after that, we'll look at four or five examples of how surface energy can help us understand powder behavior and powder processing, with particular emphasis on the pharmaceutical industry. So today, of course, though, we're talking about pharmaceutical materials, it has relevance across a range of other sectors where fine powders are involved. So let me talk about and remind you about the surface energy of a solid. And of course, the surface energy of a solid is very much analogous to the surface tension of a liquid. If I put a drop of liquid on the surface, and I want that droplet to increase its surface area, I have to do some work, I have to put some energy into the system. And this additional energy that I need to put in to create new surface is essentially the surface energy. And it turns out because molecules that are in the bulk of a liquid experience different forces to those at the surface, it turns out that liquids require additional energy for me to create new surface. And indeed, it's also the same for solid state materials. So if I want to create some new area of a solid, I have to put some energy in, I have to put some free energy in. So the thermodynamics of this process are actually quite critical. And in fact, the thermodynamics in turn relate to the intermolecular forces that appear between the molecules that make up the solid or the liquid that we might be interested in. So intermolecular forces are directly related to the surface energy and the surface tension. And it turns out, by moving sur energies and indeed surface tensions, we start to have a measure of intermolecular forces. And the two main types of forces we'll come across are long range forces called dispersive forces to operate over nanometer type scales. And we also will come across short range chemical forces, polar forces, acid base forces, hydrogen bonding forces. These operate over much smaller length scales, typically less than half a nanometer. And these two types of intermolecular forces Are key to what goes on when vapors and solids interact and also affect the way solids affect the way in which solar energy of solids are defined. So, as I said, we're instances of solid energy of solids. So it's worth just spending a moment to looking at how can you measure that? So the techniques in use. And we'll start on the right hand side of this particular slide. There are techniques that are in common use, and one of them is called a wetting balance. So in a wetting balance, you typically take a fiber or a film, you put it in contact with a known liquid, and the process of doing that will involve a certain adhesive force being exerted between the liquid and the solid of interest. And in fact, we can use the solid we're studying. And of course, the solid may be a fiber or maybe actually be a film. And wetting techniques are really not suitable for particular materials. Not only is the geometry a complication, but for materials, particularly foods and pharmaceuticals, they swell, they dissolve, they're rough particles. And so wetting techniques turn up not to work very well. Another technique that's commonly used for characterizing solids, Particularly monolithic flat solids, Are contact angles. So you put a drop of liquid on a surface. The angle that droplet makes Is characteristic of the relation between droplet surface attention and the surface energy of the solid underneath. And that is great for flat surfaces and for films, but for fibers, it's quite difficult. And for powders, it's just about impossible. I've tried it. In fact, I've tried all the techniques I've described today, except for atomic force microscopy. And generally for particular materials, contact angles and wetting bowels don't work. So the newer technique that the newest techniques have come along in terms of characterizing solids, in terms of solvengies, atomic force microscopy, again, for flat surfaces, it's rather good. But for particular materials, it's difficult. It's a slow method. And there are poor statistics in that you may need to do 50 or 100 particles before you get a reasonable statistical measurement, surface energy. And there are also some theoretical complexity in terms of doing the analysis. So all the techniques I've talked about, unfortunately, are very difficult to use for powders. But I'm pleased to report there is one technique that it turns out to be very good for powders. And that's going to be the focus of today's presentation. That technique is known as inverse gas chromatography. In a moment, I'll describe it, but let me just summarize what you can and can't do with it. It's okay for flat surfaces, but for particulates it's excellent. Fibres, granules, powders, it's very, very good. There are no problems with hysteresis, there's no problems with roughness, it's very repeatable, there's no swelling issues. It doesn't have many of the problems we encounter with the techniques on the right side of the table. And we can use a whole range of different sorts of solids or probe molecules to characterise our unknown material. And essentially we'll measure gas or indeed vapor absorption is as well as the surface energy used in this chrom technique which I'm about to describe to you. Before I describe the technique, let me just tell you a little bit more about why the thermodynamic parameters, and particularly the surface to energy is important. The surface energy allows us to understand a range of different events that powders can be involved with. It turns out many of these different events depend on the thermodynamics, that is the intermolecular force that occur between a solid and a liquid, or a solid