1

A
SEMINAR REPORT
ON
FREEZE-DRYING
PREPARED BY
KARAN K SHITOLE

GUIDED BY
MANJEET MUKHI

DEPARTMENT OF CHEMICAL ENGINEERING,

FACULTY OF TECHNIOLOGY & ENGINEERING,
THE MAHARAJA SAYAJIRAO UNIVERSITY OF BARODA.

2015-16

CERTIFICATE
This is to certify that the seminar report entitled FREEZE DRYING which is being
submitted by KARAN K SHITOLE (Roll No. 826) in partial fulfillment of the requirement
for the award of the Degree of Bachelor of Engineering (Chemical Engineering) to the
M.S.University of Baroda has been carried out by him under by supervision and guidance.
The matter embodied in this report has not submitted for the award of any other degree of
research work.

Guide,
Manjeet Mukhi.

Head,
Dr. Bina Sengupta.

ACKNOWLEDGEMENT
No one who achieves success does so without acknowledging the help of others. The wise
and confident, acknowledge this help with gratitude.
First and foremost, I am thankful to Dr. Bina Sengupta, head of Chemical Engineering
Department, for their help and guidance throughout this work.
I hereby take the opportunity to express my sincere thanks to all those people who have made
the successful completion of my project possible. I would like to express my gratitude and
respect for my guide Manjeet Mukhi Mam for her excellent guidance and support in this
project.

KARAN K SHITOLE

ABSTRACT
Freeze drying is a relatively recent method of preserving food. It involves freezing the food,
then removing almost all the moisture in a vacuum chamber, and finally sealing the food in
an airtight container. Freeze dried foods can be easily transported at normal temperatures,
stored for a long period of time, and consumed with a minimum of preparation. Once
prepared, freeze-dried foods have much the same look and taste as the original, natural
products.
The freeze-drying process was developed during World War II as a method of preserving
blood plasma for battlefield emergencies without requiring refrigeration or damaging the
organic nature of the plasma. The technology was applied to consumer food products after
the end of the war. Coffee was one of the first freeze-dried products to be marketed on a
large scale. Today, many fruits, vegetables, meats, eggs, and food flavorings are freeze-dried.
Freeze-dried food has many advantages. Because as much as 98% of the water content has
been removed, the food is extremely lightweight this significantly reduces the cost of
shipping. This also makes it popular with boaters and hikers who have to carry their food
with them. Because it requires no refrigeration, shipping and storage costs are even further
reduced.

Freeze-dried

food

is

also

relatively

contamination-free

since

the dehydration process makes it virtually impossible for yeast and potentially harmful
bacteria to survive. Finally, since the physical structure of the food is not altered during the
freeze-drying process, the food retains much of its color, shape, texture, and flavor when it is
prepared for consumption by reintroducing water. This makes it more attractive to consumers
than food preserved by some other methods.
One of the major disadvantages of freeze-dried food is its cost. The equipment required for
this process requires a large investment of money, and the process itself is time consuming
and labor intensive. These costs are usually passed on to the consumer, which makes freezedried food very expensive when compared to other methods of food preservation such
as canning or freezing.

CONTENTS
CHAPTER 1 HISTORY OF FREEZE DRYING ..............................................................8
CHAPTER 2: THE PROCESS ...........................................................................................9
2.1 Testing and preparation .............................................................................................. 11
2.2 Freezing ..................................................................................................................... 12
2.3 Primary Drying .......................................................................................................... 17
2.4 Secondary Drying ...................................................................................................... 19
2.5 Factors affecting the process rate................................................................................ 20
2.6 Freeze Drying methods .............................................................................................. 22
2.7 Determination of end process for freeze drying. ......................................................... 24
2.8 Stability of Freeze-Dried products .............................................................................. 27
2.9 Packaging .................................................................................................................. 28
CHAPTER 3 MATERIALS USED IN FREEZE-DRYING. ........................................... 30
CHAPTER 4 HEAT & MASS TRANSFER EQUATIONS DESCRIBING THE
PROCESS .......................................................................................................................... 31
4.1 Advantages ................................................................................................................ 32
4.2 Disadvantages ............................................................................................................ 33
4.3 Applications ............................................................................................................... 34
CHAPTER 5 INSTALLATION AND EQUIPMENT TECHNIOQUE .......................... 36
5.1 Freezing Installation ................................................................................................... 36
5.2 Drying Chamber and forms of tray ............................................................................. 38
5.3 Vacuum System: ........................................................................................................ 39
CHAPTER 6 CASE STUDY ............................................................................................. 43
6.1 Apple peel.................................................................................................................. 43

6.2 Pre-processing conditions........................................................................................... 43

6.3 Drying of frozen apple peel and apple peel slurry ....................................................... 43
6.4 Results and discussion................................................................................................ 44
6.5 Effect of the drying method on the total antioxidant content and capacity................... 45
CHAPTER 7 RECENT DEVELOPMENT IN FREEZE-DRYING ............................... 48
CHAPTER 8 REFERENCES ........................................................................................... 50
8.1 Journal reference ........................................................................................................ 51
8.2 Book references ......................................................................................................... 51
8.3 Web references .......................................................................................................... 51

LIST OF FIGURES
No.

Name

Page No.

1.

Phase diagram of water

2.

Schematic of freeze-dryer

10

3.

Types of freeze products

13

4.

Phase diagram of NaCl-water

14

5.

Comparison of rapid and slow freezing

15

6.

Drying process

20

7.

Batch drying

24

8.

Different types of freeze dried products.

29

9.

Comparison of drying process

33

10.

Cooling through liquid

36

11.

LN2 cooling

37

12.

Types of vacuum chamber

38

13.

Vacuum system

39

14.

Pirani gauge

40

15.

Thermocouple gauge

41

16.

Capacitance manometer

42

17.

Sample preparation

44

18.

Type of treatment

46

LIST OF TABLES
1.

Agents & Examples

31

2.

Vacuum Spectrum

41

3.

Results of process

46

CHAPTER 1 HISTORY OF FREEZE DRYING

Early freeze drying was used to preserve food by utilizing cold and dry weather
conditions often found at high altitudes.

The ancient Incas and South Americans would preserve their potatoes high in the
Andes.

The Vikings would preserve cod fish in the cold dry arctic conditions.

Towards end of the 19th c. an increasing need to preserve biological specimens

1890 Altman dried tissue at sub atmospheric pressure at temperature of -20C

(pressure

and

equipment

used not known)

1905 Benedict and Manning dried animal tissue by using a chemical pump

1936 Greaves and Adair at Cambridge study the thermodynamics of freeze drying
and promote sound scientific principles to it.

1938 Nestl in Switzerland freeze dry an abundant coffee crop for Brazil

1944 Blood plasma and penicillin produced on a commercial scale for 2nd world war
effort.

1950s Pharmaceutical freeze drying

1960s Explosion in the number of foods being freeze dried including freeze dried ice
cream for Apollo missions.

1970s Uses expand into taxidermy, museum artifacts etc.

1980 Freeze dried flowers.

1990 Freeze dried pets (already dead ones).

2000 Freeze dried fruit for breakfast cereals.

CHAPTER 2: THE PROCESS

The fundamental principle in freeze-drying is sublimation, the shift from a solid directly into
a gas. Just like evaporation, sublimation occurs when a molecule gains enough energy to
break free from the molecules around it. Water will sublime from a solid (ice) to a gas
(vapor) when the molecules have enough energy to break free but the conditions aren't right
for a liquid to form.
There are two major factors that determine what phase (solid, liquid or gas) a substance will
take: heat and atmospheric pressure. For a substance to take any particular phase, the
temperature and pressure must be within a certain range. Without these conditions, that phase
of the substance can't exist. The chart below shows the necessary pressure and temperature
values of different phases of water.

(Figure 2 Phase diagram of water.)

