Crystallisation, Filtration, Drying PDF

Transcript Crystallisation, Filtration, Drying Slide 1: Introduction............................................................................................................ 3 Slide 2: Pharmaceutical Manufacturing Train..................................................................

Transcript Crystallisation, Filtration, Drying Slide 1: Introduction............................................................................................................ 3 Slide 2: Pharmaceutical Manufacturing Train................................................................... 3 Slide 3: Alternative Processes............................................................................................ 4 Tab 1: API Manufacturing................................................................................................. 5 Tab 2: Drug Product Manufacture.................................................................................... 5 Slide 4: Section 1: Crystallisation....................................................................................... 6 Slide 5: Crystallisation......................................................................................................... 7 Slide 6: Methods of Crystallisation..................................................................................... 8 Slide 7: Nucleation and Crystal Growth............................................................................. 8 Tab 1: Supersaturation..................................................................................................... 9 Tab 2: Metastable-zone Width........................................................................................ 10 Tab 3: Crystal Size Distribution...................................................................................... 11 Slide 8: Section 2: Filtration.............................................................................................. 12 Slide 9: Filtration................................................................................................................ 12 Slide 10: Clarification.......................................................................................................... 13 Tab 1: Depth Filtration.................................................................................................... 14 Tab 2: Membrane Filtration............................................................................................ 16 Slide 11: Cake Filtration...................................................................................................... 17 Slide 12: Filter Aids.............................................................................................................. 18 Tab 1: Filter Aid Materials............................................................................................... 18 Tab 2: Pre-coating with Filter Aid.................................................................................... 19 Tab 3: Mixing with Filter Aid............................................................................................ 20 Slide 13: Section 3: Drying.................................................................................................. 20 Slide 14: Drying.................................................................................................................... 21 Slide 15: Reasons for Drying............................................................................................... 22 Slide 16: Drying Parameters............................................................................................... 23 Tab 1: Relative Humidity................................................................................................. 23 Tab 2: Equilibrium Moisture Content............................................................................. 24 Slide 17: Vaporisation of Water from a Static Powder Bed.............................................. 27 Tab 1: Moisture Content................................................................................................. 27 Tab 2: Drying Rate Curve................................................................................................ 28 Slide 18: Vaporisation of Water from a Static Porous Solid Bed...................................... 29 Slide 19: Alternative Drying Processes............................................................................... 30 Tab 1: Through Circulation Dryers.................................................................................. 30 1  Transcript Tab 2: Fluidised Bed Dryers............................................................................................ 31 Tab 3: Spray Dryer........................................................................................................... 32 Slide 20: Summary............................................................................................................... 32 2  Transcript Slide 1: Introduction Hello and welcome, my name is Anne Marie Healy and I will be leading you through this session on Crystallisation, Filtration and Drying. Slide 2: Pharmaceutical Manufacturing Train Unit operations or unit processes are industrial processes used in the large-scale manufacture of pharmaceuticals. These pharmaceuticals could be APIs, active pharmaceutical ingredients, or they could be finished products. Each of these unit processes follows on from the other if we consider, for example, a pharmaceutical manufacturing train where we're looking at the production of a solid dosage form, be that a capsule or a tablet. 