ae Drying Michael E, Aulton Satyanarayana Somavarapu CHAPTER CONTENTS KEY POINTS Leeann vss +++ 488 Drying is important at many stages of Drying of wet solids . . . 499 pharmaceutical manufacture to remove solvent Fundamental properties and (usually water) that could act as a vector for interrelationships. 499 chemical and microbiological deterioration of Moisture content of wet solids. . . 498 the drug or product. Moisture content of air - 500 * The most common form of drying is Loss of water from wet solids "501 heat-induced svaporation ofthe solvent. Great care must be taken (by controlling temperature See DO eer oe and time) to minimize any thermal degradation Choice of drying method 502 during drying, Dryers in the pharmaceutical industry . - 502 © Some fraction of the solvent is very easy to Convective drying of wet solids... . . .502 Temove (known as free moisture) and the Dynamic convective dryers 502 remainder is much more difficult or occasionally Condilctive erying ot Wat cond oil impossible to remove from a solid (bound moisture). Vacuum oven 504 * Many different types of drying processes and Radiation drying of wet solids... . . . . 505 equipment exist as there are numerous Radiant heat transmission 505 mechanisms by which moisture is lost from a Use of microwave radiation. 505 wet product or intermediary. Drying of solutions and suspensions . . .506 ° The selection of the best drying method for a product is a key decision See ne 50 + The phenomenon of solute migration during Freeze-drying (lyophilization) 510 drying should be minimized. The phase diagram for water. . 510 Stages of the freeze-drying process 511 7 Solute migration during drying . sig Introduction Intergranular migration 514 ifiretreniler migretlcn, 514 Drying is an important operation in primary phar- Consequences of solute migration 514 Maceutical manufacture (i.e. the synthesis of active . ieaterestd amin aera tat pharmaceutical ingredients or excipients) because it solute migration . 515 _ is often the last stage of manufacturing before packag- Influence of process factors on ing. It is important that the residual moisture, say solute migration... . . 516 from a final crystallization step, is rendered low Some practical means of minimizing ‘enough to prevent product deterioration during storage solute migration . 516 and ensure free-flowing properties during use. It is Bibliography... 2.2.2... 516 equally important (and probably encountered more 498 .Drying ntly) in secondary (dosage form) manufacture important terms. To avoid confusion and repetition, ing the common operation of wet granulation these terms are defined andl explained in the context Chapter 28) during the preparation of granules of water (the most commonly used pharmaceutical tablet compaction. Hence stability (see solvent) but the explanations and 47 and 49), flow properties (see Chapter applicable to other relewne h and compactability (see Chapter 30) are all 2-propanol). uenced by residual moisture. chapter is concerned with drying to the ‘dry’ Saute Starting with either a wet solid ora solution Moisture content of wet solids Pension. The former is usually achieved by of the wet solid to moving, relatively dry ‘The moisture content of a wet solid is expressed as ea air temperatures to accelerate the process kilograms of moisture associated with 1 kg of the parmmon. The later is possible with equipment _moisture-free, or bone-dry, solid, hcy a moisture bas the spray-dryer (see later in this chapter), content of 0-4 means that Ged kg of water is present eb is capable of producing a dry product froma per kilogram of the bone-dry solid that will remain ution or suspension in one operation, after complete drying. It is sometimes calculated as Pharmaceutical materials are not completely a percentage moisture content; thus this example from moisture (ie. they are not bone dry) but would be quoted as 40%, moisture content, fain some residual water, the amount of which with the temperature and humidity of the Total moisture content air to which they are exposed. This is dis- din more detail in this chapter, Total moisture content is the total amount of liquid the Purpose ofthis chapter, drying is defined associated with a wet solid: Some of cha water can removal ofall or most of the liquid associated _ be easily removed by the simple evaporative processes @ wet pharmaceutical product. All drying pro- used by most pharmaceutical dryers and some cannot. of relevance to pharmaceutical manufacturing The amount of easily removable wate, (unbound Sraporation or sublimation of the iguid phase water) is known as the free moisture content, and cha removal of the subsequent vapour. The process moisture content of the water thet ic mora difficult Provide the latent heat for these processes _ to remove in practice (bound water) is the equilibrium pug itificant temperature rise. Naturally, the moisture content. Thus the total moisture cone of prllenhance the potential of thermal degrada- a soli is equal to its bound and unbound moisture of the product. In most cases the ‘liquid’ will content or, put another way, its free moisture content ter, but more volatile organic solvents, such as lus its equilibrium moisture content panel, may also need to be removed in a drying Unbound water. The unbound water associated The physical principles of aqueous or organic with a wet solid exists as a liquid and it exerts its drying are similar, regardless of the nature full vapour pressure: Ie xn be removed readily by liquid, though volatile solvents are normally evaporation, During a drying process this unbound by condensation rather than being vented water is readily lost, but the resulting solid will not atmosphere. This is for environmental and be completely free from wary molecules as it remains ie reasons. In addition, the toxicity and flam- in contact with atmospheric air, which inevitably of onganic solvents pose additional safety contains some dissolve water. Consequently, the ocess considerations. resulting solid is often known as air dry. concepts are equally iquids (eg. ethanol, Equilibrium moisture content As mentioned already, 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 derstanding of the drying of wet solids requires Preliminary explanation of a number of 4998 humidity of the air, and with the nature of the solid (see later in this chapter) Bound water. Part of the moisture present ina wet solid may be adsorbed on surfaces of the solid or may 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 monolayer (or bilayer) 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 — ee An added complication to the drying process is that the drying air also contains moisture. Many pharma- ceutical 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 kilograms of water per kilogram of bone-dry (water-free) air. The moisture content of air is altered not only by changes in its temperature alone but also by changes in the amount of moisture taken up by the air. The moisture content of air should be carefully distin- guished from the relative humidity Relative humidity 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 called precipitation, At a given temperature, air is capable of ‘taking up’ (i. dissolving) water vapour until itis saturated (at 100% relative humidity). Lower relative humidities can be quantified in terms of percentage relative humidity, which is given by is sometimes vapour pressure of water vapour in air vapour pressure of water vapour in the air saturated at the same temperature x100 (29.1) Dosage form design and manufacture This is approximately equal to the percentage satura- tion, which is mass of water vapour present ilogram of dry air _per kilogram of dey tte mass of water vapour required to saturate kg of dry air at the same temperature (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 s 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 reexamination of Eqs 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 the moisture content éf the drying air (and therefore its relative humidity) could change signifi cantly. This arises from two separate factors: * Uptake into the drying air of water vapour that has evaporated from the drying solid. If evaporation is high and vapour removal inefficient, the drying efficiency will rapidly fall, * The cooling of the supply air (and consequently the product) as the air transfers latent heat to the wet solid. This phenomenon is known as evaporative cooling. If the cooling is excessive, the temperature of the air may fall to a value known as the dew point. Here the solubility of water in the cooler air is reduced to such a point that the saturated solubility is exceeded and liquid water will condense and be deposited.