You can see from the chart that water can take a liquid form at sea level (where pressure is
equal to 1 atm) if the temperature is in between the sea level freezing point (32 degrees

10

Fahrenheit or 0 degrees Celsius) and the sea level boiling point (212 F or 100 C). But if you
increase the temperature above 32 F while keeping the atmospheric pressure below .06
atmospheres (atm), the water is warm enough to thaw, but there isn't enough pressure for a
liquid to form. It becomes a gas.
This is exactly what a freeze-drying machine does. A typical machine consists of a freezedrying chamber with several shelves attached to heating units, a freezing coil connected to
a refrigerator compressor, and a vacuum pump.

A simplified freeze-drying machine

(Figure 2.1 Schematic of a freeze-dryer)

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With most machines, you place the material to be preserved onto the shelves when it is still
unfrozen. When you seal the chamber and begin the process, the machine runs the
compressors to lower the temperature in the chamber. The material is frozen solid, which
separates the water from everything around it, on a molecular level, even though the water is
still present.
Next, the machine turns on the vacuum pump to force air out of the chamber, lowering the
atmospheric pressure below .06 atm (for removing water). The heating units apply a small
amount of heat to the shelves, causing the ice to change phase. Since the pressure is so low,
the ice turns directly into water vapor. The water vapor flows out of the freeze-drying
chamber, past the freezing coil. The water vapor condenses onto the freezing coil in solid ice
form, in the same way water condenses as frost on a cold day.
This continues for many hours (even days) while the material gradually dries out. The
process takes so long because overheating the material can significantly change the
composition and structure. Additionally, accelerating the sublimation process could produce
more water vapor in a period of time then the pumping system can remove from the chamber.
This could rehydrate the material somewhat, degrading its quality.
Once the material is dried sufficiently, it's sealed in a moisture-free package, often with an
oxygen-absorbing material (silica gel). As long as the package is secure, the material can sit
on a shelf for years and years without degrading, until it's restored to its original form with a
bit of water (a very small amount of moisture remains, so the material will eventually spoil).
If everything works correctly, the material will go through the entire process almost
completely unscathed!

2.1 Testing and preparation

The food is first checked for contamination and purity. Fruits, meats, and some other edibles
are tested for bacterial counts and spoilage. Much of the work of the plant is dependent on
the harvest season for each food.

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Some kinds of food, like seafood and meats, must be cooked before freeze drying. They are
usually purchased already cut into small pieces. If they have not been pre-cooked and frozen,
these foods are placed in large, industrial-sized kettles and properly cooked. Fruits and
vegetables are usually purchased already cut, pitted, and peeled. These foods are simply
washed with sprays of water. Some vegetables, like peas and corn, are quickly scalded, or
blanched, before freezing. Coffee is purchased as a pre-brewed concentrated liquid. Because
the aroma of coffee is important to consumers, a small amount of coffee bean oil may be
added to the liquid. Unlike the water, the oil is not removed during the drying process.

2.2 Freezing
Since freeze drying is a change in state from the solid phase to the gaseous phase, material to
be freeze dried must first be adequately pre-frozen. The method of freezing and the final
temperature of the frozen product can affect the ability to successfully freeze dry the
material. Rapid cooling results in small ice crystals, useful in preserving structures to be
examined microscopically, but resulting in a product that is more difficult to freeze dry.
Slower cooling results in larger ice crystals and less restrictive channels in the matrix during
the drying process.
Products freeze in two ways, depending on the makeup of the product. The majority of
products that are subjected to freeze drying consisting primarily of water, the solvent, and the
materials dissolved or suspended in the water, the solute. Most samples that are to be freeze
dried are Eutectics which are a mixture of substances that freeze at lower temperatures than
the surrounding water. When the aqueous suspension is cooled, changes occur in the solute
concentrations of the product matrix. And as cooling proceeds, the water is separated from
the solutes as it changes to ice, creating more concentrated areas of solute.

These pockets of concentrated materials have a lower freezing temperature than the water.
Although a product may appear to be frozen because of all the ice present, in actuality it is
not completely frozen until all of the solute in the suspension is frozen. The mixture of
various concentrations of solutes with the solvent constitutes the eutectic of the suspension.
Only when all of the eutectic mixture is frozen is the suspension properly frozen. This is
called the eutectic temperature (TE). It is very important in freeze drying to pre-freeze the

13

product to below the eutectic temperature before beginning freeze drying process. Small
pockets of unfrozen material remaining in the product expand and compromise the structural
stability of the freeze dried product.

The second type of frozen product is a suspension that undergoes glass formation during the
freezing process. Instead of forming eutectics, the entire suspension becomes increasingly
viscous as the temperature is lowered. Finally the product freezes at the glass transition point
forming a vitreous solid. This point is called glass transition temperature (TG). This type of
product is extremely difficult to freeze dry.

(Figure 2.2 Type of freeze products)

It is generally accepted that the liquid material being frozen displays one of two different
types of freezing behaviors as shown in figure above the liquid phase suddenly solidifies
(eutectic formation) at a temperature depending on the nature of solids in solutions, or the
liquid phase does not solidify (glass formation), but rather it becomes more and more viscous
until it finally takes the form of a very stiff substance, and becomes a highly viscous liquid.

Eutectic formation:

Freezing history of an aqueous solution can have several possibilities. The simplest one is
crystallization of solute from a freeze-concentrated solution to form a simple eutectic
mixture. A typical binary eutectic system is the sodium chloride-water system as illustrated

14

in the Fig. below. Understanding the behavior of this system is useful for a conceptual
understanding of material science in freeze drying. Line ab is the freezing point depression
curve of water in the presence of sodium chloride, and line bc represents the solubility of
sodium chloride in water. The intersection of the two lines is the eutectic melting
temperature, which for sodium chloride/ice is 21.5C, and the eutectic composition is about
23.3% (by mass) sodium chloride. Freezing of a 5% solution of sodium chloride in water is
described by line defgh. At room temperature of point d, the system is entirely liquid. As the
solution cools, ice appears at point e in the absence of super-cooling. As the system cools, ice
continues to crystallize and the solution becomes more concentrated with sodium chloride.
At point f, two phases are present, ice and a freeze concentrated solution of sodium chloride
in water. This freeze concentrated solution has the composition given by point i, which is in
equilibrium with ice. At point g, the solution is saturated with respect to sodium chloride, and
solid sodium chloride begins to precipitate. It is only below the eutectic temperature that the
system is completely solidified (point h). Similarly, if the freezing path is across line bc with
an initial concentration of the solution being between b and c, the solid sodium chloride
precipitates first rather than ice. Other examples of binary eutectic systems are ammonia
chloride-water and glycine-water, which has similar freezing histories. The relevance of the
eutectic temperature to freeze drying is that it represents the maximum allowable temperature
in freeze drying, because eutectic melting would form liquid water and destroy the freeze
drying process.

(Figure 2.3 Phase diagram of NaCl-water)

15

Glass Transition:
When a material forms an amorphous phase, it remains as a liquid below the normal freezing
point but eventually goes through a rapid increase in viscosity as temperature falls. This
transition is defined as the glass transition since the material is glassy. A glass is a true solid
that has the chemical composition of the crystalline solid but does not have the ordered
molecular structure of the crystalline solid. Fig below displays how a material might form a
glass during rapid freezing although it is normally expected to crystallize under slow
freezing. The glass transition temperature of a material is strongly dependent on the moisture
content.Generally, the highest moisture content at the beginning of drying results in the
lowest TG, while the lowest moisture content at the end of drying leads to the highest TG.
Thus, there is not one single value of TG but rather a range of TG for a frozen material
corresponding to a range of residual moisture content. At particular moisture content, the
glass transition temperature of a material is termed TG .

(Figure 2.4 Comparison of rapid and slow freezing)

16

The freezing point can be determined by means of,

Theoretical thermodynamic value.

Cryo-microscope.