3  Transcript So we start with crystallisation of the API, followed by isolation or filtration to recover the crystals, followed by drying of those crystals, milling, mixing or blending with other materials such as excipients, and then moving on to the tablet manufacturing or capsule manufacturing process. The unit processes that I’m going to cover in the course of this session are crystallisation, filtration and drying. The processes of milling and mixing or blending will be covered in a later session. We're going to cover the various unit operations in this order because this is the order that you would normally encounter them in a solid dosage form manufacturing train or manufacturing process. Many of these processes can also be used and have an application in other contexts. As we’ll see later in this and other sessions, filtration can be used in contexts other than solid dosage form manufacture, as can drying, as can milling. Slide 3: Alternative Processes Click each image for more information and when you’re ready click next to continue. Image(s): 1. The impact of particles on API manufacturing. (2006). PAT and the crystallisation Toolkit 2. Drug product manufacture. (2014). All about Tablets (Pharma) 4  Transcript Tab 1: API Manufacturing This schematic illustrates, for example, some of these unit processes as they apply to the manufacture, isolation, drying and size reduction of pharmaceutical crystals, API crystals. What’s shown here is a batch crystalliser where we crystallise out the API material. Those crystals are then captured by a filtration process. After filtration, they have to be dried and post drying they might be milled to size reduce the material to make it appropriate for the drug product. This schematic also illustrates how the characteristics of the particles, or the characteristics of the crystals in this case, can impact on a number of these unit processes to which the material is subjected post the initial step of crystallisation. Tab 2: Drug Product Manufacture 5  Transcript This second schematic then outlines a drug product manufacturing process and indicates some of the unit processes or unit operations that would be encountered in the course of a drug product manufacturing cycle for a tablet product. Typically, the API will be manufactured in a separate plant. And so the API is, in this case, manufactured by a crystallisation process, followed by a filtration process, followed by a drying process. Then the API material would be sent to a separate manufacturing facility, the drug product manufacturing facility, where it might be milled, subsequently mixed or blended with excipients, and then subjected to perhaps a wet granulation process, a dry granulation process or a direct compression process. If it's a wet granulation process, there would be another drying step to dry the granules before they are compressed into tablets. Slide 4: Section 1: Crystallisation Going back to the solid dosage form manufacturing train, let’s consider crystallisation first. 6  Transcript Slide 5: Crystallisation Crystallisation is the process of forming a crystalline structure from a fluid or from materials dissolved in a fluid. As a unit operation, crystallisation is typically preceded by a reaction step and followed by a filtration step. Most APIs and their intermediate products form stable crystalline compounds at room temperature. Crystallisation has traditionally been conducted as a batch process, however, there is increasing interest in the industry in continuous crystallisation and in continuous processing in general. Continuous crystallisation is a unit operation in which the mother liquid continuously flows into the crystalliser, and the suspension or slurry (containing the crystalline API product) is continuously withdrawn. It has a number of proposed advantages over batch crystallisation in terms of reduced manufacturing costs, reduced waste and often improved product quality and consistency. 7  Transcript Slide 6: Methods of Crystallisation Crystallisation is achieved by reducing the solubility of the product in a saturated starting solution. The three options for conducting crystallisation processes are: Evaporation, Cooling crystallisation, and Anti-solvent addition, with cooling crystallisation and anti- solvent addition or a combination of these two approaches being most commonly used at an industrial scale. Differences between these different approaches are expanded on in one of the supporting recordings for this lecture, available in the study section on the session homepage. Slide 7: Nucleation and Crystal Growth 8  Transcript There are two major steps in a crystallisation process: the formation of nuclei, and the growth of crystals. Crystallisation starts with nucleation, of which there are two types – primary and secondary nucleation Primary nucleation refers to the birth of the crystal, where a few molecules come together to form an ordered structure, while secondary nucleation can only happen if there are some crystals present already. Industrial crystallisers often jump straight to secondary nucleation by ‘seeding’ the crystalliser with crystals that were previously prepared. Once nucleation has occurred crystal growth can happen. Click on each tab for more information and when you’re ready click next to continue. Reference(s): 1. https://www.researchgate.net/figure/Schematic-illustration-of-a-typical-metastable- zone-of-crystallisation-process_fig1_314199253 Tab 1: Supersaturation The driving force for both nucleation and crystal growth is supersaturation which is the difference between the actual concentration of the crystallising solute and the saturation concentration (or solubility). A supersaturated solution contains more dissolved solute than a saturated solution, i.e. more dissolved solute then can ordinarily be accommodated at that temperature. Supersaturation can be generated by a variety of methods, such as, cooling, addition of anti-solvent or evaporation. 