Crystal Properties and Tablet Compaction PDF

(Pt 1) Crystal properties and Tablet compaction Mon, 10/16 14:26PM · 28mins Transcript 00:00 Hello and welcome to this e -lecture in the PHCO 3 3 11. I am Omo Kotauchi, the module leader and today's lecture will be about crystallization, crystal properties and tablet compaction. So let's start with...

(Pt 1) Crystal properties and Tablet compaction Mon, 10/16 14:26PM · 28mins Transcript 00:00 Hello and welcome to this e -lecture in the PHCO 3 3 11. I am Omo Kotauchi, the module leader and today's lecture will be about crystallization, crystal properties and tablet compaction. So let's start with the learning objectives. 00:16 In fact, this is a series of five lectures dealing with the crystal properties and it will help you to increase the depth of your knowledge about processes that you are already familiar with, particularly tabletting the process. 00:31 So the objectives will be to explain the influence of material properties on tabletting process and the significance of the material properties on making tablets in addition to improve tabletting process by manipulating material properties. 00:49 So the more you know about your material, the better flexibility you will have during formulation. Now you can always have further reading and I've included a link for important references at the bottom of the slide and I must say they are already also included in the module shelf in the references. 01:06 So a bit of introduction. Tablets are generally manufactured from a blend of powders, different materials, they have different properties and we have to go and study these properties and link the influence to the tabletting process. 01:22 Now also tablet properties such as hardness and dissolution can be influenced by the excipients we add in the formulation. Now I give an example for the importance of this in the late 70s in Australia, one of the manufacturers of phenytoin which is anti -epileptic drug used for convulsion and they decided to switch from one diluent to another. 01:45 So they were using calcium sulfate and they decided to switch to lactose. So according to the British pharmacopoeia they are both approved excipients and are already widely used in pharmaceutical industry. 01:57 So theoretically there is no harm from switching from one deliwant to another. them. But what happened later, it was a disaster. Following this switch, they've noticed an outbreak of toxicity among epileptic patients using phenytoin. 02:12 What happened? When they use calcium sulfate, calcium sulfate binds to the drug molecules, which makes it less water soluble, affected the availability. Now when they switch to lactate, so eventually they've ended with high bioavailability, which goes toxicity. 02:32 Now the excipient's properties can be variable for the same material. So the same material that you use as excipient can be available in different grades. So this series of five lectures will focus on the solid properties of the materials and how they influence the tableting process. 02:51 The topics which will be covered in these five lectures will focus on compression mechanisms during tableting, the solid properties that can influence tablating such as crystallization, structure, crystal habit, etc. 03:07 and how the mechanical properties can be manipulated and their influence on nation. And the other area which will be Powered by Notta.ai covered also the methods we use for measuring these properties and doing the evaluation. 03:20 Now, tablet compression mechanisms. In this lecture we are going to look to this process from a different angle. So compression mechanisms for primary powder particles and granules. Let's do a comparison between compressing powder and granules. 03:40 We know the difference between the two materials. This comparison will help you to understand the process. So starting with powder. What happens when you compress a mass of powder in a tablating machine? 03:55 What are the steps? Let's look into the details. So the first process, if you imagine, we have the dye filled with a free flowing powder and after that the punches will start up and down compressing this powder. 04:11 So the sequence of events will start with increasing the pressure on the mass of powder inside the dye. This will force these particles to come closer to each other. They will be packed together. This will lead to rearrangement because at the beginning it's a porous lump full of gaps, void spaces. 04:34 The more pressure applied from up and down by the punches, the more rearrangement and clearing of these gaps and void spaces. As the load keeps increasing, the particles will keep coming together until there will be no further movement. 04:51 All of the void spaces have been cleared out and the particles are sitting very close to each other. So there is no possible movement. Now what happens if we increase the pressure or the load more. At this stage there is a stress applied on the mass of powder. 05:09 The further movement of the punches will lead to a change in the particles dimensions. Now we started to affect the particles. At the beginning all the rearrangements and the movement was affect what filling the gaps and the void spaces. 05:23 But at the end when they are very close together now it started to affect the particles themselves. The structure of these particles. So they started to deform. Now the deformation process can be one of different types. 05:40 This depends on the properties of the materials. The deformation could be elastic, could be plastic or viscoelastic. Now the visco elastic deformation is limited to the semi -solid and liquid materials and our concern for solid materials will be whether it's elastic or plastic. 06:05 Let's explain this. Elastic deformation involves stretching of the bones but the atoms do not slip past each other. While with the plastic deformation it's a permanent deformation which involves the breaking of a limited number of atoms, bones, by the movement of dislocations. 