DSC (Differential Scanning Calorimeter).

Measurement of temperature and resistance during the freezing phase.

The electric resistance of the product being dried almost always rises dramatically with the
transfer from the liquid to the solid state due to the reduced mobility of the ions and
electrons. This means that by measuring the product temperature and electrical resistance at
the same point it is possible to determine the freezing point.

Mass Transfer: The total resistance to mass transfer is the sum of several resistances in series,
which are from the partially dried layer, the vial or container, including a partially inserted
stopper and the pathway from the chamber to the condenser. The greatest resistance, and
therefore the greatest pressure drop, occurs across the dried product layer, where water
molecules have to pass the pores and channels which were created during the freezing step to
reach the condenser. The diffusion of water vapor in the partially dried layer is one of the
major factors affecting the mass transfer rate. The diffusivity is closely related to the pore
size. Large ice crystals will be helpful for the movement of water vapor as mentioned in the
previous section. The pressure difference is essentially the driving force for the transport of
water vapor. The smallest chamber pressure gives the highest ice sublimation rate. The ratelimiting factor in freeze drying is changed as drying process proceeds. Initially, the process is
limited by heat transfer when the dried layer is thin and an unrealistic heat flux is required to
push the sublimation rate to its maximum. After a certain thickness of the dried layer has
been developed, the process becomes controlled by mass transfer since, as, the required heat
flux is easily maintained for the decreasing sublimation rate.

Heat Transfer: Process control is related to the control of the product temperature vs. time
profile during freeze drying without exceeding the maximum allowable temperature, which is
determined by either the TE or TG of the product. A given product temperature results from a
balance between heat transfer rate to the product and the drying rate or mass transfer rate of

17

water vapor, and thus the primary drying stage is a problem coupled heat and mass transfers.
The heat supplied to the product is usually by conduction, convection, and/or radiation. Heat
transfer from the source to the sublimation interface is an important rate-limiting process
during primary drying. Generally, the effective thermal conductivity comes from two
contributions, i.e., the heat conduction and the phase change. When temperature is low, heat
conduction plays a major role within the unsaturated region. At high temperature, the phase
change is dominant. The controlling step of heat transfer would change from the heat
conduction to the phase transition as the moisture content decreases. The main concern for
the process in this stage is the collapse temperature, TC. On the one hand, the temperature of
a freeze drying process must be close to TC to run an effective operation. On the other hand,
it cannot exceed this temperature due to the process requirement and product quality concern.

2.3 Primary Drying

After the freezing step has been completed, the pressure within the freeze-dryer is reduced
using a vacuum pump. Typical chamber pressures in the lyophilization of pharmaceuticals
range from 30 and 300 m torr and depend on the desired product temperature and the
characteristics of the container system. The chamber pressure needs to be lower than the
vapor pressure of ice at the sublimation interface in the product to facilitate sublimation of
ice and transport of water vapor to the condenser where it is deposited as ice. Very high
chamber pressures decrease the sublimation rate by reducing the pressure gradient between
sublimation interface and chamber, thereby mitigating the driving force for sublimation and
continuing removal of ice. If the chamber pressure exceeds the vapor pressure at the
sublimation interface, no mass transfer is possible. On the other hand, very low pressures (<
50 m torr) are also counterproductive for fast sublimation rates since they greatly limit the
rate of heat transfer to the product. The ice at the sublimation interface shows a vapor
pressure that is directly correlated to the product temperature. Once the chamber pressure
decreases below the vapor pressure of ice in the product, sublimation can occur, i.e. ice is
removed from the top of the frozen layer and directly converted to water vapor. Water vapor
is transported to the ice condenser and deposited onto the coils or plates which are constantly
cooled to a temperature associated with very low vapor pressure of the condensed ice. The
sublimation of water from the product requires energy (temperature-dependent, around 670

18

cal/g), leading to cooling of the product. The energy for continuing sublimation of ice needs
to be supplied from the shelves that are heated to a defined higher temperature. The product
temperature is in general the most important product parameter during a freeze drying
process, in particular the product temperature at the sublimation interface during primary
drying. Low product temperature and the corresponding low vapor pressure of ice result in
extensive primary drying times. It has been reported that elevation of product temperature by
1C can reduce the overall primary drying time by as much as 13%, which offers enormous
potential of saving process time and manufacturing costs when administering more
aggressive product temperatures. However, an increase of product temperatures to
temperatures above the critical formulation temperature which refers to the eutectic
temperature, TE, for crystalline and to TC or TG for amorphous materials, mostly leads to loss
of cake structure. If the critical temperature is exceeded, the dried pore structure close to the
sublimation front that still contains high amounts of water can undergo viscous flow,
resulting in fusion of pores and formation of holes in the cake structure. This occurrence is
associated with a reduction of inner surface area as well as elevated moisture contents with
potentially detrimental effects on reconstitution time and completeness as well as API
(Active Pharmaceutical Ingredients) stability. Most importantly, the cake shows shrinkage or
may fully collapse, making the product unsuitable for sale and application in patients due to
the lack of elegance. The critical formulation temperature (TE or TC or TG) can be determined
using Freeze-Dry Microscopy (FDM) which allows observation of the drying cake structure
under vacuum at varying temperatures. Once the collapse temperature is reached it is possible
to observe formation of holes in the dried cake structure. Since the sample is being dried
during the experiment, the conditions are more similar to lyophilization than alternative
methods, making the results more representatives for a vial freeze-drying process.
A different approach to determine the critical formulation temperature is Differential
Scanning Calorimetry (DSC) which measures the heat flow and thermal properties of the
frozen sample. This way it is possible to determine the glass transition temperature of the
maximally freeze-concentrated solute, TG which is indicative for molecular mobility in the
amorphous matrix. Since no removal of water is involved, the critical temperature is not as
representative for vial freeze drying as the collapse temperature determined using FDM. It is
possible to increase the critical temperature by crystallizing salts (i.e. buffers) etc.

19

quantitatively during freezing or by adding amorphous excipients with high TG values such
as dextran or cyclodextrines. If formulations with high contents of crystallizing solutes are
lyophilized, a crystalline lattice is formed that is stable up to product temperatures equivalent
to the eutectic melting point TE which is much higher than common TG values. Therefore it is
possible to create formulations with a high ratio of crystallizing substances and freeze-dry at
temperatures above the TG of the amorphous ingredients which then collapse onto the
crystalline matrix. Thus no global loss of structure occurs and the cake appearance is still
elegant. It is important to pay close attention to API stability and choice of stabilizers to
obtain a product stable over the shelf life when following such an approach, but it offers huge
benefits for process optimization.

2.4 Secondary Drying

The secondary drying phase aims to remove unfrozen water molecules, since the ice was
removed in the primary drying phase. This part of the freeze-drying process is governed by
the materials adsorption isotherms. In this phase, the temperature is raised higher than in the
primary drying phase, and can even be above 0 C, to break any chemical interactions that
have formed between the water molecules and the frozen material. Usually, the pressure is
also lowered in this stage to encourage desorption (typically in the range of microbars, or
fractions of a Pascal). However, there are products that benefit from increased pressure as
well. After the freeze-drying process is complete, the vacuum is usually broken with an inert
gas, such as nitrogen, before the material is sealed. At the end of the operation, the final
residual water content in the product is around 1% to 4%, which is extremely low.

Removal of adsorbed water from the dried solute (no ice present)

Controls moisture level in product to maintain proper chemical and physical stability.

Reversible process (can de-humidify and humidify product to change moisture

content).