9  Transcript Tab 2: Metastable-zone Width The metastable zone width (MSZW) (illustrated in this schematic) denotes the region between the solubility curve and the onset of nucleation, and defines an operating boundary during the crystallisation process. Probe-based instruments that can detect the presence of particles, track the rate and degree of change to particle size, and count particles as they exist in the process, can be used to monitor crystallisation. They can be used to determine the solubility curve and the metastable zone width by identifying the point of dissolution (where we have clear points on the solubility curve) and the points of nucleation (where we have cloud points on the metastable limit curve). Operating within this region avoids excessive nucleation and may ensure the required size distribution of the final crystal product. Unlike solubility, the metastable zone width is not a thermodynamic property and depends on several process dependent parameters such as cooling rate, solvent composition, stirring rate, crystalliser geometry, and so on. The metastable zone width is also known to be influenced by parameters such as the impurity profile and solution history. Therefore, determination of the solubility curve and the metastable zone width are important to designing and controlling the crystallisation process. The level of supersaturation, the cooling rate and level of agitation used can all affect nucleation and crystal growth. 10  Transcript Tab 3: Crystal Size Distribution Crystal Size Distribution (CSD) There are two steps involved in crystal growth – diffusion of solute from the bulk solution to the crystal surface and deposition of solute and integration into the crystal lattice. The objective of crystallisation is to produce the required crystal size distribution (CSD). The actual CSD required depends on the process. Crystal growth rate has proven difficult to model and empirical relationships developed from laboratory tests are generally used. Crystal size distribution can impact on other downstream unit processes, such as filterability and drying, and can also impact on powder flowability and dissolution characteristics. 11  Transcript Slide 8: Section 2: Filtration Moving on then to filtration. Slide 9: Filtration Filtration can be used as a means of isolating the crystals that you get in the crystallisation process. Filtration is a process whereby a solid is separated from a liquid or a gas by means of a porous medium, which retains the solid and allows the fluid, so the liquid or the gas, to pass through. The material of interest could be either the solid or the fluid. So, you may want to separate out the solid and recover and retain the solid, or you may want to clean up the liquid or the gas by removing any contaminating solid material from it. 12  Transcript Filtration has a range of applications in pharmaceutical processing, including, for example, water purification, as we’ll see in a later session in this module or, as I've said, crystal isolation. Filtration can be categorised into two main types - we have what's called clarification, and we have cake filtration. Clarification can be used when you want to clean up the liquid or gas, for example, for water purification or purification of other liquids. And cake filtration might be used when you want to separate out the solid, for example, for crystal isolation or for recovering crystals from the crystalliser. We’ll take a deeper look at each of these methods starting with Clarification. Slide 10: Clarification There are two types of clarification processes or two types of filtration that can be used for clarification purposes – Depth Filtration and Membrane Filtration. Depth filtration is also sometimes called deep bed filtration. With depth filtration, the particles will often be quite a bit smaller than the pores of the filter medium. And so the particles penetrate down into the pores and are collected within the depth of the filter medium. In contrast, with membrane filtration, the particles are trapped at the entrance to the pore. So this is similar to a sieving process. The particles that will be retained or removed are those that can't pass down through the pores because the pore size is too small. Click each tab to learn more and when you’re ready, click next to continue. 13  Transcript Tab 1: Depth Filtration So, if we look first of all at depth filtration or deep bed filtration. Here, the filter is produced by weaving, gluing or sintering together particles or fibres of a polymer, such as cellulose, a metal, a ceramic or glass. This picture shows an example of a glass fibre depth filter in cross-section, showing the glass fibres that are sintered together. In this case, the filter can stop very large particles from penetrating down and going through the filter because they will be too large to pass through the pores. But with depth filtration, you can also capture particles of a smaller size that penetrate down into the filter and become trapped within the depth of the filter. Typically, the filter material, and the filter medium, will be packed into a cartridge, and this cartridge may be made of stainless steel or a plastic like polypropylene and acts as a support to the filter medium. 