and a solid, or a solid and a vapor. And the particular phenomena that we're talking about are exercising powder cohesion. So if I've got powder particles, will they stick together or not? When powders interact with vapors such as water, will a water molecule strongly interact with the solid or not? Will a liquid wet a substrate? So if I've got particles and I want to wet them into a solution, will the solvent wet the particles or not? And finally, if I'm interested in particles interacting with other particles or other surfaces, I'm interested in adhesion. It turns out for all of these four phenomena, the thermodynamics and specifically the surface energy is a sum of criticality. So in terms specifically of pharmaceutical materials, let me talk about some of the things that you can learn about if you know the surface energy of your pharmaceutical. Interactions between drugs and excipients. And basically a range of adhesion and cohesion phenomena can be studied. Adhesive interactions, powder mixing, powder segregation, powder flow, static charging. These all have a surface energy dimension to their performance and behavior. That is, they're not entirely defined by surface energy, but it is one of three all factors that is important in defining their behavior. Also process induced disorder. If we are interested in milling, grinding or micronizing materials, then that turns out to change the surface properties and specifically the surface energy of mine materials. And this leads into amorphous versus crystalline stability of materials. We'll also See today that materials that have been milled or ground, they will actually not be energetically homogeneous. And we'll introduce a concept of energetic heterogeneity, particularly surface energy heterogeneity. It also turns out surface energy is quite sensitive to batch to batch variability materials. There have been many examples we've seen over the year where manufacturers have got two or three batches of material, typically from different supplies, different processes, different plants. The materials don't process properly. And sometimes the surface energy is the only way of distinguishing between these different sorts of successful and unsuccessful materials. Now we can also look at fundamental properties, material properties. We look at the surface characteristics of powders, their acidity, basicity and stability of surface functional groups. These are all information sets that can be accessed using a surface energy determination. So in the cartoons I've got here, I show some examples of some surfaces. They're shown by the pink as well as the blue particles. And what we're describing here is the way in which a phenomena changes as the surface energy changes of substrate. Let's start on the left. On the left we can see some pink substrate. And as we go from bottom up to the top, the surface energy increases. So for the bottom surface, when I put a droplet on it of a liquid, we'll see that that droplet does not wet the surface. But as I increase the energy, the condom gets smaller, and by the time I get to the top, the liquid effectively wets the surface. In other words, the wet ability of a liquid for a particular surface depends on the surface energy of the solid as well as the surface tension of the liquid. If I've got fine powders, the cohesion or cohesiveness of that powder is partly dependent upon the surface energy. When the surface energy is low, cohesion levels will be low. When the surface energy is high of the particles, the cohesion will be high. If I've got a solid that I milled, and the bottom surface represents one that's un milled, as I mill it, I create surface disorder. This disorder will manifest itself in higher surface energies. And we'll see some examples of that later today. And the final example is adhesion, adhesion between small particles, which is shown in the blue against larger particles. The small particles could be pharmaceuticals. The larger particles could be carrier particles, as you might have in an inhalable drug system. And the adhesion between the particles, the small particles, and the large particles will partially depend on the surface energy of the materials. So here we've seen some examples of how we can actually look at the importance of surf energy in a range of important phenomena involving particulate materials. So let me now introduce you to the technique known as inverse gas chromatography. It's not a new technique, although it may be new to some of the listeners today. It's been around since the 50s. It was originally developed in Russia by some Russian research groups and work followed on later on in the USA and the UK and in the in Canada. And it's been a commercial technique for characterizing solids for about 10 years now. People have been building home built systems, however, since the 50s and we can study any type of solid state material, films, fibres, powders, particulate, semi solids. Although historically the earliest studies were on catalytic materials and after that were on polymers and composites. But the technique will give us kinetic and thermodynamic information and the process involves us absorbing vapors onto the solid or the powder we want to study. So here I've got a little cartoon that just explains very briefly the difference between traditional analytical gas chromatography and this inverse gas chromatography. So let me start by talking about analytical gas chromatography. In the analytical gas chromatography, I will start with a column that I buy from the manufacturer that has a known solid in it. And this column will be put into a gas chromatograph and