20

(Figure 2.5 Drying process)

2.5 Factors affecting the process rate:

From the figure below, it can be seen that the direction of heat and mass transfer causes the
top of the product to dry first with drying proceeding downward to the bottom of the vial.
Therefore, as drying proceeds, there exists a three-component or layer system in each vial
the upper dry product, the middle sublimation front, and the lower frozen liquid product. As
the dried layer increases, it becomes a greater barrier or the source of greatest resistance to
the transfer of mass out of the vials .These points out the importance of vial dimensions and
volume of product per vial on the efficiency of the freeze-drying process. If large volumes of
solution must be processed, the surface area relative to the depth may be increased, utilizing
larger vials or by using such devices as freezing the container in a slanted position to increase
the surface area. The actual driving force for the process is the vapor pressure differential
between the vapor at the surface where drying of the product is occurring (the drying
boundary) and at the surface of the ice on the condenser. The latter is determined by the

21

temperature of the condenser, as modified by the insulating effect of the accumulated ice.
The former is determined by a number of factors, including:

1. The rate of heat conduction through the container and the frozen material, both relatively
poor thermal conductors, to the drying boundary, while maintaining the entire product below
its eutectic temperature.
2. The impeding effect of the increasing depth of dried, porous product above the drying
boundary.
3. The temperature and heat capacity of the shelf itself.

The passageways between the product surface and the condenser surface must be wide open
and direct for effective operation. The condensing surfaces in large freeze-dryers may be in
the same chamber as the product or located in a separate chamber connected by a duct to the
drying chamber. Evacuation of the system is necessary to reduce the impeding effect that
collisions with air molecules would have on the passage of water molecules. However, the
residual pressure in the system must be greater than the vapor pressure of the ice on the
condenser, or the ice will be vaporized and pulled into the pump, an event detrimental to
most pumps. The amount of solids in the product, the ice crystal size, and their thermal
conductance affect the rate of drying. The more solids present, the more impediment will be
provided to the escape of the water vapor. The degree of super cooling (i.e., how much lower
the product temperature goes below its equilibrium freezing point before ice crystals first
form) and the rate of ice crystallization define the freezing process and efficiency of primary
drying. The larger the size of ice crystals formed, usually as a result of slow freezing, the
larger the pore sizes are when the ice sublimes and, consequently, the faster the rate of
drying. A high degree of super cooling produces a large number of small ice crystals, a small
pore size when the ice sublimes in the dried layer, and a greater resistance to water vapor
transport during primary drying. The poorer the thermal conducting properties of the solids in
the product, the slower the rate of heat transfer through the frozen material to the drying
boundary. The rate of drying is slow, most often requiring 24 hours or longer for completion.
The actual time required, the rate of heat input, and the product temperatures used must be
determined for each product and then reproduced carefully with successive processes.

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2.6 Freeze Drying methods:

Three methods of freeze drying are commonly used:
1. Manifold
2. Batch drying
3. Bulk drying.

Each method has a specific purpose, and the method used depends on the product and the
final configuration designed.

MANIFOLD METHOD
In the manifold method, flasks, ampoules or vials are individually attached to the ports of a
manifold or drying chamber. The product is either frozen in a freezer, by direct submersion
in a low temperature bath, or by shell freezing, depending on the nature of the product and
the volume to be freeze dried. The pre frozen product is quickly attached to the drying
chamber or manifold to prevent warming. The vacuum must be created in the product
container quickly, and the operator relies on evaporative cooling to maintain the low
temperature of the product. This procedure can only be used for relatively small volumes and
products with high eutectic and collapse temperatures. Manifold drying has several
advantages over batch tray drying. Since the vessels are attached to the manifold
individually, each vial or flask has a direct path to the collector. This removes some of the
competition for molecular space created in a batch system, and is most ideally realized in a
cylindrical drying chamber where the distance from the collector to each product vessel is the
same. In a tee manifold, the water molecules leaving the product in vessels farthest from
the collector experience some traffic congestion as they travel past the ports of other vessels.

Heat input can be affected by simply exposing the vessels to ambient temperature or via a
circulating bath. For some products, where precise temperature control is required, manifold
drying may not be suitable. Several vessels can be accommodated on a manifold system

23

allowing drying of different products at the same time, in different sized vessels, with a
variety of closure systems. Since the products and their volumes may differ, each vessel can
be removed from the manifold separately as its drying is completed. The close proximity to
the collector also creates an environment that maximizes drying efficiency.

BATCH METHOD

In batch drying, large numbers of similar sized vessels containing like products are placed
together in a tray dryer. The product is usually pre frozen on the shelf of the tray dryer.
Precise control of the product temperature and the amount of heat applied to the product
during drying can be maintained. Generally all vials in the batch are treated alike during the
drying process, although some variation in the system can occur. Slight differences in heat
input from the shelf can be experienced in different areas. Vials located in the front portion
of the shelf may be radiantly heated through the clear door. These slight variations can result
in small differences in residual moisture. Batch drying allows closure of all vials in a lot at
the same time, under the same atmospheric conditions. The vials can be tapered in a vacuum,
or after backfilling with inert gas. Tapering of all vials at the same time ensures a uniform
environment in each vial and uniform product stability during storage. Batch drying is used
to prepare large numbers of ampoules or vials of one product and is commonly used in the
pharmaceutical industry.

BULK METHOD
Bulk drying is generally carried out in a tray dryer like batch drying. However, the product is
poured into a bulk pan and dried as a single unit. Although the product is spread throughout
the entire surface area of the shelf and may be the same thickness as product dried in vials,
the lack of empty spaces within the product mass changes the rate of heat input. The heat
input is limited primarily to that provided by contact with the shelf as shown in figure:

24

(Figure 2.6 Bulk Drying)

Bulk drying does not lend itself to sealing of product under controlled conditions as does
manifold or batch drying. Usually the product is removed from the freeze dry system prior to
closure, and then packaged in air tight containers. Bulk drying is generally reserved for stable
products that are not highly sensitive to oxygen or moisture.

2.7 Determination of end process for freeze drying.

The following are the techniques used for determination of end point of primary drying
process,
Techniques based on gas composition in the product chamber:
1.

Comparative pressure measurement (i.e., Pirani vs. Capacitance manometer).

2.

Dew point monitor (electronic moisture sensor).

3.

Process H2O concentration from tunable diode laser absorption spectroscopy.

4.

Lyotrack (gas plasma spectroscopy).

5.

Product thermocouple response.

6.

Condenser pressure.

7.

Pressure rise test, Manometric Temperature Measurement (MTM) or variations of this

method.

COMPARATIVE PRESSURE MEASUREMENT (I.E., PIRANI VS. CAPACITANCE

MANOMETER)

25

During the drying step, the chamber pressure is controlled using a capacitance manometer,
which measures the absolute pressure in the drying chamber. However, the Pirani vacuum
gauge works on the principle of measuring the thermal conductivity of the gas in the drying
chamber. The Pirani gauge reads about 60% higher than the capacitance manometer during
primary drying when essentially all of the gas in the chamber is water vapor. This is because
the thermal conductivity of water vapor is 1.6 times the thermal conductivity of nitrogen.
With this inherent property, the Pirani vacuum gauge can be used to detect the end of
primary drying. The point where the Pirani pressure starts to sharply decrease (i.e., onset)
indicates that the gas composition is changing from mostly water vapor to nitrogen; i.e.,
sublimation is essentially complete.
DEW POINT
An electronic moisture sensor can be used to measure the frost point, which is the
temperature at which ice has an equilibrium vapor pressure equal to the measured partial
pressure of water. The measurement is based on the principle of changes in the capacitance
of a thin film of aluminum oxide arising from adsorption of water at a given partial pressure.
Similar to the Pirani, the point where dew point starts dropping indicates that the
sublimation is essentially complete, i.e. gas composition is changing from mostly water
vapor to nitrogen.