14  Transcript Tab 1.1: Depth Filtration Particles are retained by the filter, by entrapment, impingement and electrostatic forces on the surfaces of the filter bed. So effectively by adsorption onto the surface of the filter bed, and onto the surface of the pore walls of the filter. So, for example, these particles here, represented by the pink shapes, have penetrated down into the filter and are trapped within the filter. The opportunity for contact and retention will depend on a number of parameters. It will depend on the surface area of the bed, and the higher the surface area, the greater the opportunity for contact and retention and the more efficient the filtration will be. It will also depend on what's called the tortuosity of the void space or the windiness of the void space. And the windier the pores are, the greater the opportunity for contact of the particles against a pore wall and adsorption and retention within the pore. So, the higher the tortuosity of the void space, the greater the efficiency of filtration. The interstitial speed of the liquid, how quickly the liquid passes down through the filter, will also have an influence on retention of particulates in the filter. Because if you flush too quickly through the filter, then you reduce the propensity for solid particulates to be retained by adsorption on the surface of the filter. 15  Transcript Tab 2: Membrane Filtration Another way of carrying out clarification processes is to use membrane filters and with membrane filtration, the pores are considerably smaller than the size of the particles that you want to remove. And the pores are considerably smaller than you will find in depth filters. So here filtration is mainly by sieving with some adsorption. You'll see here that the pores are much more regular and less tortuous than you will find with a depth filter. The depth of the membrane is also much less than you'll find in a depth filter. The mechanism of filtration is really exclusion, by excluding particles that are too large to pass down through the pore and that are trapped at the entrance to the pore because they're too big to fit inside. Membrane filtration can be used for a range of different purposes in pharmaceutical processing and in a pharmaceutical context. They can be used for sterilisation, bacterial reduction, removal of particulates, clarification and analysis of particulates or microbial matter. And, of course, for water purification. In terms of analysis of particulates or microbiological matter, what you would do is, retain the membrane and examine or assay in some way the material that is retained on the filter. There are three types of membrane filters: microporous membranes, ultrafiltration membranes and reverse osmosis membranes. Further details of these different membrane filters are available in the study section on the session homepage. 16  Transcript Slide 11: Cake Filtration We're going to turn our attention now to the second type of filtration process, which is cake filtration, and these schematics will illustrate this process. In cake filtration the suspended solid usually constitutes at least 5 to 10 percent of the system, and often will constitute a lot more. So, when we have a very concentrated suspension, we refer to it as a slurry, and as much as 50, 60, 70 percent of the total weight or volume of the slurry could be the solid component. With cake filtration you start off with a suspension or a slurry of solid material in a liquid. This slurry is forced through the filter medium, which may be sitting on a coarser support which holds it in place, and the slurry is forced through the filter medium by means of positive pressure or negative pressure, which means that you're pulling a vacuum. The idea is that the material that's in the suspension or slurry that you're filtering builds up as a layer on the surface of the filter medium to form a cake. It's that cake which acts as the true filter to filter out more solid material, allowing the clear filtrate to pass down through the cake and then through the filter medium. In the case of cake filtration, the function of the filter medium is to act as a support for the filter cake, while the initial layers of cake are what provide the true filter. The filter medium should be strong, should be resistant to the corrosive action of any fluid that's being passed through it, and offer little resistance to the flow of the filtrate. Woven materials with high porosity or high aperture size between the strands of the material are commonly used. 17  Transcript Slide 12: Filter Aids Now, if the solid component of the slurry forms a good cake of adequate porosity to allow the liquid to pass through, but good enough rigidity to also trap the solid particulates, then it will filter of its own accord. But in some cases, you have to facilitate the filtration process and facilitate the construction of a suitable cake on the surface of the filter medium by using an added component, which is called a filter aid. Click each tab for more information on filter aids and when you’re ready click next to continue. I expand further on factors that can affect cake filtration and the filtration equipment that's used, in other recordings in the study section of this session. Tab 1: Filter Aid Materials 18  Transcript Filter aids are materials which are added in concentrations of up to five percent to slurries which filter only with difficulty, to slurries where you find that you can't form a suitable rigid cake, of sufficient porosity and permeability that will allow the liquid to easily pass through while retaining the solid. The filter aid then is used to form this desirable type of cake, and the cake then supports the fine particles that are originally present in the slurry of interest. So, it will retain the particles of the slurry that you want to filter out. Filter aids which are used in pharmaceutical processing are things like diatomite, which is a purified