Drying
Michael E. Aulton
Chapter contents
Fundamental properties and interrelationships
Moisture content of wet solids
Dryers in the pharmaceutical industry
Types of pharmaceutical dryers
Convective drying of wet solids
Conductive drying of wet solids
Radiation drying of wet solids
Dryers for solutions and suspensions
Stages of the freeze-drying process
Solute migration during drying
Consequences of solute migration
Influence of formulation factors on solute migration
Influence of process factors on solute migration
Some practical means of minimizing solute migration
Key points
• The selection of the best drying method for a product is a key decision.
• The phenomenon of solute migration should be minimized during drying processes.
Introduction
Drying is an important operation in primary pharmaceutical manufacture (i.e. the synthesis of active pharmaceutical ingredients or excipients) since it is usually the last stage of manufacturing before packaging. It is important that the residual moisture, say from the final crystallization step, is rendered low enough to prevent product deterioration during storage and ensure free-flowing properties during use. It is equally important (and probably encountered more frequently) in secondary (dosage form) manufacture following the common operation of wet granulation (see Chapter 28) during the preparation of granules prior to tablet compaction. Hence, stability (see Chapter 48 and 49), flow properties (see Chapter 12) and compactability (see Chapter 30) are all influenced by residual moisture.
This chapter is concerned with drying to the ‘dry’ solid state, starting with either a wet solid or a solution or suspension. The former is usually achieved by exposing the wet solid to moving, relatively dry air (elevated temperatures to accelerate the process are common). The latter is possible with equipment such as the spray dryer (see later in this chapter) that is capable of producing a dry product from a solution or suspension in one operation.
Most pharmaceutical materials are not completely free from moisture (i.e. they are not ‘bone dry’) but contain some residual water, the amount of which may vary with the temperature and humidity of the ambient air to which they are exposed. This is discussed in more detail in this chapter.
For the purpose of this chapter, drying is defined as the removal of all or most of the liquid associated with a wet pharmaceutical product. All drying processes of relevance to pharmaceutical manufacturing involve evaporation or sublimation of the liquid phase and the removal of the subsequent vapour. The process must provide the latent heat for these processes without a significant temperature rise. Naturally the latter will enhance the potential of thermal degradation of the product. In the majority of cases the ‘liquid’ will be water but also more volatile organic solvents, such as isopropanol, may need to be removed in a drying process. The physical principles of aqueous or organic solvent drying are similar, regardless of the nature of the liquid, though volatile solvents are normally recovered by condensation rather than being vented into the atmosphere. This is for environmental and economic reasons. Also, the toxicity and flammability of organic solvents pose additional safety and process considerations.
Drying of wet solids
Fundamental properties and interrelationships
An understanding of this operation requires some preliminary explanation of the following important terms. To avoid confusion and repetition, these terms will be defined and explained in the context of water (the most commonly used pharmaceutical solvent) but the explanations and concepts are equally applicable to other relevant liquids (e.g. ethanol, isopropanol, etc.).
Moisture content of wet solids
The moisture content of a wet solid is expressed as kg of moisture associated with 1 kg of the moisture-free or ‘bone-dry’ solid. Thus, a moisture content of 0.4 means that 0.4 kg of water is present per kg of the ‘bone-dry’ solid that will remain after complete drying. It is sometimes calculated as percentage moisture content; thus this example would be quoted as 40% moisture content.
Total moisture content
This is the total amount of liquid associated with a wet solid. Some of this water can be easily removed by the simple evaporative processes employed by most pharmaceutical dryers and some cannot. The amount of easily removable water (unbound water) is known as the free moisture content and the moisture content of the water that is more difficult to remove in practice (bound water) is the equilibrium moisture content. Thus, the total moisture content of a solid is equal to its free moisture content plus its equilibrium moisture content.
Unbound water.
The unbound water associated with a wet solid exists as a liquid and it exerts its full vapour pressure. It can be removed readily by evaporation. During a drying process this unbound water is readily lost but the resulting solid will not be completely free from water molecules as it remains in contact with atmospheric air that inevitably contains dissolved water. Consequently the resulting solid is often known as air dry.