PROCESS H2O CONCENTRATION VIA TDLAS

Tunable Diode Laser Absorption Spectroscopy (TDLAS) directly measures the water vapor
concentration (molecules/cm3) in the duct connecting the chamber and the condenser. The
TDLAS unit is commonly installed with two laser beams, one directed with and the other
directed against the vapor flow. TDLAS works on basic spectroscopic principles measuring
absorption of radiation by water vapor to monitor the trace concentration of water vapor in
real time. A laser beam is passed through a gas mixture containing a quantity of the target
gas, and the beams wavelength is tuned to one of the target gas absorption lines to
accurately measure the absorption of that beam from which one can deduce the average
concentration of target gas molecules integrated over the beams path length. The

26

sublimation rate can be determined from the gas flow velocity and concentration of water
vapor. The point where water concentration starts decreasing sharply (i.e., onset) indicates
that the gas composition is changing, and hence sublimation is essentially complete.

LYOTRACK (GAS PLASMA SPECTROSCOPY)

This method is the latest addition to the online monitoring devices for freeze-drying and is
manufactured by Alcatel Vacuum Technology, France. Lyotrack is based on optical emission
spectroscopy and measures water vapor concentration during the drying process. It consists
of a plasma generator and an optical spectrometer. Lyotrack gas composition signal was
sensitive to gas composition in the chamber as well as the duct but not in the condenser. The
wavelengths of the emitted light are the characteristic signatures for the identification of the
atom or molecule. The point where water vapor concentration starts sharply decreasing (i.e.,
onset) indicates that the gas composition is changing, and hence sublimation is essentially
complete
PRODUCT TEMPERATURE DURING PRIMARY DRYING
The end point of primary drying can also be determined from the product thermocouple
response, assuming the vials containing the thermocouples are representative of the batch as
a whole. Product temperature approaching the shelf temperature set point (i.e., offset) is
commonly taken as an indication of the end of primary drying.

CONDENSER PRESSURE DURING PRIMARY DRYING

Yet another indicator of the end point of primary drying is the condenser pressure. During
primary drying, most of the gas in the chamber is water vapor, and because the total vapor
flux is high, a high P (difference between chamber and condenser pressure) develops to
remove the water from the chamber. However, once primary drying is over, P decreases
(i.e., condenser pressure (P cond) increases since chamber pressure (Pc) is held constant). The
point where condenser pressure starts increasing (i.e., onset) indicates that the sublimation is
essentially over since the high mass transfer portion of the process (i.e., sublimation) is
largely over. A capacitance manometer installed in the condenser reads the condenser
pressure.

27

PRESSURE RISE TEST MTM

It is a procedure to measure the product temperature during primary drying by quickly

isolating the chamber from the condenser for a short time (25 s) and analyzing the pressure
rise during this period. This analysis yields vapor pressure of ice at the sublimation interface,
the product temperature, and the mass transfer resistance of the dried product.25 However, the
data obtained measure the vapor pressure of ice accurately only as long as the system
remains in primary drying. At the end of primary drying, there is little or no pressure rise
because all ice is gone, and hence the calculated vapor pressure of ice becomes equal to the
chamber pressure. Thus, a close approach of the calculated vapor pressure of ice to the
chamber pressure forms the basis of the criterion for end of primary drying.

2.8 Stability of Freeze-Dried products:

Several factors can affect the stability of freeze dried material. Two of the most important are
moisture and oxygen. All freeze dried products have a small amount of moisture remaining
in them termed residual moisture. The amount of moisture remaining in the material depends
on the nature of the product and the length of secondary drying. Residual moisture can be
measured by several means: chemically, chromatographically, manometrically or
gravimetrically. It is expressed as a weight percentage of the total weight of the dried
product. Residual moisture values range from < 1% to 3% for most products. By their nature,
freeze dried materials are hygroscopic and exposure to moisture during storage can
destabilize the product. Packaging used for freeze dried materials must be impermeable to
atmospheric moisture. Storing products in low humidity environments can reduce the risk of
degradation by exposure to moisture. Oxygen is also detrimental to the stability of most
freeze dried material so the packaging used must also be impermeable to air. The detrimental
effects of oxygen and moisture are temperature dependent. The higher the storage
temperature, the faster a product degrades. Most freeze dried products can be maintained at
refrigerator temperatures, i.e. 4-8C. Placing freeze dried products at lower temperatures

28

extends their shelf life. The shelf life of a freeze dried product can be predicted by measuring
the rate of degradation of the product at an elevated temperature. This is called accelerated
storage. By choosing the proper time and temperature relationships at elevated temperatures,
the rate of product degradation can be predicted at lower storage temperatures.

2.9 Packaging:
Freeze-dried foods must be sealed in airtight containers to prevent them from absorbing
moisture from the air. Several types of containers may be used: plastic laminated foil
pouches, metal and plastic cans, or metal and fiber drums for bulk packaging. Some freezedried food is vacuum packed, in which the air is evacuated from the container before sealing.
Other food has an inert gas like nitrogen injected into the container before sealing to displace
the oxygen in the air and prevent oxidation or spoiling of the food. The packaging is done in
the freeze-dry plant almost as soon as the foods come out of the drying chamber. The plant
can form, fill, and seal the packages to the desired weight for the end user. Packages that are
to be sold directly to the consumer are packed in cartons, stacked on pallets, and transported
to the grocery warehouse. Other freeze-dried food is packaged in bulk and sold to a
secondary processor for incorporation into other food products.

Freeze dried ice cream

Freeze dried apple peels

29

(Figure 2.7 Different types of Freeze-Dried products.)

Properly dried material produces a well formed cake with no apparent shrinkage. Product
temperature is critical during primary drying. Changes in product temperature during drying
may influence appearance of final product. Damage which occurs during primary drying
cannot be repaired.

30

CHAPTER 3 MATERIALS USED IN FREEZE-DRYING.

Agents

Examples

Buffer

Phosphate buffers tris, citrate, and histidine buffers.

Bulking Agent

Mannitol, sucrose or one of the other disaccharides

Stabilizer

Sucrose, trehalose, Glucose, lactose, maltose

Tonicity Adjuster

Mannitol, sucrose, glycine, glycerol, sodium chloride.

(Table 3.1 Agents and examples.)

Buffers: Buffers are required in pharmaceutical formulations to stabilize pH. E.g. Phosphate
buffers, especially sodium phosphate, tris, citrate, and histidine buffers.

Bulking agents: The purpose of the bulking agent is to provide bulk to the formulation. This
is important in cases in which very low concentrations of the active ingredient are used.
Crystalline bulking agents produce an elegant cake structure with good mechanical
properties. However, these materials often are ineffective in stabilizing products such as
emulsions, proteins, and liposome but may be suitable for small-chemical drugs and some
peptides.

Stabilizers: In addition to being bulking agents, disaccharides form an amorphous sugar glass
and have proven to be most effective in stabilizing products such as liposome and proteins
during lyophilization. Sucrose and trehalose are inert and have been used in stabilizing
liposome, protein, and virus formulation.

Tonicity Adjusters: The need for such a formulation may be dictated by either the stability
requirements of the bulk solution or those for the route of administration. Recipients such as
mannitol, sucrose, glycine, glycerol, and sodium chloride are good tonicity adjusters.

31

CHAPTER 4 HEAT & MASS TRANSFER EQUATIONS

DESCRIBING THE PROCESS

PC = chamber pressure/(Above dried solute)

RP = product resistance
RS = stopper resistance
M = rate of sublimation
PO = vapor pressure of ice

Relationship between chamber pressure and vapor pressure of ice

AV = surface of vial
KV = vial heat transfer coefficient
TS = shelf temperature
HS = enthalpy of sublimation
T = temperature difference across ice slab
TI

= temperature at the ice interface.

The relationship between vapor pressure of ice and ice temperature:

Combining Eq. 1, 2 and 3 we get,

32

Eq. 4 describes the relationship between product resistance, vapor pressure of ice (product
temperature), the shelf temperature, and chamber pressure).

4.1 Advantages:

Stored in dry state, so stability problem is few.

Product is dried without elevated temp.

Good for O2 & air sensitive drugs.