fractionated powder. It's a clay like material, also called Kieselguhr. Various cellulose derivatives can also be used as filter aids, as can perlite, which is a volcanic glass. Tab 2: Pre-coating with Filter Aid In this case, the blue shaped particles here are particles of a filter aid which has been added as an initial slurry through the filter medium to build up a cake on the surface. This pre-coat of the filter aid cake acts to filter out the slurry of interest when it's subsequently added. And then if it's the solid material that you're interested in retaining, you can scrape off that solid material, so in this case, those pink particles from the surface, while avoiding removal of the pre-coat of the cake that's comprised of the filter aid. 19  Transcript Tab 3: Mixing with Filter Aid Another way of improving the filterability of a suspension is to mix in a filter aid with the material that's in the slurry or in suspension already. And, in that case, you'll get a mixed cake comprised of both the filter aid and the solid component of the slurry. This mixed cake, then, is useful if you want to get good filtration and collect the filtrate, provided it's the filtrate that you are interested in collecting. If it's the solid component that you're interested in collecting, then mixing in the filter aid can make things a bit more complicated because you may have to have some additional subsequent process which will allow you to separate out the filter aid again from the solid material of interest. Slide 13: Section 3: Drying 20  Transcript Finally in this session, drying. Slide 14: Drying Drying can be defined as the vaporisation and removal of water or another liquid from a solution, a suspension or other solid liquid mixture to form a dry solid. Often when we think of drying, we only think of it in the context of vaporisation of water but drying can also apply to the removal by vaporisation of another solvent, another liquid. And we'll also see that there is one drying process – freeze drying or lyophilisation - whereby the removal of water occurs, not primarily by a vaporisation process, but by a sublimation process. We often also think of drying in the context of removing a liquid from a damp solid, for example, the damp cake that we get post a filtration process, but drying can also apply to the removal of liquid from a solution or a suspension or a slurry presentation of a liquid- solid mixture. Drying ultimately refers to the final removal of water or other solvent to leave you with minimal residual solvent levels, and the operation often follows on from other unit processes or other unit operations, such as evaporation, crystallisation or filtration. 21  Transcript Slide 15: Reasons for Drying Reasons for drying are many. We often dry to improve the handling capability and the flow characteristics of the material, for example, post recovery of crystals from a crystalliser, perhaps by filtration. We may then move on to a drying process to improve the flow and the physical characteristics of the batch of crystals, and to improve their handling characteristics. Drying will reduce transport costs because, by drying, we remove an amount of volume and weight that's associated with the material and thereby reduce the cost associated with handling, moving and transporting that material. And of course, drying may be very important for particular APIs that are very prone to degradation as a result of residual moisture or solvent levels. So, in order to stabilise moisture sensitive materials, we want to make them as dry as possible. 22  Transcript Slide 16: Drying Parameters Parameters to consider during the drying process include Relative Humidity and Moisture Content. Click each tab for more information and when you’re ready, click next to continue. Tab 1: Relative Humidity Now, a reminder of what we saw in the session on mass and heat transfer where we were looking at the importance of mass transfer and heat transfer in the context of a drying process. In drying of, we'll say, a bed of granules or a bed of solid pharmaceutical material, we often use a hot gas or air and pass it over the surface of that material so that heat is 23  Transcript transferred from the hot gas or air to the material that we want to dry. We’ll say that water is the solvent we want to get rid of, any water that's in there, if it reaches a high enough temperature, will be converted into vapour and that water vapour can be removed in a mass transfer process, and will be transferred into the warm gas or the warm air stream that's passing over the bed of granules or powder. In order to successfully carry out such a drying operation that uses this warm air or gas, the temperature and the humidity of the air or the gas that we're using for drying must be considered. The term that's generally used to express the humidity is the percentage relative humidity, which is the partial pressure of water vapour in the air, which is a measure of the amount of water that's in the air, divided by the vapour pressure of water at the same temperature, and multiplied by one hundred to get a percentage. So the percentage relative humidity is the amount of water vapour that's in the air as a percentage of what it would hold, at the same temperature, if the air was saturated with water vapour. Very dry air will have a very low percentage relative humidity, maybe less than five percent. And air that has a lot of moisture or water vapour already in it will have a very high relative humidity, maybe up as high as 70 percent. The humidity of the air will affect the partial pressure gradient and will determine the driving force for mass transfer. And so, the relative humidity of the air, as well as the temperature of the air will determine the efficiency of a drying process. Tab 2: Equilibrium Moisture Content Another parameter that we have to be aware of is what we mean by moisture content. When we consider the moisture content of, we'll say, a pharmaceutical solid or a pharmaceutical material that we're trying to dry, the moisture content is defined as the weight of water per unit weight of dry solids. So it's considered in the context of the mass of dry solids. 