Equilibrium moisture content
As mentioned above, evaporative drying processes will not remove all the possible moisture present in a wet product because the drying solid equilibrates with the moisture that is naturally present in air. The moisture content of a solid under steady-state ambient conditions is termed the equilibrium moisture content. Its value will change with the temperature and humidity of the air, and with the nature of the solid (see later in this chapter).
Bound water.
Part of the moisture present in a wet solid may be adsorbed on surfaces of the solid or be absorbed within its structure to such an extent that it is prevented from developing its full vapour pressure and therefore from being easily removed by evaporation. Such moisture is described as bound water and is more difficult to remove than unbound water. Adsorbed water is attached to the surface of the solid as individual water molecules which may form a mono- (or bi-) layer on the solid surface. Absorbed bound water exists as a liquid but is trapped in capillaries within the solid by surface tension.
Moisture content of air
An added complication to the drying process is that the drying air also contains moisture. Many pharmaceutical plants have air-conditioning systems to reduce the humidity of the incoming process air, but removing water from air is a very expensive process and therefore not all the water will be removed. The moisture content of air is expressed as kg of water per kg of ‘bone-dry’ (water-free) dry air.
The moisture content of air is not altered by changes in its temperature alone, only by changes in the amount of moisture taken up by the air. The moisture content of air should be carefully distinguished from the relative humidity.
Relative humidity (RH) of air
Ambient air is a simple solution of water in a mixture of gases and as such follows the rules of most solutions – such as increased water solubility with increasing temperature, a maximum solubility at a particular temperature (saturation) and precipitation of the solute on cooling (condensation, rain!). Incidentally, this is exactly why rain is sometimes called precipitation.
At a given temperature, air is capable of ‘taking up’ (i.e. dissolving) water vapour until it is saturated (at 100% RH). Lower relative humidities can be quantified in terms of percentage relative humidity, which is given by:
(29.1)
This is approximately equal to the percentage saturation, which is:
(29.2)
Percentage saturation is the more fundamental measure but the expression ‘relative humidity’ is most commonly used. The two differ only very slightly in practice and only because water vapour does not behave exactly like an ideal gas.
These relationships show that the relative humidity of air is dependent not only on the amount of moisture in the air but also on its temperature. This is because the amount of water required to saturate air is itself dependent on temperature. As mentioned before, in ambient air, water is in solution in the air gases and in this case its solubility increases with increasing temperature. If the temperature of the air is raised whilst its moisture content remains constant, the air will theoretically be capable of taking up more moisture and therefore its relative humidity falls. A re-examination of Equations 29.1 and 29.2 will show this.
It is important to understand the difference between moisture content and relative humidity of air. This is important in many contexts (powder properties, granulation, drying, compaction, storage conditions) but these terms are often confused.
An additional complication to be taken into account is that during a drying process both the temperature and moisture content of the drying air (and therefore its relative humidity) could change significantly. This arises from two separate factors:
Relationship between equilibrium moisture content, relative humidity and the nature of the solid
The equilibrium moisture content of a solid exposed to moist air varies with the relative humidity and with the nature of the solid, as shown in some typical plots (Fig. 29.1). If we assume that the atmospheric conditions are of the order of 20 °C and 70–75% relative humidity, a mineral such as kaolin will contain about 1% bound moisture, while a starch-based product may have as much as 30% or more.
Loss of water from wet solids
As explained above, unbound water is easily lost by evaporation until the equilibrium moisture content of the solid is reached. This is shown in Figure 29.2. Once the solid reaches its equilibrium moisture content, extending the time of drying will not change the moisture content since an equilibrium situation has been reached. The only way to reduce the moisture content of the solid shown in Figure 29.2 is to reduce the relative humidity of the ambient air. This can be achieved on a large scale with an air-conditioning system. On a laboratory scale, desiccators are used. Silica gel (a common laboratory and packaging desiccant) does not directly take water from a solid; instead it acts by removing the water from the air, thereby reducing its relative humidity to around 5–10%. This in turn causes the equilibrium to move along the drying curve in Figure 29.2 to the left, thus reducing the moisture content of the solids. Phosphorus pentoxide works in an identical manner but it has an even greater affinity for the water in the storage air.