Rapid reconstitution time.

Constituents of dried material remain homogenously dispersed.

Product is process in the liquid form.

Storage of dry material is less expensive than solution form.

In some specialized laboratories, scientists are developing more sophisticated

processes that combine freeze-drying technology with electron microscopy,
biochemistry, and refined surgery.

At the same time, the cosmetics industry is increasing its use of lyophilization to help
prepare beauty masks, hair dyes, and sophisticated supports for face creams.

Chemical industries also are beginning to use freeze-drying to prepare refined

chemicals, catalysts, and selective filters.

Freeze-drying can preserve food and make it very lightweight.

If a freeze-dried substance is sealed to prevent the re absorption of moisture, the

substance may be stored at room temperature without refrigeration, and be protected
against spoilage for many years.

Preservation is possible because the greatly reduced water content inhibits the action
of microorganisms and enzymes that would normally spoil or degrade the substance.

33

Freeze-drying also causes less damage to the substance than other dehydration
methods using higher temperatures.

Freeze-drying does not usually cause shrinkage or toughening of the material being
dried.

Flavors and smells generally remain unchanged, making the process popular for
preserving food.

Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily
because the process leaves microscopic pores.

The pores are created by the ice crystals that sublimate, leaving gaps or pores in their
place. This is especially important when it comes to pharmaceutical uses.

Lyophilization can also be used to increase the shelf life of some pharmaceuticals for
many years.

Here is a graph showing differences in drying process:

(Figure 4.1Comparsion of drying processes.)

4.2 Disadvantages:

Volatile compounds may be removed by high vacuum.

Expensive unit operation because pumps are more expensive.

Stability problems associated with individual drugs.

34

Some issues associated with sterilization & sterility assurance of dry chamber &
aseptic loading of vials into chamber.

Freeze-drying is facing difficult challenges as the sensitivity, complexity, and price of

treated products steadily rise.

New antibiotics and drugs, immunological products, substances derived from genetic
engineering, high molecular weight proteins, and sophisticated peptides are very
fragile, difficult to freeze, and all highly sensitive to residual moisture content.

Amorphous (glassy) materials do not have a eutectic point, but do have a critical
point, below which the product must be maintained to prevent melt-back or collapse
during primary and secondary drying.

Large objects take a few months to freeze-dry.

If too much heat is added, the materials structure could be altered.

Freezing damage can occur with labile products such as liposome, proteins, and
viruses.
A rapid nucleation and growth rate resulting from a large degree of super cooling
leads to a larger number of small ice crystals, which in turn presents a large icewater
interface. Exposure of proteins to this icewater interface can lead to denaturation

Freezing stresses also can disrupt the liposome bi-layer and emulsion structure.

Small ice crystals produce pores with lower volumesurface area, thus resulting in
lower diffusive flux and slower sublimation rates.

Removal of the hydration shell from proteins and products such as liposome during
drying in the absence of the appropriate stabilizers can cause destabilization of the
protein structure and fusion of liposome.

Extremely low water content in the final product can result in destabilization, and
optimal water content should be determined.

The desired residual moisture must be correlated to stability during long-term storage
as part of development studies.

4.3 Applications

35

Preservation of temperature sensitive products, particularly those of biological origin,

such as enzymes, blood plasma, vaccines, etc.

To achieve a chemical balance, such as for biological reagents.

To provide a practical solution for certain delivery problems, for example, the
packaging of constituents that cannot be mixed in the liquid state, but which are
solidified in successive stages and then freeze dried.

To implement an important stage of a product (such as concentration).

To improve storage life and improved marketing of the end product.

To resolve certain filling problems. It may be difficult, for instance, to divide several
milligrams of powder into precise vial dosages, due to the difficulty of measuring tiny
amounts, homogeneity, granulation, static electricity etc... The distribution of the
product from the liquid state eliminates such production problems.

Product temperature sensitivity and its relation to taste.

The biggest market for freeze-drying is the food industry. Freeze-dried food is used
by hikers, hunters, astronauts, the military, as well as being used in the food industry
for dehydrated soups and meals for consumers in the supermarket. The largest
application is freeze-dried coffee. Yet compared to the quantity of food that is
annually preserved, freeze-dried food still only represents less than one per cent of the
total.

Another important application of freeze-drying is freeze-dried microorganisms,

frequently used for fermentation reactions. The dried microorganisms are
reconstituted, cultured, and used in bioconversion reactions. Also, the freeze-dried
microorganisms are stored for research. After decades, the strains can be revived.

The pharmaceutical industry has been revolutionized by the freeze- drying process.
Life saving medicines that have very short shelf lives are now being freeze-dried,
shipped and stored in many places that could never previously receive or store these
medicines, thus saving many lives. Another life saving substance in which freezedrying has made progress is in that of blood. Although freeze-drying blood is still
extremely difficult due to the very delicate nature of the blood cell, parts of the blood,
as well as blood mixed with glycerol, have been successfully freeze-dried, thus also
saving lives.

36

CHAPTER 5 INSTALLATION AND EQUIPMENT

TECHNIOQUE:

5.1 Freezing Installation:

Cooling by Liquids: Shell-freezing and Spin-freezing:
The freezing of liquids in vials, bottles or flasks in a liquid bath is the most common freezing
method used in laboratories. As the liquid must have a low melting point, alcohol (ethanol,
melting point 114 C) cooled by CO2 (boiling point 80 C at 1 atm) is frequently used. The
bath can also be cooled by refrigerated coils. In the cooled bath the container can be rotated
slowly (shell-freezing) or quickly (spin-freezing), as shown in Figure 2. The aim of both
methods is to reduce the thickness of the liquid product before freezing, to e.g. 1520 mm.
For production purposes, this cannot be used since, first, the sterility of pharmaceutical
products cannot be assured and the liquid must be removed from the surfaces before loading
the vacuum plant. This can be done by hand for a limited number of containers, but not on a
production scale.

(Figure 5.1 Cooling through liquid)

37

The freezing of pharmaceutical products is almost always done in vials, bottles, ampoules,
syringes or sometimes trays. Food or similar products can be frozen in a flow of cold air in a
fluidized bed freezer, if the product is granulated or in small pieces. These conveyor belt or
fluidized bed freezers are available commercially in various forms. Figure below shows a
plant in which vials with product are cooled and frozen in LN2. Whether and when such a
process provides enough advantages of quality to justify the cost can only be decided from
case to case. Two advantages are (i) freezing in a sterile gas with little O2 and (ii) very rapid
freezing. These plants have a capacity between 1500 and 5000 kg/h and require 0.50.8 kg
LN2 per kg of product, which has to be frozen totally on a conveyor belt.

(Figure 5.2 LN2 cooling)

This figure shows an LN2 freezing device in which 50 mL vials with a high (approximately 30 mm) product
filling are frozen quickly. The freezing speed is >10 C/min.

The freeze-drying of coffee and tea extracts, fruit pulps or small pieces of meat requires a
multi- stage pretreatment. The granulated end product from coffee and tea extracts should
have a defined grain size, a desired color and a predetermined density. Fruit pulps should
become granulated, with the appearance of fruit pieces, while meat pieces should not stick
together like a small meat ball, but be recognized as single pieces when presented in a meal.
Coffee and tea extracts are therefore foamed by N2 or CO2 during cooling and partially
freezing (e.g. to 5 C) in a type of ice-cream machine. This foam must have a desired
density, with the inclusion of certain amount of small ice crystals. The foam is cooled on a
conveyor belt not to 18 C, but to 40 C or colder, as this product must pass a grinding and
sieving system to achieve a desired grain size and density.