I will introduce some unknown materials, in this case the red and blue species. And these unknown species will pass through my known column. They'll be separated by an absorption process. And in the end from the blue peak and from the red peak, from the area that peaks, and from the retention time I will identify and indeed quantify the red and the blue species. That's traditional gas chromatography, unknown vapors, typically using a known solid column. But in the case of inverse chromatography, the roles are reversed. So now I'm going to pack your unknown material into a column. This GC column, which we'll see an example of later, will then be used in a special sort of chromatograph. And I will, through that column, essentially some known molecules. Known molecules will pass through my unknown material and I'll then analyze the retention time, which is seen here as that blue peak. And because I know the molecule I've injected, I can use that data combined with some information about the solid to determine a range of properties on my unknown materials. That's why it's called inverse, where the role of the mobile and the stationary phase are inverted. So what we're going to be using gas phase Molecules as our probe. So what do I mean by gas phase molecules? Hexane vapor, octane vapor, ethanol vapor, hexanol vapor. We can use a range of different vapors to probe the surface chemistry of my unknown powder or particular material. So really, it turns out, these molecular interactions when the molecules in the gas phase, my unknown solid, forms the whole basis of this technique. We can characterise surface properties on materials, and sometimes, if the materials are amorphous, I can characterise bulk properties as well. The technique has the additional benefit that effects the temperature and humidity can also be introduced into the study relatively easy. And we can investigate a wide range of properties that are thermodynamically determined, such as the surface energy. So as well as surface energy, which I've listed here on this overhead, there are a range of other properties we can measure. We can measure the acid base or the polar properties or hydrogen bonding properties of our surface. We can measure the heterogeneity because, as we'll discover soon, the surface energy of materials are not commonly uniform. They actually vary. And we can quantify those. We can measure the BET surface area. Some of you may use nitrogen absorption at the moment to do BET for materials. We can also measure the BET surface area using molecules like hexane and cyclohexane. Using this IGC method, we can also measure heat absorption. And at the bottom you can see we can also measure some bulk solid properties. So for amorphous materials, we can measure glass transition temperatures, solubility parameters and crossing densities. So we can work with both crystalline or amorphous materials and provide very interesting data sets for those materials. So let me talk about the column and how the experiment's done. So the column is typically about one foot long and is about a quarter inch id, and we can pack into that anywhere from a few milligrams up to maybe 500 milligrams of material. And we'll put a little bit of glass at the end of the column, just a bit of glass wool so that the powder doesn't come out. This is a straight column and typically we can pack a column in about five minutes. And we've packed hundreds, maybe thousands of columns. And what we do know is that almost all materials can be packed very easily and very reproducibly. So actually, the column packing sometimes people think is difficult or complicated. It turns out to be the easiest part of the experiment. So we pack the columns and in five minutes we're ready to put into our IGC instrument and start looking at some of the surface properties. So let me describe how an experiment's taken or undertaken. So let's look at this overhead here, but let's look at the bottom left. So in this particular experiment we've got some microcrystalline cellulose, abicell if you like, mcc and we've done a series of injections for heptane octane, non endocane for a column packed with about 25 milligrams of microcrystalline cellulose. So we have helium passing through the column, we inject a small amount of the alk and it slowly elutes through the column and eventually is detected by a flame ionization detector, sort of detector you have in your normal gas chromatography in your analytical lab. And what you can see here from this series of peaks as I go from heptane to octane to nonane to decane, that as the molecules get bigger and they become heavier and they have higher subs energies and they become more attractive molecularly because they've got larger molecules, the retention times become longer. And this increase in retention time relates directly to the interaction between these known molecules and my unknown material, in this case microcrystalline cellulose. And indeed it turns out this retention behavior is directly related to the surface energy of the powder. And to be more specific, it relates to the dispersive component of that surface energy. You may recall earlier on I mentioned there are short range chemical forces and long range chemical forces present in surface tension and surface energy effects. And we are measuring in this little experiment the dispersive or the long range forces because hexane and decane octane, they have van der Waals molecules and they sense long range van der Waals forces and we talk about those being dispersive forces. So over here we've got gamma D and gamma D is taken from the slope of the following plots. On