DRYING

Drying is often the last step in downstream processing for recovery of solid products from
fermentation. The aim is to remove relatively small amounts of residual water or solvent from
materials such as crystals, precipitates, and cell biomass, thus rendering the product suitable for
packaging and storage. Drying may be necessary to minimise chemical or physical degradation of
solids during storage, for example, due to oxidation or aggregation. Drying is a relative term: material
containing 0 to 20% water by weight may be considered dry depending on the product and the
specifications for acceptable product quality. Drying is an energy-intensive unit operation;
accordingly, drier effectiveness and energy efficiency are of concern for economical processing. In
this section, we will consider drying to be the removal of water from solid material into air; however,
the same general principles apply for other liquids and gases. Drying is achieved by vaporising liquid
water or ice contained within a solid and then removing the

3. PHYSICAL PROCESSES
vapour. In many drying operations, a stream of hot air supplies the heat needed for vaporisation
and the means for transporting the water vapour away from the solid. Particular attention is required
when drying heat-sensitive biological materials to ensure that thermal degradation does not occur.
Vacuum drying and freeze-drying are used to dry fermentation products such as proteins, vitamins,
vaccines, steroids, and cells at temperatures below 0_C to protect their biological properties and
activity. Freeze-drying is considered in
more detail in Section 11.13.5.

11.13.1 Water Content of Air

Moist or humid air is a mixture of dry air and water vapour. The humidity of air, also
known as the absolute humidity or humidity ratio, is a dimensionless parameter defined as:
Humidity5
Mw
Ma
ð11:155Þ
where Mw is the mass of water vapour carried by mass Ma of dry air. Humidity is measured
using instruments called hygrometers.
The total pressure of humid air is equal to the sum of the partial pressures of its constituents,
including water vapour. The partial pressure of water vapour in air, pw, depends
on the molar concentration of water in the gas phase:
pw 5ywpT ð11:156Þ
where yw is the mole fraction of water vapour in the air_vapour mixture and pT is the
total pressure. Air is said to be saturated with water vapour at a particular temperature
and pressure if its humidity is the maximum it can be under those conditions. Addition of
further water vapour to saturated air results in the condensation of liquid water in the
form of droplets or a mist. Under saturation conditions, the partial pressure of water
vapour in air is equal to the saturation vapour pressure psw of pure water at that temperature.
Values for the saturation vapour pressure of water as a function of temperature are
listed in Table D.1 in Appendix D.
If a mixture of water vapour in air is cooled, the temperature at which the mixture
becomes saturated is called the dew point or saturation temperature. The dew point is the
temperature at which pure water exerts a vapour pressure equal to the partial pressure of
water vapour in the mixture. The relative humidity of air is defined as the ratio of the partial
pressure of water vapour in the air to the saturation vapour pressure of pure water at
the same temperature, expressed as a percentage:
Relative humidity5
pw
psw
3100% ð11:157Þ
The thermodynamic properties of air and its associated water content, including the relationships
between temperature, humidity, enthalpy, and specific volume, are represented
564 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
in psychrometric charts. Examples of psychrometric charts for air and water vapour mixtures
can be found in handbooks (e.g., [42]).
11.13.2 Water Content of Solids
At a given temperature, the moisture content of a wet solid depends on the humidity of
the atmosphere surrounding it. When a solid is brought into contact with a relatively large
amount of air, the conditions of the air remain essentially constant even if the water content
of the solid changes. After a sufficient period, equilibrium between the air and wet
solid is reached. Results at a fixed temperature for the equilibrium moisture content of the
solid as a function of air relative humidity are presented as an equilibrium moisture content
isotherm or equilibrium water sorption isotherm. Measured equilibrium moisture content isotherms
for yeast cells, insulin, lysozyme crystals, and benzyl penicillin are shown in
Figure 11.56(a). The equilibrium moisture content of solids is usually expressed on a dry
weight basis using units of, for example, g of water per 100 g of dry solid.
Data for equilibrium water sorption isotherms are obtained by exposing solid material to
air of varying relative humidity and measuring the equilibrium water content of the solid at
0 10 20 30 40 50 60 70 80 90 100
Equilibrium moisture content
(g water per 100 g dry weight)
0
10
20
30
40
50
60
70
80
90
(a)
Relative humidity (%)
0 100
Equilibrium moisture content
(g water per 100 g dry weight)
(b)
Relative humidity (%)
Adsorption
Desorption
FIGURE 11.56 Equilibrium moisture content isotherms.