38

5.2 Drying Chamber and forms of tray:

Bell with base-plate

Rectangular or cylindrical chamber

Tunnel with round cross-section

(Figure 5.3 Types of Drying chambers)

Basic types of freeze-drying chambers. (a) Bell-jar or vertical cylinder; (b) rectangular or
cylindrical chamber with one (or two door(s); (c) tunnel dryer, in which the trays are
transported in and out by a system (shown as a carrier on a monorail). 1, Temperaturecontrolled shelves; 1*, temperature-controlled plate, to expose the product on the upper shelf
to the same conditions as on the other shelves; 2, trays or vials; 3, transport system for trays.

(Figure 5.4 Images of actual drying chambers)

39

5.3 Vacuum System:

Its main purpose is to evacuate the system down to the processing working pressure. Its
secondary purpose is to then to control at this pressure and remove the non-condensable
gases during the drying process. The design of vacuum system can be designed by:

Total volume of system to be evacuated.

The size of the vacuum pumps to be fitted.

The type and number of vacuum pumps to be fitted.

With modern construction methods, quality of fittings, types of pumps available and
accuracy of modern instruments, ultimate chamber pressures of <5 bar are achievable. A
modern pharmaceutical freeze-dryer will have a leak rate in the order of 10-2mbar.L.s-1,
which means a 1000L chamber at 1bar would take >3 years to leak back to 1 bar.

(Figure 5.5 shows a three vane rotary pump and a blower to form a vacuum system.)

Main types of valves used in freeze drying for vacuum system:

1. Ball valves.
2. Diaphragm valves.
3. Butterfly valves.

40

(Table 5.1 Vacuum Spectrum)

Types of gauges:

1.

Pirani Gauge-

(Figure 5.6)
Heated metal filament inside gas. Loses heat to the gas molecules surrounding it. Reduce the
number molecules and the heat loss is reduced causing temperature to rise. Resistance is a
function of Temperature. Change in resistance measured.

Atmospheric pressure to 1 x 10-3 mbar.

Easily Calibrated.

41

Stable output.

15% accuracy across working range (can be 2% at a fixed point).

Different values for different gases. Sterilization will shorten life and stability.

2. Thermocouple Gauge-

(Figure 5.7)
Works on a similar principle to Pirani. Thermocouple attached to a heating filament. Heater
supplied at constant current. Change in pressure causes a change in heat loss. Filament
temperature changes. Thermocouple measures temperature change.

2 mbar to 1 x 10-3 mbar.

Can only be zeroed for calibration.

Signal output drifts over time.

10% accuracy across working range.

Different values for different gases.

Can be sterilized.

42

3. Capacitance Manometer-

(Figure 5.8)
Works on the principal of direct pressure acting on diaphragm. Measures change in electrical
capacitance as diaphragm moves away from fixed capacitor electrodes.
capacitance is converted into a change in output voltage.

Change in

The thickness of diaphragm

determines measuring range.

2 mbar to 1 x 10-4 mbar.

Perfect linear output.

Very accurate (can be < 0.15%).

Some types can be sterilized.

Hydrostatic independent of gas present.

Immune to contamination.

Instrument of choice for Explosion-Proof machines (when processing organic

solvents).

43

CHAPTER 6 CASE STUDY

Comparison of drying process for apple peels:

6.1 Apple peel:

Two batches of peels (10 kg per batch) were collected. Immediately after mechanical
peeling, the peel fractions (pieces around 5 5 mm, with some attached pulp) were packed
into polyethylene bags, frozen at 720o C, transported to the laboratory, and stored in a freezer
at 720o C until used. The sample corresponds to a pool of apples randomly chosen from
different commercial plantations from the same geographical zone.

6.2 Pre-processing conditions:

Frozen apple peel was prepared for the drying process in two batches: frozen (F) and slurry
(S). In order to prepare the peel S, water was added to form a mix suitable for drum drying.
The selected solid/water rate was 100 g frozen peel +60 mL distilled water. Since apples are
highly susceptible to enzymatic browning that may affect the level of antioxidant
compounds, a pre-processing step was to inactivate polyphenoloxidase (PPO). For this
purpose, after homogenization with water, the mix was added 5 g/kg ascorbic acid. This antibrowning agent was chosen since it is proved to be the most efficient compound in
decreasing PPO activity while it avoids the loss of phenolics, compared with 2 g/kg ascorbic
acid, 5 or 2 g/kg citric acid, or blanching). Figure indicates the experimental set up.

6.3 Drying of frozen apple peel and apple peel slurry:

44

(Figure 6.1Sample preparation.)

It was not possible to use the drum dryer system to dry the F peel, due to the large particle
size (1 cm 1 cm). Consequently, we prepared an S mix formed by water apple peel in the
water/peel ratio indicated in section Preprocessing conditioning to allow the use of all
three drying systems. Immediately after drying, the apple peel was stored in high-density
polyethylene plastic bags and kept at room temperature until analysis.

6.4 Results and discussion:

The chemical composition of the apple peel ingredients obtained is shown in Table (A and B
for F and S, respectively). Moisture content of F and S were 874.4 and 909.0 g/kg sample
(wet basis), respectively. The moisture content was similar in all the apple peel products,
independently of the drying system used , and ranged from 26.9 to 34.0 g/kg (prepared with
F) and from 28.8 to 30.3 g/kg (prepared with S).
The aW (activity of water) is a major determinant of the product stability, since water acts as a
solvent to support enzymatic and chemical reactions that influence antioxidant stability,
color, flavor, and nutritional value. It is used to predict the stability and safety of foods with
respect to microbial growth, rates of deteriorative reactions, and chemical/physical
properties. Difference in appearance was also seen in the different methods. The color of the
freeze dried ingredient was similar to the fresh peel. On the other hand, the drum-dried

45

ingredient showed a slight redness compared with oven-dried samples, which exhibited more
browning and redness.
Chemical parameters of apple peel and ingredients elaborated with frozen (A) or slurry (B) peel
using different drying systems.

(Table 6.1 Results of the process)

6.5 Effect of the drying method on the total antioxidant content and capacity:

The amount of antioxidants (phenol content) is very important to know after the drying
process. This helps in deciding which process retains the property of the original product to
its maximum.
The total phenolics in the apple peel were 9.64 and 26.66 mg / kg Water for F and S apple
peels, respectively. Phenolics in the ingredient obtained from peel S were higher (2.8-fold) in
comparison with the frozen peel, since ascorbic acid was added to inactivate PPO and to
avoid the loss of phenolics during the pre-processing. This result demonstrates that it is
possible to retain a high proportion of these putatively bioactive compounds during the
drying process.

There was a significant reduction of phenolics during the drying process. The samples dried
as F peel reached 8.86 and 5.50 mg peels/ kg water, depending on the drying system used
(freeze- and oven drying, respectively). The loss of phenolics in the ingredient obtained from
F peel ranged from 8 to 43% for freeze and oven drying, respectively. On the other hand, in
the ingredients dried as S the total phenolics content ranged from 24.38 to 14.07 mg peels/ kg
water, depending on the drying system used. In these samples the loss ranged between 8 and

46

47%, respectively. Thus, the phenolics reduction observed in the ingredients developed from
frozen peel were higher, while the ingredients obtained from peel slurry showed higher
antioxidant contents than those dried as frozen peel: 2.7- and 2.6-fold higher in freeze- and
oven-dried products, respectively. These data indicate that freeze drying retained most of the
phenolics contained in the apple peel. Also amongst air, oven and freeze drying, the latter
retained 92 % phenolics while drum drying retained 70 % phenolics which concluded that it
is the most economical process.

(Figure 6.2 Type of treatment)

The apple peel powdered ingredients developed may be used in the formulation of functional
foods and beverages. They contain nutrients and a series of bioactive phytochemicals
(important chemicals present in plants) with putatively health beneficial effects, add
economical value to secondary products from the apple processing business, and represent a
new opportunity for the apple industry. Additionally, the use of this solid waste helps to
reduce the environmental impact by re-utilization of a huge amount of residues, which is part

47

of a modern vision of an integral exploitation of food resources. The drying system used to
obtain the ingredient modifies a series of chemical parameters, color, and putatively health
promoting properties, such as the antioxidant content and capacity, thus affecting the quality
of the final product. As expected, freeze drying retained most of the phenolics present in
apple peel at the fresh state. Our results indicate that drum drying, a simple procedure, and
energy efficient, of low capital investment, represents an attractive drying system able to
retain over 30% of the phenolic compounds in apple peel.