the right hand side I've plotted RT log of the retention volume. Retention volume comes from the retention time times the flow rate. So it's very easy for us to measure that. And this axis here, this simply relates to some properties of the molecule that we've used, that is the hexane, heptane, octane. It depends on the cross sectional area which is a and the dispersive surface energy of the material, which is basically the surface tension of the liquid. So these plots in red and blue relate to the surface energy of the powder. Let's look at the red one. That's one we're interested in today. The red one is at 0% humidity. So it's a dry ab cell. And from the slope of that line, I can tell you the surface energy is 57. And the units we have here are millijoules, that is thousands of joules per meter squared. That's the standard unit for surface energy and the surface tension. So we see that for this material, this microcrystalline cellulose, we basically got a 57 millijoules meter squared. And just to remind you, the surface tension of water is about. Surface tension of hexane is about 20. So 57 is a fairly high energy for a solid, for an organic solid at least. So I want to talk to you now for a few minutes about surface chemistry heterogeneity. Because when we started in this area, in terms of characterizing pharmaceuticals, about seven, eight years ago now, we were under the view that many organic solids, including pharmaceuticals, would be homogeneous from a surface chemistry perspective. And it turns out that we were wrong. It turns out that materials, and particularly crystalline materials, they are not energetically homogeneous. And in fact, there's a number of reasons for that. They have both chemical heterogeneity and structure heterogeneity. And here are some of the reasons. So from a chemical perspective, we've got contaminants and impurities in our crystalline materials. In crystalline materials, we've got different crystal planes, different facets. Facet 001111. These different crystal facets have different surface chemistries. And they there chemical energies, crystallinity, amorphicity, these all affect the heterogeneity or homogeneity of the surface. And it turns out that most pharmaceutical materials, and certainly both crystalline and amorphous materials, they are not homogeneous. As well as these chemical reasons, we also have structural reasons. We have steps, growth flaws, pores, all these irregularities and crystallatoses affect the heterogeneity of a surface. And it turns out, as we'll see soon, that the ability to measure these is one of the great benefits of these inverse gas chromatographic techniques. Because indeed the other three techniques I talked about measuring salt energy, cannot measure heterogeneity, which turns out to be really important. So in terms of us measuring heterogeneity of material, let me just briefly describe where we're actually doing these measurements. So here is a measurement where we're talking about the concentration of the probe molecules that we have in the gas phase on the X axis and on the Y axis here we have the amount of material absorbed. So this is what we Typical. And the black line represents the adsorption isotherm. It's a very low concentrations. We work in the Henry Laws region, but in our case we're working in the BET region. BET represents where there's a monolayer of molecules on the surface, also known as the finer concentration regime. As we'll see today. Our experiments, we typically we will be looking at coverages up to maybe 20 or 30% surface coverage. And in our experience, the heterogeneity of materials by atomic to about 30% is fairly disappeared. So in terms of the method that we use for characterizing heterogeneity, it's based on a method known as isosteres. So what we will do is we'll inject a series of vapor phase molecules at a range of different concentrations. And from those different concentrations we can essentially build up a profile of the surface energy and how other distributed. So we send a few molecules in at the start. These tend to sample the high energy sites. And then later on we're seeing in many more molecules and they tend to sample the average surface properties. So between these different sort of injection sizes, we are able to characterize materials in terms of their high energy and low energy sites. And this, this drawing here tells a little bit more about the method. We really, when we run the experiment, we take into account the fact that heptane, molecul, octanel are different in size. And because they're different in size, they essentially occupy different amounts of surface. And the software which analyzes the data is very accurate in taking into account molecular size. So we therefore do experiments effectively at constant surface coverage. And those constant surface coverage experiments are known as ISO skew experiments. A couple of questions which have come into me so far, which I will try and answer now while they're fresh, is how much material do we need to use? So if we just briefly go back here for a moment, I'll just point out something here. When we pack our materials, we typically don't pack it based on mass. We typically pack it based on the surface area of the material. So for example, we had a material that had 1 meter squared per gram of surface area. If we wanted to pack half a meter squared, we would pack half a gram. That would be a relatively large amount of material. Most materials have high surface area and therefore require less sample. So if the material was 100 meters squared per gram, then of course we would need 100 times less. We basically