(a) Experimentally measured isotherms (K). Saccharomyces cerevisiae yeast during hydration at
30_C. Data from
S. Koga, A. Echigo, and K. Nunomura, 1966, Physical properties of cell water in partially dried
Saccharomyces cerevisiae.
Biophys. J. 6, 665_674.
(&) Crystalline insulin at 25_C. Data from M.J. Pikal and D.R. Rigsbee, 1997, The stability of insulin
in crystalline and
amorphous solids: observation of greater stability for the amorphous form. Pharm. Res. 14,
1379_1387.
(¢) Lysozyme crystals at 22_C. Data from E.T. White, W.H. Tan, J.M. Ang, S. Tait, and J.D. Litster,
2007, The density
of a protein crystal. Powder Technol. 179, 55_58.
(x) Sodium benzyl penicillin at 25_C. Data from N.A. Visalakshi, T.T. Mariappan, H. Bhutani, and S.
Singh, 2005,
Behavior of moisture gain and equilibrium moisture contents (EMC) of various drug substances and
correlation with compendial
information on hygroscopicity and loss on drying. Pharm. Dev. Technol. 10, 489_497.
(b) Isotherms for moisture adsorption (hydration) and desorption (dehydration) showing water
sorption hysteresis.
11.13 DRYING 565
3. PHYSICAL PROCESSES
constant temperature. Exposure to air of progressively increasing humidity gives an adsorption
or hydration isotherm as the solid gains water to equilibrate with the air. Conversely,
exposure to air of progressively decreasing humidity gives a desorption or dehydration isotherm
as the solid dries to achieve equilibrium. Some materials display hysteresis, in that
the adsorption and desorption isotherms do not coincide, as shown in Figure 11.56(b). This
occurs when wetting or drying leads to irreversible changes in the structure of the solid.
For drying applications, the desorption isotherm is of greater importance than the adsorption
isotherm. Sorption isotherms are also dependent on external pressure; however, for
practical purposes, this effect is usually neglected. Equilibrium moisture content isotherms
cannot be predicted from theoretical consideration of the material of interest: they must be
determined by experiment. Methods for measuring sorption isotherms are described elsewhere
[42].
Equilibrium water sorption isotherms are important in drying operations because they
indicate how dry a solid can become if it is brought into contact with air of a given relative
humidity. After drying, the moisture content of a solid cannot be less than the equilibrium
moisture content on the isotherm corresponding to the relative humidity of the air entering
the drier. For example, from Figure 11.56(a), using air at 30_C with relative humidity
60%, the yeast cells tested cannot be dried to water contents below the equilibrium value
of about 7.5 g per 100 g dry cells.
EXAMPLE 11.14 MOISTURE CONTENT AFTER DRYING
A filter cake produced by vacuum filtration of bakers’ yeast (Saccharomyces cerevisiae) contains
38 g of water per 100 g of dry cells. The cells are dried before packaging. Atmospheric air at
10_C and 90% relative humidity is heated to 30_C at constant pressure for use in a tray drier.
Assuming that equilibrium is reached during the drying process and that the equilibrium moisture
content isotherm for yeast shown in Figure 11.56(a) applies, what is the moisture content of
the cells after drying?
Solution
From Table D.1 in Appendix D, the saturation vapour pressure psw of water at 10_C is
1.227 kPa. Therefore, from Eq. (11.157), the partial pressure of water vapour in air at 10_C and
90% relative humidity is:
pw 5
90%
100%
ð1:227 kPaÞ51:104 kPa
From Eq. (11.156), this partial pressure is proportional to the mole fraction of water vapour in
the air. When the air is heated to 30_C, because the composition of the air_vapour mixture and
the total pressure remain constant, pw in the air at 30_C is also 1.104 kPa. From Table D.1 in
Appendix D, the saturation vapour pressure psw of water at 30_C is 4.24 kPa. Therefore, using
Eq. (11.157) for the heated air:
Relative humidity5
1:104 kPa
4:24 kPa
3100%526:0%
566 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
From Figure 11.56(a), the equilibrium moisture content of yeast exposed to air at 30_C and 26%
relative humidity is around 6 g of water per 100 g dry weight. Note that the initial water content
of the wet yeast does not figure in this calculation.
