Post on 08-Aug-2018
8/22/2019 Christ Theorie Katalog en Web
1/54
8/22/2019 Christ Theorie Katalog en Web
2/54
Smart Freeze Drying
Basic principles, optimum procedures
and applications
8/22/2019 Christ Theorie Katalog en Web
3/54
2
8/22/2019 Christ Theorie Katalog en Web
4/54
Contents
1 Introduction 4
2 Basic principles 6
3 Freeze Dryer Design 84 Procedures 10
4.1 Overview 10
4.2 Freezing 12
4.3 Primary drying and secondary drying 16
5 Practical aspects 24
5.1 Warm up / Cool down 24
5.2 Shell-Freezing and Spin-Freezing 24
5.3 Achievable vacuum values 25
5.4 Determining the end o drying / PAT 26
6 Summary of procedures 30
7 Further literature 32
Some examples of freeze drying applications 34
Impress 52
8/22/2019 Christ Theorie Katalog en Web
5/54
4
Freeze-drying or lyophilisation is an eective way o drying
materials without harming them. It makes use o the physical
phenomenon o sublimation, which involves the direct
transition between the solid state and the gaseous state
without passing through the liquid phase. To achieve this, the
rozen product is dried under vacuum, without being allowed
to thaw out. The process is suitable or a wide range o
applications:
or preserving the characteristics o the initial substance
(e. g. pharmaceutical products, milk)
or or preserving the initial orm (e. g. taxidermy,
or conserving archaeological nds or fowers)
or conditioning materials (e. g. reeze-dried ruit in yoghurt)
or chemical analyses (e. g. investigating trace organic
substances in oodstus, slurries, soils)
Freeze drying is used or more than 30 categories o
substances or materials. The most important markets are the
pharmaceutical industry and biotechnology as well as the
ood industry.
In general, a distinction is made between reeze-driers
used only in batch procedures, and continuously operating
systems. Non-continuous systems are available to processes
loads rom 2 kg up to approximately 1000 kg. We specialise
in this product group, and we are the only manuacturer
worldwide to oer a complete range rom laboratory bench-
top systems and pilot reeze-dryers through to large-scale
production machines:
1 Introduction
The food industry accounts or the largest volumes o reeze-dried
products, such as instant coee, but biotechnology and pharma-
ceutical products, e. g. vaccines, require systems which meet the
highest quality standards
i n t r o d u c t i o n
8/22/2019 Christ Theorie Katalog en Web
6/54
5
Laboratory reeze-drying equipment
Ice condenser capacity rom 2 to 24 kg
Mostly air-cooled rerigeration system
Broad range o accessories or
wide-range applications
Pilot reeze-drying systems
Ice condenser capacity rom 6 to 16 kg
Air- or water-cooled rerigeration systems
Freezing and drying in the drying chamber
on liquid-controlled shelves
Production reeze-dryers
Ice condenser capacity rom 20 to > 1000 kg
Water-cooled rerigeration systems
Freezing and drying in the drying chamber
on liquid-controlled shelves
SIngle-or-double chamber systems
Customized project engineering
SIP / H2O
2disinection, CIP, IQ / OQ,
Process integration (loading systems,additional equipment)
i n t r o d u c t i o n
8/22/2019 Christ Theorie Katalog en Web
7/54
6
E I N F H R U N G
2 Basic principles
The principle o sublimation can be explained with reerence
to a phase diagram (= vapour-pressure diagram). The process
is usually carried out with aqueous systems, although in recent
years reeze drying o solutions with special solvents have
become increasingly important.
The vapour-pressure diagram shows the phase transition
o the substance in a graph o pressure and temperature.
For example, it shows the boiling point o water at precisely
100 C at normal atmospheric pressure. At lower pressures,
the boiling point is reduced (the principle on which vacuum
distillation is based), and conversely, at higher pressures
the boiling point is raised (which is the principle on which
a pressure cooker operates).
Figure 2.1 Phase diagram o water [1]
I the pressure is higher than 6.11 mbar, H2O passes through
all three states (solid, liquid, and gaseous) as the temperature
increases or decreases. Below this point however, i. e. i the
pressure is less than 6.11 mbar, it passes directly rom the solid
to the gaseous state. At exactly 6.11 mbar the melting-point
curve, vapour-pressure curve and sublimation-pressure curve
meet at the so-called triple point. At the triple point all three
phases can coexist.