use about 5 milligrams. So we use typically about 0.5 meters squared of material in our column, and that's obviously in a certain mass range of 10 to maybe 500 milligrams. In terms of how long it takes to do an experiment, if we wanted just to measure a single surface energy, an average result, not heterogeneity plot, that would take us a couple of hours. If we want to measure one of the full heterogeneity plots that's coming up in a moment, that will typically take us maybe 12 hours to do that. So it's not a fast experiment, but in some cases the only way you can get heterogeneity plot. So the data is quite unique. So they talk about heterogeneity plot. So here we've got one in schematic form on this overhead in slide number 20. So I'm plotting on the Y axis the surface energy. So that's my measure of intermolecular forces. And on the X axis I'm measuring the surface coverage. So what I'm really talking about is how many surface have a surface energy of particular sorts. So if I go right, left, what I'm saying is for low surface coverages, I have high energies, and by the time I get to quite high coverages, I've got much lower energies. And the red curve and the blue curve represent two, if you like, examples. In one example, which is a blue line, I'm having a much more substantial variation in the surface energy, if you like, there are more defects in that material. And the red curve represents a material that's actually got less defects. And the little cartoon at the top represents the red and the blue surface. And from the surface energy data I've got on the left, I can construct the surface energy distribution just like a particle size distribution, except that rather than particle size of the x axis, I have surface energy. And what you can see here is the red curve has low energy and also not much variation in it, whereas the blue curve has a big higher energy and a much broader range of energies. So that is represented on the left curve and it's clearer in my distribution plot. And we can also, just like you can for particles, determine D50, we can also determine a gamma 50 representing the surface energy of 50% raw material. So now let's talk about some examples. So I've talked for quite a while now about the theory. So now let's push on and start to use some examp and show you why this is an important data. So the work we're going to talk about predominantly involves the use of a particularly important excipient called mannitol. D mannitol is used in the pharmaceutical and food industries quite a lot. And we used two different sorts of mannitol. We used normal D mannitol and the structured D mannitol shown down the bottom here, if you've forgotten. And we also prepared a special type of mannitol, which was a cyanised demonitol, which we'll show you the chemistry of in a moment. But essentially I will replace these hydroxyl groups with methyl groups and I'll make a hydrophobic mannitol. And what we're going to do is we're going to have two different classes of mannitol. We're going to have mannitol powder because obviously we're going to be in powders, but we're also going to grow some large crystals. And you can see some of these large crystals on the bottom right image. These crystals are typically about half an inch by an inch in dimension. And we're going to use those to characterize fundamentally the surface properties of different crystal phases. And we indicate end we're going to compare that with our surface energy from igc. So let me say again, we're going to measure surface energy using wetability on large crystals, and we're going to validate that by comparing it with the surface energy of powders as determined using igcsea. So we're going to do the wettability and the surface energy together using IGC and wettability. So let's start with the wettability. As I said, for flat surfaces like big crystals and films, wett method, it's no good for powders, but for large crystals it's very good. And we can see here, I've measured the surface energy of a range of different crystal faces. Mannitol has three dominant crystal faces, 010120011. They're shown on the cartoon picture above. And by using liquids such as water and di iodomethane, I can measure the surface energy. D is the dispersive and P is a polar. And you can see that the polar surface energy varies quite a lot for these materials. So for 01 facet, it's actually quite high. And as we'll see in a moment, that relates to the fact that that particular facet is very rich in hydroxyl groups, lots of LH groups there. And if you do the XPs, which we've done, the 011 surface has lots of hydroxyl groups as shown in the bottom left in the XPS data for the carbon 1s spectrum. And if you look at the crystal structure, you can see lots of hydroxyl groups populating the 011 fat. So that's a instant data set for our large crystals of mannitol. And now we're going to do is cyanise it. Here's a solidization chemistry. But essentially hydroxyl groups turn into methyl groups. So we're going to get rid of all the hydrophilic groups and have a hydrophobic material. And what's good about that is we end up with materials that are actually same particle size, same particle shape, same particle density. Their only difference is their surface to energy. And here we see what the surface energy is. And this is done using the wettability of large crystals. And what you can see here is a Gamma D for the solenoid material is much different to the untreated and moreover it's highly uniform. It varies within experimental error. Minimally quite different to the untreated materials and also no difference between different crystal