The moisture content of the cells after drying is 6 g of water per 100 g dry cells.
The distribution and binding strength of water within wet solids vary depending on the
properties of the material. Many crystalline solids do not contain water within their lattice
structures, which generally are packed too tightly to admit hydration. Therefore, most of
the moisture removed during drying of crystals is from the surface of the particles.
However, some crystalline solids form crystal hydrates as water molecules are incorporated
either on a stoichiometric or nonstoichiometric basis within the solid. Water of crystallisation
is generally relatively immobile, being held within the solid by very strong
water_solid interactions. Nevertheless, it can be removed by drying if sufficient heat and
time are provided. Compared with crystals of inorganic compounds, protein crystals contain
unusually large amounts of water within the crystal lattice: water contents of around
50% are not uncommon. In general, however, the amount of water incorporated within the
bulk structure of solids increases as the degree of crystallinity is reduced.
In Figure 11.56(a), benzyl penicillin displays the characteristics of a moderately hygroscopic
solid, as it has an enhanced ability to attract and hold water molecules from the surrounding
atmosphere, resulting in a marked increase in equilibrium moisture content at
relative humidity levels above about 50%. As amorphous and partially amorphous solids
allow penetration and dissolution of water within their matrix, these materials typically
contain significant amounts of internal moisture as well as surface water. The strength of
water_solid interactions in amorphous solids depends on whether the solid is polar or
nonpolar, and the plasticising effect of water entering the solid structure on the mobility
of both the moisture and solid components. Porosity is also an important factor determining
moisture distribution and water mobility in solids. The interconnected pores and
channels of porous solids fill with water after wetting and capillary flow mechanisms contribute
to the process of water removal in drying. In contrast, molecular diffusion may be
the only mechanism available for water removal from nonporous solids that lack internal
flow channels.
11.13.3 Drying Kinetics and Mechanisms
Drying is a complex process involving simultaneous heat and mass transfer. Because
the physical properties of solids may be changed during drying, predicting the rate of drying
from theoretical principles is often impossible. Drying occurs by vaporising water
using heat. As the heat is usually provided by a hot gas stream, convective heat transfer is
required to heat the outer surface of the solid while conductive heat transfer allows penetration
of heat within the material. Mass transfer is also important, as water within the
solid must be transported to the surface as either liquid or vapour before being removed
into the gaseous environment.
11.13 DRYING 567
3. PHYSICAL PROCESSES
The rate of drying N is defined as the rate at which the mass of water associated with a
wet solid reduces with time:
N52Ms
dX
dt
ð11:158Þ
where Ms is the mass of completely dry solid, X is the moisture content of the solid
expressed on a dry mass basis (e.g., kg kg21 of dry solid), and t is time. The dimensions of
N are MT21; typical units are kg h21. Because dX/dt is negative during drying, the minus
sign in Eq. (11.158) is required to make N a positive quantity. The rate of drying can also
be expressed on a unit area basis as a flux na with units of, for example, kg m22 h21:
na52
Ms
A
dX
dt
ð11:159Þ
where A is the area available for evaporation. Alternatively, the specific drying rate per
unit mass of dry solid, nm, is:
nm52
dX
dt
ð11:160Þ
Typical units for nm are kg kg21 h21.
Drying Curve
The kinetics of drying are assessed by plotting experimentally determined values for
the rate of drying against the moisture content of the solid X. The result is a drying rate
curve as illustrated in Figure 11.57. The shape of the drying rate curve depends on the
material being dried, its size and thickness, and the drying conditions. Drying rate curves
are measured using constant drying conditions, that is, constant air temperature, humidity,
flow rate, and flow direction. The moisture content and other properties of the solid
change under constant drying conditions, which refer only to the gas phase.
Drying rate, N (kg s–1)
Constant drying
rate period
(external heat
and mass
transfer control)
Induction
period
X* Xc
Falling drying rate period
(internal heat and mass
transfer control)
Moisture content, X (kg kg–1 dry solid)
Time
FIGURE 11.57 Drying rate curve
for constant drying conditions.