06:30 Let's have a closer look to this figure showing the different patterns of behaviors of materials under stress. So the first one on the left is showing elastic deformation so it will stretch. But what happens when you release the pressure? 06:49 Because they are elastic the material will bounce back retaining the original shape and dimensions. While with the plastic material on the far right the material will resist until it reaches the yield point. 07:04 Once it reaches the yield point the bone will snap but the molecule will change position it will move to another location without breaking. So this is the process of reshaping. So at this stage you are reshaping the material changing the shape Powered by Notta.ai changing the dimensions with a plastic deformation. 07:27 Now let's focus on the elastic and plastic deformation. So compressing a mass of powder make a tablet. So it's a loose lump of powder changed into a compact mass. Now if the material is going to be elastic is this going to be helpful to make a tablet? 07:46 Of course not we are not going to be able to reshape it because it will bounce back and it will cause problems later. So we are relying on the plastic behavior of the material. Now, having an idea about the compression of powder, let's discuss the compression of granules and see the difference. 08:11 What happens when we have granules? But let's see the difference at the molecular level. So when we fill the dye with granules and start to apply the pressure, what will happen? The particles similar to powder and the pressure, they will start to move, become closer to each other, filling the void spaces similar to what powder did in terms of the rearrangement. 08:34 Further increase in the pressure will lead to deformation in the granular structure. Now, what happens here? The granules can deform in both ways, plastically or elastic. But at the same time, they have a property which is the densification. 08:51 The powder consists of small units that are solid while the granules, they are made of an aggregate. of particles and these aggregates they are porous so this porosity gives the property of densification and the compression the more you compress them the more they will become denser and denser and denser and allow the compaction. 09:14 So with further pressure the granules can be broken down by erosion of fracture so these granules after your arrangement and deformation to certain extent they will resist and then they will start to break down. 09:31 After that the final compression cycle will lead to the tablet formation. Now what happens if the pressure keeps increasing this will lead again to the repeat of the same cycle so there will be fragmentation they will start to break down and the process will be repeated from A to D until you have a compact mass. 09:57 Now as a consequence of compression what happens to particle these are the three main events we are bringing those particles close together generating fresh surfaces with high energy and then bones can be formed between those particles. 10:18 Now let's try to understand the molecular mechanism in tablet compaction. So we have a variety of mechanisms that can explain the process of tablet compaction. The first one is the solid bridges caused by melting, centering or chemical reaction. 10:38 So under pressure when we bring those particles together and start to stress them and start to compress them more and deform them there will be heat generated during this process. Now this heat could either melt these particles making them fusing together or it can cause sintering. 10:58 Now sintering means softening off the outer surface of these particles and then they start to fuse on the surface. This is sintering, so it's not complete melting. Chemical reaction is through specific chemical reaction on active groups on the surface. 11:13 The second mechanism is the bonding by movable liquids. So the liquids by capillary action and surface tension forces, they will move between those particles bridging between them, creating a network interconnecting those particles. 11:31 Powered by Notta.ai Non -freely movable binder bridges. Example for this, a viscous binder and adsorption layers. They use gelatin or PVP, different molecular ways, to set on the surface of the granules, creating a thin layer which allow bonding between the particles and aggregating them together into lumps to compact those aggregates later into a tablet. 11:58 Intermolecular forces, these are at a molecular level depending on the charge on the surface and the association between those particles will be through electrostatic interaction and Finally the mechanical interlocking So these particles they have irregular Sizes and shapes so mechanical interlocking can be achieved during compression so after having an understanding about the compression of powder and the compression of granules and the Bonding mechanisms at the molecular level the question now which mechanism applies for the granule and which one applies mainly for the powder The answer is that for powder we rely mainly on Intermolecular forces and solid bridges While for the granules is the binder and remember the weight of granulation the binder played a crucial rule to Aggregate those powder particles and later on to enhance the to modify the properties of the powder and makes it Compactable into a mass and into a tablet So a summary for tabulating a process we have particles these particles and The go rearrangement to form less porous structure Just remember the more compression the more they are close together filling their gaps and avoid spaces and then there are Different scenarios. 