faces. In other words, we've passivated entirely by cyanising our mannitol material. So now what we could do is we take a mannitol powder and we use IGC to measure the surface inducer pattern. We want to compare the powder with the wettability data. So here's the data and let's look at the curves. Firstly is the blue curve. The blue curve is a cyanized material. Cyanized material gives a Gamma G dispersus, has an energy of about 30 within 1 unit of the 34.8 we measured using the wettability. So in other words, excellent correlation between wettability on crystals and IGC of powders. And here's the other material, here's my AS received mannitol. And what you can see here is a lot more variation in energies, they're much higher. And these variations are consistent with some of the numbers we saw for the wettability of the cyanide material. We have a much bigger variation in Gamma D for the AS received material. So the red lines as received it's not homogeneous, it's more heterogeneous. And the conundangle data was also much more heterogeneous for the azure seed material. So generally good agreement between wettability and igc, that's a starting point. And we did a similar determination using the short range measurements, short range energies, acid base energies. We also see homogeneous solenoid materials and heterogeneous AS received mannitol. So we're able to confirm the homogeneity of one material and the heterogeneity of the other. So once we've measured the surface energy, now we can start to do some interesting science. So the first thing we can do once we've got the surface energy is predict the powder cohesion. That is, if I take some silica, some amandhole powder that's cyanized and some mannitol powder that's as received, I can predict the attractive force, the work of, of cohesion between them. What you can see here on slide 26 is that the as received material has a much higher cohesion than a cyanized material. So what you might expect is, for example, that powder flow would be easier with the cyanised material compared to the as received. So next thing is, is that true? Well, obviously we tested it. Let's see what we discovered. So what we discovered is the following. We did a powder cohesion measurement using an FT4 powder fluoriometer, and the data is shown here. Here. And we have on the Y axis the total flow of energy and the air velocity and the blue curve and the red curve represent, respectively, the solenoid and the as received material. And what you can see very clearly here is the as received material, which is the red line, requires much more energy for it to get to flow compared to the silonized. And do remember, the only difference between these powders is the surface energy, the shape, size, density has all been kept as and even in the material that was as received. We ran a blank experiment. So we did it. We did a solenization experiment with no silane present, just to make sure there was nothing affecting the material besides the actual reaction. So we see here very clear evidence. When all powder properties are the same, the surface energy directly impacts on powder flow. So the next example we've got is dissolution. So what we've taken here are some aspirin materials and we've milled them and we've got materials that are actually in the same size fraction. So we've got the same size fraction. We're going to milled and unmilled to. And then we've made some tablets and basically we've looked at the dissolution profile. And so what we've got here is dissolution behavior of unmilled and milled powders. And you can see here that the milled materials actually dissolve much faster. This is absorption, which is basically dissolution time, dissolution concentration. So the milled materials dissolve much faster than unmilled materials. We know for this material there are no amorphous phases present. We've got the same particle size for them fractions. So the difference, we believe, is differences in the surface energy of the material. Because it turns out when we measure the surface energy of these aspirin materials, we see quite clear differences in the surface energy. The milled materials, which are shown at the top have much higher energies and are indeed a more heterogeneous surface chemically. So higher energies, more heterogeneity, and in the end we have a faster solution rate. So that is also an important and interesting observation in terms of milled materials. And indeed, we believe that's due to the presence of a higher fraction of.011 facets which are prevalent for a material that's been milled. So my colleagues Raimondo and Dave and Jerry have done some work looking at the effect of sozinigium crystal habit. So they took some pharmaceutical materials, they sieved them in such a way to get different habit fractions. And what they were able to establish was that by looking at different sieve fractions, they got different SONIA distributions. And they related that to the shape of the population particles. And that in turn relates to the population of different crystal facets that's present in the actual powder mix or in the powder fractions they've got. They've also done some similar work on mannitol. And as you take mannitol powders, you fracture them, you change the population of different surface facets as shown here. That in turn affects the surface energy. And when we measure gamma D distributions for these different materials that have been been milled, you get different surface energy distributions. And that can be related to differences in the population of surface facets. So again, relating crystal engineering, crystal habit populations