Freeze drying under atmospheric conditions is widely believed to have been
irst developed by the aboriginal peoples living and hunting in the Arctic
Circle, but this is a myth. In act when they dry ood it passes through a series
o melting and evaporation processes, but the evaporation is so rapid that it
is not possible to see any liquid phase orming.
b a s i c p r i n c i p l e s
liquid
triple point
critical point
solid
gaseous
0 100 200 300 400
t temperature in C
10-5
10-4
10-3
10-2
10-1
1
10
102
II
102
104
H2O
III
I
p pressure in bar
8/22/2019 Christ Theorie Katalog en Web
8/54
7
E I N F H R U N G
The ollowing table contains values or part o the
ice-pressure curve:
For the conversion o units:
C = mbar C = mbar C = mbar C = mbar
0 6.110 -20 1.030 -40 0.120 -60 0.011
-1 5.620 -21 0.940 -41 0.110 -61 0.009
-2 5.170 -22 0.850 -42 0.100 -62 0.008
-3 4.760 -23 0.770 -43 0.090 -63 0.007
-4 4.370 -24 0.700 -44 0.080 -64 0.006
-5 4.020 -25 0.630 -45 0.070 -65 0.0054
-6 3.690 -26 0.570 -46 0.060 -66 0.0047
-7 3.380 -27 0.520 -47 0.055 -67 0.0041
-8 3.010 -28 0.470 -48 0.050 -68 0.0035
-9 2.840 -29 0.420 -49 0.045 -69 0.0030
-10 2.560 -30 0.370 -50 0.040 -70 0.0026
-11 2.380 -31 0.340 -51 0.035 -71 0.0023
-11 2.170 -32 0.310 -52 0.030 -72 0.0019
-13 1.980 -33 0.280 -53 0.025 -73 0.0017
-14 1.810 -34 0.250 -54 0.024 -74 0.0014
-15 1.650 -35 0.220 -55 0.021 -75 0.0012
-16 1.510 -36 0.200 -56 0.018 -76 0.0010
-17 1.370 -37 0.180 -57 0.016 -77
-18 1.250 -38 0.160 -58 0.014 -78
-19 1.140 -39 0.140 -59 0.012 -79
1 mbar = 100 Pa = 1 h Pa
1 Pa = 0,010 mbar
T = thermodynamic temperature K (Kelvin)
t = Celsius temperature C
tF
= Fahrenheit temperature F
Temperature
T = t + 273
t = T 273
tF= 1.8 x t + 32
t =tF 32
1.8
Pressure
b a s i c p r i n c i p l e s
8/22/2019 Christ Theorie Katalog en Web
9/54
8
3 Freeze Dryer Design
The basic components o a reeze dryer are:
a) Vacuum drying chamber (see accessories
catalogue, Section 3.1)
b) Vacuum pump to extract air rom
the drying chamber (gas pump)
c) Ice condenser operating at temperatures
rom - 55 C to -105 C (depending on
the type o system) to extract water vapour
rom the chamber (vapour pump)
d) Heated or unheated shelves or drying in dishes
(see accessories catalogue, Section 3.3 and 3.4)
e) Shelves with sealing device or drying in vials
(see accessories catalogue, section 3.2)
) Rubber valves or the connection o round-bottomed
fasks, wide-necked fasks, etc. (see accessories
catalogue, section 4.4)
g) Maniolds or connection o round-bottomed fask,
wide-necked fasks etc. (see accessories catalogue,
section 3.5.)
Figure 3.1 Freeze dryer with acrylic glass drying chamber (a)and rubber valves ()
Figure 3.2 Freeze-dryer with sealing device or drying in vials (e)
(placed inside during operations)
For both the laboratory reeze-dryers and the production-scale
systems a distinction is made between single-chamber and
double-chamber systems. Only the laboratory systems are
presented here:
Generally, a lyophilisator consists o a recipient (product chamber) in
which the substance is placed, an ice condenser, and a vacuum pump.
However, various technical developments have been made, and these
are now incorporated in a wide range o available systems.
f r e e z e d r y e r d e s i g n
8/22/2019 Christ Theorie Katalog en Web
10/54
9
Figure 3.3 Laboratory system shown in single chamber operation
As shown in Figure 3.3, in the single-chamber system the
reezing and then the drying o the product are carried out in
the ice condenser. The reezing o the sample results rom the
low temperature o the ice condenser (- 55 C or the single-
compressor system or - 85 C or the double-compressor
system). The interior can then be cooled down to about - 20 C
or - 40 C, respectively. Using a an during the reezing phase
proves to be very eective or transerring energy betweenthe sample and the ice condenser (see Article no. 121423).
During the primary drying phase it is necessary to introduce a
moderate amount o energy to the rozen sample and this is
provided rom the heated shel. The attachment unit shown in
Figure 3.2 (see Article no. 121009) makes it possible ater
the completion o drying to close the injection vials under
vacuum or inert gas, so that the reeze-dried sample is also
vacuum-sealed.