568 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
As drying commences, the water content of the solid is high. After an initial warmingup
or induction period, the first water to evaporate comes from the surfaces of the wet
solid that are in direct contact with the air stream moving across them. If water is supplied
by mass transfer from within the solid to the surface at a sufficiently rapid rate, the surface
remains saturated with water and a constant drying rate period ensues. This period is represented
in Figure 11.57 by the flat section of the curve. During the constant drying rate
period, the surfaces of the solid remain wet so that free water is always available for evaporation,
and heat and mass transfer take place at the surface. Accordingly, the resistances
to heat and mass transfer are located within the external gas boundary layer surrounding
the material.
With continued drying, as the water content of the solid decreases, a critical moisture
content Xc is reached. The rate of drying begins to decline at this point as the process
enters the falling drying rate period. The reduction in drying rate below Xc reflects a change
in the heat and/or mass transfer conditions in the system. At first during the falling rate
period, the drying surface becomes partially unsaturated and there is no longer a continuous
or nearly continuous liquid film at the surface of the solid. This situation extends
gradually until the entire surface becomes dry. As a solid layer of dried material builds up
at and then below the surface, heat must be transferred by conduction to the remaining
water further inside the solid; in effect, the evaporating surface recedes into the material
as drying proceeds. Because the dried solid near the surface is generally a poor conductor
of heat, the rate of heat transfer declines progressively.
As the surfaces become dry, water must be transported from deeper within the solid to
the surface before it can be removed into the gas phase. As heat and mass transfer become
controlled completely by internal resistances, the drying rate continues to decline and the
process is characterised as diffusion or hindered drying. The moisture content of the solid
reduces further until it approaches the equilibrium moisture content X_. As described in
Section 11.13.2, this is the lowest moisture content that can be achieved at the temperature
and relative humidity used for the drying process.
The curve in Figure 11.57 is somewhat idealised: significant deviations can occur for
particular materials and constant drying conditions are often not applied in practical drying
operations. The critical moisture content Xc is a property of the material being dried
but also varies with material thickness and drying rate: it reflects the magnitude of the
heat and mass transfer resistances in the solid. For example, Xc can be reduced by decreasing
the thickness of the solid, as this reduces internal transfer resistance. Many materials
exhibit a constant drying rate period; however, for some solids, internal heat and/or mass
transfer always determines the rate of drying so a constant drying rate is never achieved.
Constant drying rates also do not occur if the starting moisture content of the solid is less
than Xc.
If structural or chemical modifications occur within the solid as drying takes place, the
drying rate curve may be significantly more complex than that shown in Figure 11.57,
with many inflections or abrupt changes as the nature of the material is altered. During
drying, the solid may shrink, expand, harden, become more or less porous, or change its
crystallinity; as a result, its properties such as thermal conductivity and moisture diffusivity
can change with drying time. In nonporous colloidal solids, shrinkage of the rapidly
drying outer layers of material and the accompanying decline in moisture diffusivity
11.13 DRYING 569
3. PHYSICAL PROCESSES
result in case hardening, as the solid develops a skin or crust at the surface that is virtually
impenetrable to water so that further drying is prevented.
Mechanisms of Moisture Transport in Solids
Several mechanisms of moisture transport operate during drying to deliver water from
within the solid to the surface. These include:
• Molecular diffusion of liquid water
• Capillary flow of liquid water within porous solids
• Molecular diffusion of vapour evaporated within the solid
• Convective transport of vapour evaporated within the solid
In porous solids, moisture is usually transported more effectively by capillary forces than by
diffusion, depending on the pore size. Capillary flow relies on the pressure differences that
occur within solids as a result of surface tension effects in very small pores. If the rate of
water vaporisation within the solid exceeds the rate of vapour transport to the surroundings,
mass transfer is affected by the resulting build-up of pressure inside the material. Pressure
gradients can also drive mass transfer if shrinkage of the solid occurs during drying.
Drying Kinetics during Constant Rate Drying
The rate equation for heat transfer during drying is analogous to that derived in
Chapter 9:
^Q
5UAh
ðTa 2TÞ ð11:161Þ
where ^Q is the rate of heat transfer, U is the overall heat transfer coefficient, Ah is the area
available for heat transfer, Ta is the air temperature, and T is the temperature of the solid
surface that is drying. During the constant drying rate period, convective heat transfer is
the principal transport mechanism and the gas film boundary layer external to the solid
provides the main heat transfer resistance. Under these conditions, U in Eq. (11.161) can
be replaced by hs, the individual heat transfer coefficient for the fluid boundary layer at
the solid surface:
^Q
5hsAh
ðTa 2TÞ ð11:162Þ
If the heat transferred during drying is used solely to evaporate water, the rate of vapour
production can be related to ^Q using the latent heat of vaporisation (Section 5.4.2):
Rate of production of water vapour5
hsAh
ðTa 2TÞ
Δhv
ð11:163Þ
where Δhv is the latent heat of vaporisation at temperature T.