24  Transcript If a material is exposed to air at a given temperature and humidity, the material will either lose or gain water until an equilibrium condition is established. In other words, it has reached a steady state where moisture is neither being lost nor gained. So, the temperature is going to be important in terms of heat being transferred to the material that we want to dry. And humidity is going to be important in terms of the capacity of the air to take in that moisture or that water vapour that we're trying to get transferred into that air. The equilibrium moisture content expresses the moisture content that we can achieve, having exposed material to a particular condition of temperature and humidity, once it's in steady state or once it's reached that equilibrium position. Tab 2.1: Equilibrium Moisture Content (2/3) For a particular powder if we plot the equilibrium moisture content, at a particular temperature, when the material is exposed to different relative humidities against that humidity, we get an equilibrium moisture content curve or graph – an E.M.C. chart or graph. So how can we make use of these E.M.C. graphs or these E.M.C. charts? Here, for example, we have two powders and we have the E.M.C. graph. If we know that we need to dry powder 1 to less than five percent moisture content, then the air that we need to use to dry the product should have a relative humidity less than 40 percent. On the other hand, looking at powder 2, it doesn't take up as much water, even at very high relative humidity. So with powder 2 we can maintain the moisture content at less than five percent even at relative humidities higher than 60 percent, 70 percent, possibly even 80 percent relative humidity. This means that with powder 2 we need to take much less care about the relative humidity of the air to which it is exposed. 25  Transcript If we want to decrease the relative humidity, the air temperature has to be increased. If you increase the temperature, the amount of water vapour the air can hold increases, so the relative humidity decreases. However, a higher air temperature may cause degradation of a drug if it is very thermo-sensitive – if it undergoes thermo- degradation, or degradation as a result of heating. So, in this case, it's possible to dry with lower temperatures and higher relative humidities if powder 2 is used, but not if powder 1 is used. If these were two different formulations of the same active pharmaceutical ingredient, we have much more flexibility in terms of our drying process with powder 2 compared to powder 1. The E.M.C. charts can also provide us with information regarding storage conditions. For example, suppose a water content of 10 percent or more produces poor flow characteristics for powder 1, the E.M.C. chart shows us that this powder has to be stored at less than 60 percent relative humidity if we want to achieve an equilibrium moisture content less than 10 percent. So, it informs us about our storage conditions and the environmental conditions that the powder can be exposed to while maintaining its flow characteristics. Tab 2.2: Equilibrium Moisture Content The moisture in any solid can be present in two forms. We have free moisture, which is the moisture that's in excess of the equilibrium moisture content, and which we can relatively easily remove from the solid material. And then we have bound moisture. Bound moisture is the water that's retained in such a way that it exerts a vapour pressure less than that of free water at the same temperature. Bound water is usually held onto the solid by the forces of capillary action or is strongly adsorbed onto the surface of the solid in some way. It is very hard to remove bound moisture, so the residual moisture or residual solvent that we end up with, is invariably this bound moisture that is difficult to remove because it's held so tightly onto the solid surface. 26  Transcript Slide 17: Vaporisation of Water from a Static Powder Bed Let’s now consider one of the ways in which a solvent can be removed from a solid material, and that's by getting it to vaporise into a warm air stream or warm gas stream. In the simplest case, let's consider the drying of static or fixed beds of non-porous solids. Click on each tab for more information and when you’re ready, click next to continue. Tab 1: Moisture Content So, you might have a mass or a bed of crystals that you've recovered from a crystallisation process, passed perhaps through a filtration process, but there's still some residual water or residual solvents that you need to remove from those crystals. This represents our bed of non-porous crystalline solid material. 