If dried materials are exposed to humid ambient conditions they will quickly regain moisture from the atmosphere since this relationship is an equilibrium. Figure 29.1 shows this. Thus it is unnecessary to ‘overdry’ a product and there is no advantage in drying to a moisture content lower than that which the material will have under the normal conditions of use.
If low residual moisture content is necessary due to a hydrolytic instability in the material, the dried product must be efficiently sealed during or immediately after the drying process to prevent ingress of moisture. It also worth noting that some solid pharmaceutical materials perform better when they contain a small amount of residual water. Powders will flow better; the flow of very dry powders is inhibited by static charge. Tablet granules have superior compaction properties with a small amount (1–2 %) of residual moisture.
Types of drying method
Choice of drying method
When considering how to dry a material, the following points should be considered:
• heat sensitivity of the material being dried
• physical characteristics of the material
• nature of the liquid to be removed
The general principles for efficient drying can be summarized as:
Dryers in the pharmaceutical industry
The types and variety of drying equipment have reduced in recent years as pharmaceutical companies strive for standardization and globalization of manufacturing. The types of dryers that have proved the most successful have become commonplace and less efficient (or more damaging) drying processes have largely disappeared. An additional trend is the manufacture of ‘mini’ versions of manufacturing equipment to be used in formulation and process development. Previously, very distinctly different dryers were sometimes used in laboratories but this resulted in numerous problems during scale-up. The use of the miniaturized production equipment (processing just a few hundred grams) will minimize later problems during the scaling up to manufacturing batches (typically a few hundred kilograms).
Types of pharmaceutical dryers
A variety of pharmaceutical dryers are still used and it is convenient to categorize these according to the heat transfer method that they employ, i.e. convection, conduction or radiation.
Convective drying of wet solids
Dynamic convective dryers
Fluidized-bed dryer
An excellent method of obtaining good contact between the warm drying air and wet particles is found in the fluidized-bed dryer. The general principles of the technique of fluidization will be summarized before discussing its application to drying.
Consider the situation in which particulate matter is contained in a vessel, the base of which is perforated, enabling a fluid to pass through the bed of solids from below. The fluid can be liquid or gas, but air will be assumed for the purposes of this description, as it is directly relevant to the drying process.
If the air velocity through the bed is increased gradually and the pressure drop through the bed is measured, a graph of the operation shows several distinct regions, as indicated in Figure 29.3. At first, when the air velocity is low, in the region A to B, flow takes place between the particles without causing disturbance, but as the velocity is increased a point is reached, C, when the pressure drop has attained a value where the frictional drag on the particle is equal to the force of gravity on the particle. Rearrangement of the particles occurs to offer least resistance, D, and eventually they are suspended in the air and can move. The pressure drop through the bed decreases slightly because of the greater porosity at D. Further increase in the air velocity causes the particles to separate and move freely and the bed is fully fluidized, region D to E. Any additional increase in velocity separates the particles further, that is, the bed expands, without appreciable change in the pressure drop. In the region E to F, fluidization is irregular, much of the air flowing through in bubbles; the term boiling bed is used to describe this. At a very high air flow rate, F, the air velocity is sufficient to entrain the solid particles and transport them out of the top of the bed in a process known as pneumatic transport.
The important factor is that fluidization produces conditions of great turbulence, the particles mixing with good contact between air and particles. Hence, if hot air is used, the turbulent conditions lead to high heat and mass transfer rates, the fluidized-bed technique therefore offers a means of rapid drying.
The fluidized-bed dryer was developed to make use of this process of fluidization to improve the efficiency of heat transfer and vapour removal compared with the older static tray dryers that it replaced. A reason for this is the more efficient transfer of the required latent heat of evaporation from the air to the drying solid. The rate of heat transfer (dH/dt) in convective drying may be written as:
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