An equation similar to those derived in Chapter 10 can be used to represent the rate of
mass transfer of water being evaporated from the solid surface during constant rate
drying:
NA 5kGa ðY2YaÞ ð11:164Þ
570 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
where NA is the rate of mass transfer, kG is the mass transfer coefficient for the gas boundary
layer with dimensions ML22T21, a is the area available for mass transfer, Y is the
humidity of air in equilibrium with water at the surface temperature of the solid, and Ya is
the humidity of the air.
At steady state, the rate of production of water vapour due to input of latent heat is
equal to the rate at which the vapour is removed from the solid by mass transfer. Both
these rates are also equal to the constant drying rate Nc. Combining Eqs. (11.163) and
(11.164) gives:
Nc 5
hsAh
ðTa 2TÞ
Δhv
5kGa ðX2XaÞ ð11:165Þ
To apply Eq. (11.165), the heat and/or mass transfer coefficient must be determined for
the particular drying equipment and operating conditions used. Calculation of the drying
rate is usually based on the heat transfer component of Eq. (11.165), as application of the
mass transfer equation is less straightforward. Because the distribution of moisture in the
solid changes during drying, there is considerable uncertainty about the driving force for
mass transfer at any given time.
Drying Time
The time required to achieve a desired state of dryness can be found by integrating the
expressions for drying rate with respect to time. Under constant drying conditions and
during the constant drying rate period, from Eq. (11.158):
Nc52Ms
dX
dt
ð11:166Þ
As Nc and Ms are constant during constant rate drying, the only variables in Eq. (11.166)
are X and t. Separating variables and integrating gives:
ðt1
0
dt5
2Ms
Nc
ðX1
X0
dX ð11:167Þ
or
Δt5
Ms
Nc
ðX0 2X1Þ ð11:168Þ
Equation (11.168) is used to estimate Δt, the time required to dry solids from an initial
moisture content of X0 to a final moisture content of X1 when the drying rate is constant.
From the definition of drying rate in Eq. (11.158), X0 and X1 are moisture contents
expressed on a dry mass basis using units of, for example, kg kg21 of dry solid.
During the falling drying rate period, the drying rate N is no longer constant. Equations
for drying time during this period can be developed depending on the relationship
between N and X and the properties of the solid. Kinetic models for predicting the drying
rate curve, including during the falling rate period when internal heat and mass transfer
mechanisms are limiting, are described elsewhere [43].
11.13 DRYING 571
3. PHYSICAL PROCESSES
EXAMPLE 11.15 DRYING TIME DURING CONSTANT
RATE DRYING
Precipitated enzyme is filtered and the filter solids washed and dried before packaging.
Washed filter cake containing 10 kg of dry solids and 15% water measured on a wet basis is
dried in a tray drier under constant drying conditions. The critical moisture content is 6%, dry
basis. The area available for drying is 1.2 m2. The air temperature in the drier is 35_C. At the air
humidity used, the surface temperature of the wet solids is 28_C. The heat transfer coefficient is
25 J m22 s21 _C21. What drying time is required to reduce the moisture content to 8%, wet basis?
Solution
The initial and final moisture contents expressed on a wet basis must be converted to a dry
basis:
15% wet basis5
15 g water
100 g wet solid
5
15 g water
15 g water185 g dry solid
X0 5
15 g water
85 g dry solid
50:176
Similarly:
8% wet basis5
8 g water
8 g water192 g dry solid
X1 5
8 g water
92 g dry solid
50:087
As X1 is greater than the critical moisture content Xc50.06, the entire drying operation takes
place with constant drying rate. Equation (11.165) is used to determine the value of Nc. From
Table D.1 in Appendix D, the latent heat of vaporisation Δhv for water at 28_C, the temperature
of the surface of the solids where evaporation takes place, is 2435.4 kJ kg21. Therefore:
Nc 5
25 J m22 s21 _C21 ð1:2 m2Þ ð35228Þ_
C
2435:43103 J kg21
58:6231025 kg s21
Applying Eq. (11.168) to calculate the drying time:
Δt5
10 kg
8:6231025 kg s21
_1h
3600 s
____
____
_ ð0:17620:087Þ52:87 h
The time required for drying is 2.9 h.