27  Transcript In the drying process, we pass heat, a heated gas or a heated airstream across that solid material, getting heat transferred into it and then moisture transferred away from it. Or it could be another solvent, not necessarily water. So obviously, what we're hoping will happen is that the moisture or solvent content of the solid will decrease over time. And indeed, what we'll see is that the moisture content will decrease over time until we get as far as the minimal residual moisture content remaining. Tab 2: Drying Rate Curve Now we can convert this type of a graph where we're looking at moisture content versus time into what's called a drying rate curve, and in a drying rate curve we're looking at the rate of drying against the moisture or solvent content. We have different regions in this drying rate curve that we can identify. From A to B we have what's called the constant rate period. So the rate of drying remains constant for this period. At B, we have what's referred to as the critical moisture content. And past B then from B to C, the drying rate falls and we have what's called the first falling rate period. We then see a slight inflexion in the graph and from C to D we have what's called the second falling rate period. So what's happening in these different periods? Well, from A to B, moisture is evaporating from a saturated surface. So there's sufficient moisture at the surface of the solids to keep it saturated. From B to C, though, when we see a drop in the drying rate; what's happening there is that the diffusion of moisture through the bed, so from further down into the bed, towards the surface, is not sufficient to keep the surface saturated. The surface is not saturated with moisture any longer and because of that, the rate of drying declines, the rate of drying falls. From C to D then the rate of drying falls off again, because here moisture is no longer getting as far as the surface. The surface is actually now dry, and evaporation takes place along a receding plane which goes back and back 28  Transcript further down, deeper and deeper into the solid. Usually we want to avoid this second falling rate period because we don't want to enter into a situation where the surface gets too dry, particularly if we're dealing with a thermolabile material. Slide 18: Vaporisation of Water from a Static Porous Solid Bed What I’ve spoken about just now is the situation as it occurs in drying of static, not moving, fixed beds of non-porous solids. If we consider the same situation, but now for drying of fixed beds of porous solids, do we see any difference in the drying rate curve? This situation might arise, for example, where we granulate the material, and have pores within the granules. Here the rate of drying is often faster than in the case of non-porous solids. And that's because of the porosity, and the fact that moisture can be removed from the pore surfaces. So the surface area of the individual granules is increased relative to a non-porous situation. The rate of drying can be faster than a non-porous situation and tends to be independent of particle size. Whereas for non-porous solids, the particle size is important because the smaller the particle size, the higher the surface area available for heat and mass transfer, the faster the drying process. The constant rate period tends to be shorter. The first falling rate period falls very sharply and is attributed to the drying of surface granules. And then the second falling rate period tends to fall even more steeply and is affected by the diffusion of moisture from within the pores in the granules. 29  Transcript Slide 19: Alternative Drying Processes There are various alternative drying processes and types of dryer which are designed to improve efficiency. Click on each tab to learn more and when you’re ready click next to continue. In the study section for this session, you will find recordings where I expand on the factors that should be considered when choosing drying equipment, the different types of dryer available and their use in pharmaceutical drying processes. Tab 1: Through Circulation Dryers One option is to pass air or gas down through the bed of material and by doing so, it means that the surface area of material in contact with the drying gas is increased 30  Transcript and that improves the heat and mass transfer processes, which in turn increases the efficiency of the drying process, improving the drying rate. This is seen in what are called through circulation dryers. Here you might have a bed of solid material sitting on a screen with apertures small enough that the particles of the solid material won't pass through, But at the same time, the warm air or gas can pass through, and in doing so, dry off the solid material that is loosely distributed onto the screen. Tab 2: Fluidised Bed Dryers Another option is to pass a high velocity air or gas stream up through the bed of material causing that bed of solid material to fluidise. In other words, it behaves as if it's a fluid. So the particles are suspended in a warm air or gas stream, and this is seen in what are called fluidised bed dryers. In both through circulation and fluidised bed dryers an inert gas like nitrogen can be used for drying, rather than air, if there’s a concern about oxidation of the material being processed. 31  Transcript Tab 3: Spray Dryer Another option for drying, if we're starting off, not with a solid material, but with a liquid material, such as a suspension or a solution, for example, is to break that liquid into small droplets and pass those droplets at high velocity through hot air or gas. We see this process being used in a dryer, which is known as a spray dryer. In all of these cases, there's a high surface contact between the drying air or the drying gas and the material to be dried, and so drying times can be significantly reduced. Slide 20: Summary Having completed this session you should now be able to: 32  Transcript List the methods of crystallisation Identify the driving forces that affect nucleation and crystal growth Weigh the differences and benefits of: Different methods of filtration, Filtration types Filter aids Define drying and consider the parameters that can affect the drying process. 33