to actually use surface energy materials. So the last two examples I'll give today are about powder. And this first one is on powder cohesion. So we talked about powder flow and this particular case we're about going to talk talk about weak powder cohesion. How sticky are pharmaceutical powders? And this relates to a range of applications, including the filling of DPI capsules for inhalable drugs. So let me describe the experiment we're doing. This experiment involves the formation of a soft cylindrical powder compact. We take a gram of powder, we put it in a dye, and we apply a few kilograms of load to make this weekly consolidated cylindrical powder block. And this test is called an unconfined compression test. It's a simple test used, it's borrowed from the people in the area of soil mechanics. And what you do is once you very carefully make These powder compacts, you then do a uniaxial compression experiment on them and you basically look to see if you can fail them, which of course you can. And you measure the failure conditions for either plastic or elastic failure. And it turns out we did that for a range of mannitol powders. We looked at both the azure seed mannitol as well as the mannitol material that was cyanized. So before we did that, some experiments for manufacturing the actual tablets or these large compacted structures, here are the force displacement curves for different loads for making them. So these are loaded with 1, 2 and 3 kg. And you can see here I've got made these cylindrical compacts. And then I basically measured the load displacement curves as they are crushed. So as the load goes up, they deform and eventually get to a certain load and they start to fail and they basically fall apart. And as you increase the load for actually making them, then they become a little bit stronger. But we're going to use a similar experiment to look at the relationship between the adhesive forces and the strength, if you like, of these powdered compounds. So here's the important experiment. So now we've got some mannitol compacts cyanized in the open dots, non cyanide in the black dots. And what you can see here, these are N equals three experiments. They're 40 to 63 micron powders that are made into compacts. About a gram of powder in each compact. And what you can see is that the solenoid material, which is the lower curve, it fails at much lower load and the energy it absorbs is much less. This is entirely consistent with our flow experiments. The flow occurred at lower yields and the actual failure of the powder compact also occurred at lower loads. So you can see at about 0.8 Newton we have failure, whereas the non cyanide, the regular material, is about twice the actual force. So the energy of failure of these materials is much different. So again, what we're saying is for powders of the same size, shape, density, surface chemistry can change the cohesive forces by at least a factor of two for these sorts of materials. And we can in the end work out the shear stress lessons, normal stresses for these different manitols. Again, just quantifying the difference in interfacial mechanics of these different parts of materials. The final example that I'll only talk about briefly because I'm running out of time today is we also did a study looking at wet granulation. So the question is very simple. If I take D Mannitol and I take D mannitol of solanized and I make a series of powder mixtures, 100% d mannitol, 100% cyanide diamantal and 25% of 175. 50. 50. If I make those mixes and I do a wet granulation, do the granule properties vary? Again, same particle size, particle shape, particle. The particle properties are identical, except the surface energy alone has changed. So of course, it turns out that granulation, one of the critical steps of granulation, is wetting of the binder fluid on the powder particles. And of course, wetting depends on service energy. So in this particular study, we had identical wet granulation conditions, same binder and same primary particle fractions. The binder was PvP and we actually made a series of powder mixtures with different amounts of silanized and unsalinised diamantitol. We in the end measured two properties of the final granules. We measured the particle size, or indeed the granule size, and we measured the strength or how strong the granules were to compaction or failure. So some pictures of the untreated and treated mannitol powders, some information on spreading which we won't go through today. And finally, an important bit of data. This shows the granules. These were big granules, up to a millimeter or two in size. And what you can see was that the granule size varies. As we increased the cyanide content, that is, made it more hydrophobic, the granule sizes got smaller, and basically the granule size varied by roughly a factor of three. So in other words, as we put more hydrophobic material in, we got smaller granules. The second thing we measured was the mechanical properties of granules. We took a single granule, we squashed it, and we looked at how strong it was. The granules we looked at were all the same size, but they have been made with different formulations of solenoid and unsalinised mannitol. And we can see here the forces, displacement curves for these 1 to 1.4 millimeter granules. And what you'll see there is that the properties vary enormously. So what we can tell you is that the mechanical properties varies depending on how you, how much unsalinised material you have. So the mechanical properties are different. And I think on the next thing we port the modulus. So what you can see here, if we look at the