11.13.4 Drying Equipment
A diverse range of equipment is used industrially for drying operations [42], including
tray, screen-conveyor, screw-conveyor, rotary drum, tunnel, bin, tower, spray, fluidised
bed, and flash driers. Some driers have a direct mode of heating, whereby air entering the
drier is brought into contact with the wet solid. Other types of equipment apply indirect
572 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
heating to the drying material through a metal wall or tray. Some drier installations use a
combination of direct and indirect heating.
Most driers operate at or close to atmospheric pressure. However, tray and enclosed
rotary driers may be operated under vacuum, generally with indirect heating. The advantage
of using vacuum drying is that evaporation of water occurs at lower temperatures when the
pressure is reduced; for example, the boiling point of water at 6 kPa or 0.06 atm is only about
36_C (Table D.2, Appendix D). This makes vacuum operation suitable for processing heatsensitive
fermentation products. Rates of drying are also enhanced under vacuum compared
with atmospheric pressure. The water vapour produced during vacuum drying is usually
condensed during operation of the drier to maintain the vacuum. As an alternative to vacuum
drying, flash or spray drying may be suitable for heat-labile solids because drying in
these systems occurs very rapidly, usually within 0.5 to 6 seconds, so that thermal damage
from prolonged exposure to heat is avoided. The creation of dust during drying is a potential
concern for processing of fermentation products and may influence the choice of drier equipment.
For materials with biological activity, exposure to the large amounts of fine particle
dust generated by, for example, some rotary driers, is undesirable.
Large-scale driers cannot be designed or sized using theoretical analysis alone. The drying
properties of numerous batches of material must be assessed experimentally. Scale-up
of drying requires appropriate laboratory- and pilot-scale testing to characterise the material
being dried and the transport processes that occur. To improve energy use and costeffectiveness,
the operating efficiency of large-scale drying equipment can be improved
using measures such as preheating the inlet air with hot exhaust air, recycling some of the
exhaust air, and reducing air leakage.
11.13.5 Freeze-Drying
Freeze-drying, also known as lyophilisation or cryodesiccation, is used to dry unstable or
heat-sensitive products at low temperature, thus protecting the material from heat damage
and chemical decomposition. The wet solids are placed in vials that are partially stoppered
so that water vapour can escape. The material is frozen and then exposed to low pressure,
which causes the frozen water within the solid to sublimate directly to vapour without
passing through a liquid phase. Sublimation of ice crystals leaves networks of cavities
within the solid, so that the dried material has a porous, friable structure with high internal
surface area. Because drying takes place at temperatures below 0_C, damage to biological
molecules is minimised and any volatile substances are retained.
Freeze-drying is used commonly in the pharmaceutical industry; it is also used for drying
some foods and for downstream processing of proteins, vaccines, and vitamins. However,
the energy required for freeze-drying is substantially greater than for other drying methods,
and the time required for drying is generally longer. The drying time for freeze-drying is
roughly proportional to the material thickness raised to the power 1.5 to 2.0 [44, 45].
Freeze-drying comprises three steps:
1. Freezing
2. Sublimation or primary drying
3. Desorption or secondary drying
11.13 DRYING 573
3. PHYSICAL PROCESSES
The changes in operating variables during an entire freeze-drying cycle are illustrated in
Figure 11.58. Freezing takes place at roughly atmospheric pressure as the temperature is
progressively reduced. When the temperature is low enough to ensure that liquid water
does not form when the pressure is reduced, primary drying is initiated by dropping the
chamber pressure. Under these conditions, ice is sublimated to water vapour, which is
transported away from the solid material and condensed. After the ice crystals are
removed, the temperature of the material being dried increases and a period of secondary
drying begins. Unfrozen water is removed during the secondary drying process at low
pressure. The duration of a complete freeze-drying cycle is typically 24 to 48 hours.