48

CHAPTER 7 RECENT DEVELOPMENT IN FREEZEDRYING:

Freeze drying is the unique drying process for heat-sensitive materials involving not only in
pharmaceuticals and biological products but also in food, as well as nonmaterial. In
pharmaceutical and biological industries, water in a dilute aqueous solution is usually
removed by freeze drying, leaving the dried products to be packaged or further processed.
Freeze drying of pharmaceutical proteins is often a greater challenge to the scientists than
that of more traditional, and low molecular weight compounds.
A detailed and comprehensive review on the basic physics, chemistry and material science of
freezing and freeze drying is available elsewhere with particular reference to protein postprocessing. The article involved a variety of aspects concentrating on frozen materials
formulation and freeze-drying process development seeking ways to work smarter, not
harder. In the former part, it was emphasized that it is wise to keep the formulation as
simple as possible, and the concentration should be kept to a minimum if an additional agent
has to be used during freezing no matter what kinds of buffers, salts and excipients. The latter
part involved enhancement of heat and mass transfer during freeze-drying. It was
recommended elimination of product trays and changes in vials to improve the thermal
efficiency. Meanwhile, it was reaffirmed that the controlling resistance to mass transfer is
almost always located at the partially dried layer, and concluded that very high
concentrations of solute may not be appropriate for optimum freeze-drying due to lower
inherent porosity.
In the food industry, freeze drying is used to dry a wide range of products including dairy
products, meats, fruits, vegetables and sea foods. Quality inspections of a dried food product
are usually conducted in terms of texture, flavor and aroma, color and appearance, nutritive
value, and sensory evaluation. Materials involved are strawberries, tropical fruits, cabbage,
potato, carrot, banana and sea foods, etc. It has to be pointed out, however, that shelf food
processed with freeze drying method may have a market bearing problem, i.e. the high price.
The better solution to the problem is freeze drying combined with dielectric heating,
minimizing drying time without a measurable adverse effect on product qualities. This can be

49

done by application of electric and magnetic field to the freezing and the freeze drying
process that is anticipated in commercial application.
Freeze drying can not only remove the solvent but also offer various advantages desired for
different applications of the nano-materials. Not surprisingly, freeze drying can be found in
this area for removing solvent from electrochemical, environmental, engineered materials. A
review on role of freeze drying in nanotechnology highlighting the opportunities and
challenges of freeze drying in processing of such nanoparticles as pharmaceuticals, catalysts,
ceramics, aerogels and electrochemical materials. It was concluded that primary reason for
choosing freeze drying is that the nanoparticles can be easily formed in solution where the
homogenous properties can be retained. The relatively cheap operation cost compared to
supercritical fluid extraction is another reason. An another review involving in discussion of
the theory of freezing, basics of freeze drying, and the dependence of pore size, pore volume
and pore morphology on variables such as freeze temperature, solution concentration, nature
of solvent and solute, and the control of the freeze-direction during freeze drying. Recently,
multifarious nanoparticles were experimentally prepared with the freeze drying technique
including polymeric nanoparticles, silver nanopowder, Co-doped ZnO nanomaterials as well
as W-Cu nano-composite powder.
Improving the process economy by reducing freeze drying time is well accepted to be an
ultimate goal in R&D of freeze drying. The authors research team has been engaged in
looking for ways to increase energy utilization efficiency of the process since 2000.
Dielectrically assisted heating offers a prospective to settle this problem. Because ice hardly
absorbs electric and magnetic wave, microwave energy absorbed by solid matrix in frozen
materials from dilute aqueous solution is not enough to enhance the process. Therefore, a
novel idea was proposed, i.e. dielectric material assisted microwave freeze drying, for the
first time in an attempt to improve the process heat transfer. The results of theoretical
investigations demonstrated that the dielectric material can significantly enhance the
microwave freeze-drying of aqueous solutions. Experimental verifications were later on
conducted, which indicates that dielectric material assisted microwave freeze drying is
workable, and about 20% of drying time can be saved compared with conventional freeze
drying under the operating conditions tested.

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It was also found that excessive microwave input might cause materials overheating and even
crack due to sublimated vapor accumulation within the materials. This suggests that the idea
only solves heat transfer problem. As a consequence, researchers proposed an alternative new
idea, i.e. freeze drying of initially porous frozen material, to enhance the process mass
transfer. Perhaps, combination of the two ideas is the optimal destination in settling the issue,
i.e. simultaneous enhancement of mass and heat transfer, using porous materials with a
certain initial porosity to enhance mass transfer, at the same time using microwave heating
with the assistance of dielectric material to enhance heat transfer.
Mathematical modeling of solids drying remains an important technique in understanding the
drying mechanism and in guiding the dryers design. A review was published on this topic
analyzed various aspects including solid material as a porous medium, transport mechanisms,
equilibrium relationship, volumetric heat source, drying induced deformation, basic
assumptions, and current research state. The relationship among accuracy, generality and
complexity/simplicity was discussed. The accuracy and generality have similar significance
when evaluating an acquired model. At the same time, they pointed out some fundamental
data are still lacking due to either lack of understanding of the process or limitation of
measurements.
More recently, a brief review was published. In the article presented how the mathematical
model for various drying purposes evolves from a general mathematical model based on the
analysis of coupled heat and mass transport mechanisms. The specific applications studied
include the low intensity convective drying, the fixed bed drying, the fluidized bed drying of
porous particles, the freeze drying of various high value materials with (or without)
microwave heating.

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CHAPTER 8 REFERENCES

8.1 Journal reference.

1. M. Henrquez, S. Almonacid, M. Lutz, R. Simpson & M. Valdenegro. CYTA-Journal
of food. 11:2, 127-13.5 Comparison of drying process for apple peels.
2. Sandip Khairnar, Rajesh Kini2, Mallinath Harwalkar, Dr. Kishor salunkhe1,
Dr.S.R.Chaudhari. IJRPS 2013, 4(1), 76 94. International Journal of Pharmacy and
Science.
3. WANG Wei, CHEN Mo and CHEN Guohua .Issues in Freeze Drying of Aqueous
Solutions. Chinese Journal of Chemical Engineering, 20(3) 551559 (2012).
4. Soham Shukla. International Journal of Pharmaceuticals Science and Research. 2011;
Vol. 2(12): 3061-3068.
5. Agnieszka Ciurzyska, Andrzej Lenart. Polish Journal of Food and Nutrition Science.
2011, Vol. 61, No. 3, pp. 165-171.
6. Nathenial Milton. Ph.D. Eli Lilly & Co.
7. Kevin R. Ward, Ph.D. FRSC. Director of Research & Development, BTL, Winchester
SO23 0LD.

8.2 Book references

1. Louis Rey and Joan Mey. Freeze Drying of Pharmaceutical and Biological Products.
2. Georg-Wilhelm Oetjen and Peter Haseley.Freeze Drying.

8.3 Web references

1. http://freezedrying.com/freeze-dryers/general-principles-of-freeze-drying.
2. http://science.howstuffworks.com/innovation/edible-innovations/freeze-drying2.htm
3. http://www.madehow.com/Volume-2/Freeze-Dried-Food.html.
4. http://www.marketsandmarkets.com/PressReleases/freeze-drying-lyophilizationequipment.asp

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5. http://www.cuddonfreezedry.com/products.
6. http://pslc.ws/macrog/tg.htm.
7. http://www.gea.com/global/en/products/lyovac-freeze-dryer.jsp.

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