13:27 They are either bonding to each other or start to fragment breaking down or Which is what we are looking for is the deformation the plastic deformation Changing in their dimensions to have the shape of a tablet at the end now this deformation again could be reversible or could be irreversible Now the irreversible one is the wanted one which is the plastic deformation when remember the bone will snap and the Molecular change location into a different position and give you the shape of a tablet if they will keep the deformation the pressure and then bounce back when the pressure released and this is an elastic deformation and this can cause lots of problems which needs to be addressed and sorted out during manufacturing. 14:08 For example, one of these common problems is the capping and lamination where the tablet starts to stratify or losing the cap when the pressure is released. Solid properties. Now particle size, this is an influential factor during the tableting process. 14:41 We have a blend of powders with different size ranges and these can have an important influence on the tableting process. Particle shape as well is another important determinant during the tableting process and these powder particles can be present in different shapes, could be spherical, cubic, prismic, blades, spindles, etc. 15:05 Mechanical properties is another important parameter which we will investigate as well, and we've already talked about the elasticity and the plasticity in the first part of the lecture, explaining the importance of having a plastic property to allow the permanent deformation during compression, while the elastic material will cause problems during tabulating process. 15:33 And finally the surface as well of those particles or the bonding, and this by itself is important and will be discussed in a separate lecture. So we will look at each of these areas and how they can be manipulated in order to improve your formulation. 15:52 Crystal engineering. Modification of crystalline solid physically or chemically to produce a particle with the desired properties. So this will give you flexibility to change the properties through this crystal engineering, to change the properties to get the best formulation at the end, also allows selection of the commercially available excipients using the same knowledge of crystalline material. 16:15 Now examples of how we can modify particles with the crystal engineering, for example tablet compaction, this can have an influence when we change the crystalline properties we can have an influence on the tablet compaction and the mechanical behavior of the material. 16:29 Powered by Notta.ai We can also modify the dissolution by changing the surface of the particles or the particle size, the powder properties as well in terms of flow and mixing and dry powder inhalation systems. So these are just examples of how we can modify the formulation by having a better understanding to manipulate these crystal properties. 16:51 So event properties of a crystalline solid that can be manipulated include the size, the shape, the internal structure, and the surface of the crystalline material. Let's start with the crystal size. 17:05 So how would you expect the strength of a tablet to vary with particle size? What's the influence of particle size on the final tablet strength? Is it going to be higher with the small particles or lower? 17:25 That's what we are going to investigate in this part of the lecture. So let's have an example. So this figure illustrates the relationship between the crushing force and the crystalline diameter. So we have the x -axis showing the crushing force to crush these particles. 17:41 At the same time, it's linked on the y -axis with the change in the crystal diameter. Let's see how this diameter is responding to the crushing force. So the first material is sodium chloride widely used in the pharmaceutical industry and hexamine, which is API used as a unidirectional antiseptic. 17:59 Anyway, so the pattern for the two materials is the same. So the higher the crushing strength, the smaller the particles, the lower the crushing strength, the larger the particles. The pattern is the same, but there are differences between the two materials. 18:17 That's what we are going to study. So in general, it is assumed that increased tablet strength results from smaller original particle size. And my emphasis is on original. So if you have originally small particle size and this size kept preserved, didn't change during the process, then these smaller particles will give you stronger tablet. 18:44 Now, some materials, they have a complex relationship. Why is that? This is because there are changes happening during the compaction process changes in another property. So if we preserve the particle size, they will give you a stronger tablet. 19:04 However, if these particles start to change in terms of the size and shape, so if there is a change in other properties, the relationship will be different here. More explanation in the next slide. So let's take tablet surface area, for example, as another property which may change during compression or increasing the compression pressure. 19:24 This can be assessed by measuring the change in a specific area of particulate solid before and after compaction using techniques such as gas adsorption or mercury intrusion. So we have three materials sodium chloride, lactose and incompress. 19:41 And we are going to measure the change in the surface area with the increased pressure. So the x -axis showing the surface area for these materials and the y -axis corresponds to the maximum pressure during compression. 19:57 So basically we are going to assess the change in the surface area of these materials during compression by using this technology, gas adsorption or mercury intrusion. So your material is non -porous during compression. 20:10 If there is any change in the surface area, there will be the particles start to break down, there will be pores and there will be gaps. So it's a dynamic process. If this happens, then the mercury and the gas will start to penetrate to fill these gaps and these pores and will give you an idea about the change in the surface area. Powered by Notta.ai 20:28 Now, materials showing a sharp increase in the surface area with rise in punch pressure means an indication of particles fragmentation. Let's go back to the figure. So, in compress and lactose showing sharp increase. 