material, for example, there's 100% cyanide material, so it's the most hydrophobic material. It has a Lower modulus by a factor of three, roughly compared to the material that's 100% as received mannitol. So for the same particle size, in this case granule size, the mechanical properties of the granules are directly affected and that's shown here diagrammatically. So a few conclusions. That IGC can be used to map surface energy variations of powders. It agrees well with single crystal wetting data, we can understand milling dissolution behavior, wet granulation, powder flow and powder adhesion. And we can conclusively show that surface energy is one of the critical properties that determines many facets of powder processing operations for pharmaceutical materials. And I'd like to thank all my various co workers did all the hard work and I hope that gives you an insight. And I'm happy to answer any questions you have. I've got some questions already, but if you'd like to email me your questions via the method that Bill described, I'll be happy to answer those during the next five to 10 minutes. So while we're waiting for further questions to come in, I've got a couple here which I will answer. Is it possible to measure the surface energy of metals or larger particles? Yes. There's no reason why you cannot measure the surface energy indeed of any material. So metal powders, certainly larger particles, providing we've got a certain amount of surface area, ideally that half a meter squared per gram is ideal. We can do a bit less than that. But providing some surface area, we can measure metals for certain. How do some common processes alter the surface energy? Well, there are two or three ways that operations can change the surface energy of material. I'll give you some examples. If we mill a material, we will disrupt and change the crystal lattice. By changing the crystal lattice, we will change the surface properties. That's why way if the materials are amorphous, then by putting the energy into a system that we do when we mill it, we can change the free volume and the viscolastic behavior. And that too can change the surface energy of a material. So they're just two examples. Amorphous materials, we change the surface energy for crystalline materials, we can change the defects, we can change the crystal facets that are present and all those can affect the surface energy of our material. So I think at the moment I've answered the first few questions I've got and I'm ready to take any more questions that you have from the floor.

I do have another question here for you, Darrell.

Thank you, Bill.

How popular is mannitol for being used in formulations?

It's used substantially in the area of freeze dried formulation. It's occasionally used in pharmaceutical formulations. I'm not really a formulation expert. I couldn't tell you how common it is to use, but it's certainly we use it as a model compound. So though we used mannitol, our argument would be we could have chosen any number range of a number of other active or less active materials. So really I would view it as an as a model material and I would be fairly confident that what we saw for mannitol would be true of many other pharmaceutical materials, be they excipients or actives.

Okay, another question here for you, Darrell. You showed the example of our columns that we typically use for powders. Is it possible to measure surface energy of larger particles or flat surfaces or different geometries?

Right, so let's talk about that question. That's a good question. So, so in terms of the column, this going back to the overhead. Bear with me a moment. Just so we get it in context. Right. So in terms of the columns that we saw here, we've got columns that will allow us to put samples in there up to 10 mil in diameter. So we can theory, put in catalysts, pellets, large granules up to about 10 millimeter OD can go inside our 10 millimeter ID columns. So we can put in five, we can put in films. We also have a film accessory which allows essentially flat monolithic samples such as metal films or other flat materials to be studied as well. So essentially flat films can be studied and anything which you can pack into a column up to 10mil ID can also be studied.

Okay, one last question. How long does a typical IGC experiment take and what might be some of the factors that determine the duration?

Yeah, so it really depends on the level of detail you want in your study. If you simply wanted to measure a surface energy data point at a fixed surface coverage for a single sample, you could probably measure that in a couple of hours, maybe even an hour hour without too much trouble. If you want to measure the surface energy heterogeneity, then typically we have to do typically five or six times more experiments. So to measure the full heterogeneity profile, we're probably going to have to run for at least 12 hours to do that. So that does slow down the process. We obviously typically do duplicate injections just because that's good experimental practice. Again, that adds timing. So there are some ways that you could streamline the process a little bit, but you are talking about a number of hours to get a relatively rich data set. Okay.

And I think that's it for questions. Now, if anyone has any more questions, please feel free to send them to scienceurfacemeasurementsystems.com or you can also find that on our website.

Website.

I want to thank Darrell for presenting, and I want to thank everyone for joining us today. I hope it was informative.

Okay, thanks, Bill. And thanks for all the various people listening today. Okay, take.