Freezing
The first stage of freeze-drying is cooling of the wet solid so that the material solidifies
completely. Typically, temperatures of 240_C to 280_C are used and the freezing step
takes about 2 hours. Freezing is crucial because the microstructure formed determines to a
large extent the quality of the final freeze-dried product. Information about the freezing
behaviour of the solid is required, including whether the material forms a crystalline or
amorphous matrix, and the maximum temperature that can be used while ensuring that
water in the system sublimates during primary drying. To consider these points further,
we need to understand the phenomena associated with freezing of water and solutions
containing water and solutes.
Pure water can exist in three phases: solid or ice, liquid, and gas or vapour. The phase
diagram for water showing the relationship between these phases and the prevailing temperature
and vapour pressure is shown in Figure 11.59. At the triple point indicated as TP
in Figure 11.59, ice, liquid water, and water vapour coexist in equilibrium. The triple point
for water occurs at a temperature of 0.0098_C and a water vapour pressure of 0.61 kPa.
Along the lines shown in Figure 11.59, two phases exist together at equilibrium. Liquid
and solid coexist at the combinations of temperature and pressure represented by line
Freezing Primary drying Secondary drying
40
20
0
–20
–40
–60
Temperature of solid (°C)
Heating applied
100
10
1
0.1
0.01
0.001
Chamber pressure (kPa)
Time
Atmospheric
pressure
FIGURE 11.58 Variation of solids temperature
and chamber pressure during a complete freezedrying
cycle.
574 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
A_TP, liquid and vapour coexist at the conditions represented by line B_TP, and solid
and vapour coexist at the conditions represented by line C_TP. If the temperature is
raised at constant pressure, the condition of the system can be followed by moving horizontally
across the phase diagram.
As an example, starting with ice at point a1 on the diagram, adding heat increases the
temperature, melts the ice as the phase boundary with liquid water is encountered, and
then moves the system into the liquid phase. Further temperature increase causes the liquid
water to evaporate as it passes the liquid_gas phase boundary to finish at point a2 as
water vapour. If the same process is repeated at a lower pressure below the triple point,
starting with ice at point b1, adding heat and raising the temperature causes a direct phase
change from solid to vapour as the phase boundary C_TP is encountered and the ice sublimates
to vapour without passing through a liquid phase. If the water vapour is heated
further, the process is completed at b2.
For freeze-drying of pure water, it is essential to cool the system to below the triple
point so that sublimation rather than melting occurs when the pressure is reduced for primary
drying. However, water in wet solids is not often present in pure form: it exists
instead as a solution containing dissolved solutes. In an ideal two-component solution, both
the water and solute may crystallise during freezing. A typical freezing curve for such a
system is shown in Figure 11.60. Here, cooling starts with liquid solution at point a and
continues to point b. As point b is below the equilibrium freezing point of the solution, the
solution at b is supercooled. Supercooling induces the nucleation of ice crystals. The phase
change from liquid water to solid ice results in an increase in temperature as the latent heat
of fusion Δhf (Section 5.4.2) is released. As cooling continues to point c, the ice crystals
grow in size, there is less and less liquid water present, and the solute concentration in the
remaining liquid increases progressively as more water is crystallised. The liquid solution
approaches saturation, meaning that no further increase in solute concentration can occur.
At point c, the solute begins to crystallise. A eutectic point Te may be reached, which means
that the water and solute solidify as if they were a single pure compound and the material
TP
AB
C
Solid
Liquid
Vapour
Temperature
Pressure
a1 a2
b2 b1
FIGURE 11.59 Phase diagram for water.
11.13 DRYING 575
3. PHYSICAL PROCESSES
becomes wholly crystalline. After eutectic freezing is complete at Te, no liquid remains in the system.