20:42 So this means they are fragmenting into smaller sized particles, creating new surfaces, creating smaller particles and more gaps. So. this is an indication of a change in the particle size and the surface area during compression. 20:58 Unlike sodium chloride it's almost flat. So the higher the pressure the minimum they change which continue to the end. So this is a good example for a stronger tablet with original small particle size. 21:14 I mean the sodium chloride. So clearly the effect of the original size on the strength may be limited and this is a good explanation for the influence of the pressure, pressing pressure or during compaction of lactose and incompress because the change in the, because of fragmentation of the particles creating new surfaces and the relationship is no longer valid in terms of having smaller particles and stronger tablet. 21:39 Materials with a flat plot like sodium chloride has a limited change in the surface area with the rise in punch pressure. So no fragmentation with harder tablet. So eventually we have a harder tablet with particles that are smaller in size and that are not changing significantly during the compression unlike the incompress and lactose which are subjected to fragmentation creating new surfaces and changing in the particle size. 22:08 So manipulation of a crystal size or reduction can be achieved by grinding or crushing or milling. Now how to produce the crystals in the first instance? Crystals can be made or prepared by having a saturated solution of the material followed by precipitation. 22:29 Simplest example for this is dissolving sugar in glass of water. So you keep dissolving sugar until you will have saturated solution where after the saturation the sugar start starts to precipitate. So you've exceeded the maximum capacity of the solvent to dissolve the sugar which is water. 22:50 So we have a saturated solution. So this is the first requirements. Now the methods for achieving the precipitation can be also controlled. For example, evaporation of some of the liquid. So if the water starts to evaporate then this will make the solution more concentrated and it will start to crush and the sugar will precipitate or changing the temperature of the solution. 23:16 If we are going to cool it down again this will affect the thermodynamics and the... Again this will affect the thermodynamics and the particles or the sugar molecules will start to escape from the liquid and precipitate or adding another liquid. 23:42 And here you will have a competition between the two liquids, and then it might kick out the sugar molecules. If it's less soluble in the other liquid, which is more miscible with water, let's say if we add alcohol. 23:54 So the sugar is insoluble in alcohol, and it's miscible with water. So the water and alcohol will be miscible kicking out the sugar, and again, you will start to have precipitation. So these are different examples for how we can manipulate the crystallization process. 24:08 Now, this can be summarized in this nice figure, showing the relationship between the temperature and the concentration. The x -axis corresponds to the concentration of the solute and the y -axis for the temperature. Powered by Notta.ai 24:22 So if you look at the bottom, we have a stable solution. All the molecules dissolved. If we increase the concentration, so let's fix the temperature. If we start to increase the concentration, this stable solution will start to enter a critical area, which is a sub -saturation. 24:38 So we are saturating the solution until we reach the metastable region. So it's like a borderline. So this is a borderline area where above it, we will start to have chances for precipitation or crystallization. 24:50 This metastable region, also followed by a dotted line. After this, there is a high chance of nucleation. So these are the seeds that will start to form. And after that, the solution will become super saturated and will start precipitation. 25:07 Now, if we increase the temperature, we will have less chance of precipitation. Because we are adding more energy, which will help to solubilize the molecules. Manipulation of a crystal growth rate. The growth rate and the size of crystals may be manipulated by varying the conditions such as the temperature to induce the crystal growth. 25:29 The growth rate and hence size of crystals may be manipulated by changing the conditions such as the temperature to induce crystal growth. So if you look to this figure, we have a crystal growth rate and we have super saturation. 25:41 I thought increasing the temperature the temperature to some extent will improve the solubility and delay the crystallization. But here we are having a lower crystal growth at a lower temperature. So the reason for that is that to some extent when we increase the temperature we are putting more energy improving the solubilization of the solids. 26:03 Remember one of the methods to induce crystallization is the evaporation of the solvent. So the higher temperature meaning the faster evaporation of your solvent and in this case it's water. So this will change the ratio between the solvent and solute and that's why the crystallization is happening at a slower rate at lower temperature and higher at higher temperature. 26:31 I believe we came to an end for this lecture and just to put everything in a context. Today we've considered how tablets are compressed from powder and granules. We had a comparison between compressing powder and granules and then we came across the mechanisms for compacting powder and granules or different materials tabletting and also another important area which we started and will continue for the next four lectures is the key properties that can influence the compaction process. 27:04 Next lecture we will consider crystal shape and internal structure. Powered by Notta.ai