Further reduction in temperature cools the frozen mixture. The eutectic temperature is important for
freeze-drying as it is the maximum temperature that can be allowed to occur during primary drying. If
the temperature exceeds Te, melting occurs and liquid is formed, and drying takes place from the
liquid phase rather than from the solid phase. As a consequence, the open porous structure
characteristic of freeze-dried solids is not produced. Not all aqueous solutions exhibit eutectic
behaviour, as some solutes do not crystallise during freezing. In amorphous systems, after ice begins
to form and the solution becomes more and more concentrated, the solution viscosity increases so that
the material becomes syrupy and then rubbery. If the temperature is reduced further, a glass transition
occurs at temperature Tg as the solution changes from a viscous liquid to a glass-like material. The
glass transition temperature represents the maximum temperature suitable for primary drying of
noncrystalline systems because, above that temperature, liquid is present. If the temperature during
primary drying exceeds either the eutectic or glass transition point, the dry solid may collapse. This
occurs when the material remaining after sublimation of ice is not sufficiently rigid to support its own
weight. Primary drying at temperatures below Te or Tg is necessary to ensure that the residual dried
material is not able to flow and thereby destroy the microstructure of the crystalline or amorphous
product. Primary Drying During primary drying, the pressure is reduced to below the triple point of
water and heat is supplied to the material to provide the latent heat of sublimation (Section 5.4.2).
This heat is required to vaporise the frozen water. Typically, primary drying takes around 10 hours.
For crystalline eutectic systems, primary drying normally removes about 95% of the water contained
in the solid.
Time
a
b
c
20
0
–20
–30
–10
Temperature (°C)
10
Solution cooling
Ice forms
Freezing of ice and
cooling of concentrated
solution
Cooling of
frozen eutectic
solution
Solution + ice
Eutectic
ice +
solute
Solution
Te
30 FIGURE 11.60 Freezing curve for an ideal two-component
solution forming a eutectic solution.
576 11. UNIT OPERATIONS
3. PHYSICAL PROCESSES
The situation within the solid during primary drying is shown in Figure 11.61.
Vaporised water leaves the solid and is removed to a condenser; this allows the low
vapour pressure in the chamber to be maintained. As water is removed from the top of
the solid, a layer of dried material is formed. With further drying, the thickness of this
layer increases while the thickness of the remaining frozen material containing water
decreases. As a result, the sublimation front where vaporisation takes place moves down
from the top of the solid through the depth of the drying material.
Heat transfer is often the rate-limiting step in freeze-drying. Heat for sublimation is
provided either from below through the frozen material or from above through the lowpressure
atmosphere and layer of dried solids, or from both directions. To avoid melting,
the temperature in all parts of the solid must be maintained at less than the eutectic or
glass transition temperature. Consequently, the thermal gradient through the material that
provides the driving force for heat transfer at the sublimation front remains low to avoid
overheating the solid at the bottom of the vial. In addition, the partial vacuum in the
freeze-drying chamber has a substantial insulating effect in terms of heat transfer through
the atmosphere from any heat sources above the vial. The low density of gas in the chamber
means that convective heat transfer is minimal.
Mass transfer is required in primary drying to transport water vapour out of the solid.
The primary resistance to mass transfer is the increasing thickness of dried solid that
forms above the sublimation front. It is important, therefore, to minimise the depth of
solid applied for freeze-drying. When mass transfer is the rate-limiting step, the drying
rate decreases with time as the thickness of the dried layer increases. Mass transfer rates
are affected by the conditions used in the freezing step of the freeze-drying process. The
formation of large ice crystals by slow freezing creates a dry solid of greater porosity after
sublimation compared with that created after the formation of small ice crystals by rapid
freezing. Mass transfer of water vapour through the solid by either convective flow or
molecular diffusion is greater when the porosity is high.
Secondary Drying
When all the ice crystals have been removed by sublimation, if heat continues to be provided
after primary drying, the temperature of the solid rises as heat is no longer needed for
Frozen material
Vial
Sublimation
Direction front
of mass
transfer
Water vapour
removed to
condenser
Dry solids
FIGURE 11.61 Mass transfer and the sublimation front
during primary drying.
11.13 DRYING 577

3. PHYSICAL PROCESSES
the phase change from ice to vapour. Secondary drying thus commences to remove any residual
water from the solid. When solutes crystallise during freezing, virtually all of the water
present in the wet solid is transformed to eutectic ice and is removed during primary drying.
Secondary drying is therefore more important when solutes form an amorphous material
during freezing, as frozen amorphous solids can contain significant amounts of water that are
not removed by sublimation. Secondary drying of these materials relies on the removal of
water by molecular diffusion through the glassy frozen matrix and can be a relatively slow
process taking 10 to 12 hours. The temperatures used during secondary drying are higher
and the pressures lower than for primary drying. After secondary drying, the residual water
content of most dried biological materials is reduced to 1 to 4% by weight.