In the array shown in Figure 3.4 the rack with shelves is
under an acrylic glass cover outside the ice condenser, so that
this is reerred to as a two-chamber system. The advantage othis is that it oers a much greater product capacity or the
same ootprint area. Furthermore, by separating the product
chamber o rom the ice condenser (by means o the inter-
mediate valve shown in the sketch) it is possible to carry out
a so-called pressure-increase test to determine the end o the
drying process. This is explained on page 27. The disadvantage
is that it requires additional handling o the samples, which
have to be rozen externally in advance, e. g. in a rerigerator
or reezer. Ater transer to the reeze-drier, the acrylic
chamber is put in place and the sublimation itsel is started.
All laboratory systems rom Christ which are equipped with
shel temperature control can be operated either as a single-chamber or double-chamber system as required.
Figure 3.4 Laboratory system with two chambers
f r e e z e d r y e r d e s i g n
8/22/2019 Christ Theorie Katalog en Web
11/54
10
4.1 Overview
Beore loading a new product, it is important to remove any
water rom the previous batch that remains in the ice condens-
er chamber. When this has been done the outlet valve and the
ventilation valve are closed. The product should only orm a
layer o 12 cm, because i it is too thick this will have a
detrimental eect on the drying time.
As shown in Figure 4.1, the reeze-drying process can be
controlled by the selection and alteration o only two master
parameters in the system:
Figure 4.2 shows a record o the reeze-drying process or a
ceramic suspension. Because it has a reezing point near 0 C
and no dicult product properties, this can be reeze-dried
already at a pressure o 1 mbar and with a shel temperature
o + 40 C. As the drying reaching completion, the temperature
sensors in the 3 cm-thick layer o the suspension (yellow, green
and blue lines) reach values close to the shel temperature.
Beore this, a mixed temperature is measured combining
the sublimation temperature and the temperature o the dried
cake. The ice condenser temperature (black line) rises at the
start o primary drying rom - 83 C to about - 70 C, because
large quantities o water vapour have to be rozen out. Ater
about 20 hours this eect has declined to some extent so that
the ice condenser again reaches a temperature o about - 85 C.
4 Procedures
Figure 4.1 Vacuum and shel temperature
Figure 4.2 Process graph or the reeze-drying o a ceramic
suspension
Freeze-drying process
Two key parameters o the system Vacuum p = (fd-step) Shel temp. t = (process time)
p r o c e d u r e s
Vacuum Lyo RxShel Icecond. Product 1 Product 3 Lyo Temp
-10000 4020 6010 5030 705 4525 6515 5535 75
0,001
0,001
0,100
1.000
10.00
100.0
Atm.(mbar)
-905
-4030
1055
6080
-8010
-3035
2060
7085
-7015
-2040
3065
8090
-6020
-1045
4070
90
(C)
100
95
(%)
100
-5025
050
5075
8/22/2019 Christ Theorie Katalog en Web
12/54
11
As a rule, the product is rozen under atmospheric conditions,
analogous to a conventional reezer.
As already explained, the substance is rozen in small
amounts in the ice condenser chamber (process A) or separate-
ly in the laboratory in conventional reezer unit (process B).
A rozen product in round-bottomed fasks or wide-necked
lter fasks is oten preerred or drying because the fasks canbe attached and removed separately, without aecting the
drying process o the other fasks. As explained in Chapter 5.2,
the time required or the drying is aected by the thickness o
the layer, which can be considerably reduced by reezing under
rotation rather than using conventional stationary reezing.
The rotation leads to the ormation o a uniorm ice layer
inside the glass vessel.
When reezing in a separate process it is advisable,
particularly with small charges, to cool the shel so as to avoid
a partial melting during the evacuation process.
Ater the reezing, the system should then be taken
through a warm-up / cool-down phase. The vacuum pump can
warm up with the pressure control valve closed, and in this
way improve its perormance and its ability to withstand water
vapour. At the same time the ice condenser is pre-cooled, so
that it will be able to cope with the water vapour rom the
primary drying step. The preparation phase should take
between 15 and 30 minutes.
In order to start the sublimation process, the pressure
control valve to the vacuum pumps is opened so that the
pressure drops. The primary drying is started.
The optional secondary drying involves reducing the pressure
as low as possible in connection with a slightly elevated shel
temperature (both o these measures improve the desorption).
This desorption phase is subject to dierent thermodynamic
laws than the actual sublimation.
Ater the end o the process the drying chamber is
aerated through a rubber valve or the ventilation valve. It isalso possible to introduce nitrogen or an inert gas through
the aeration valve. The system can then be switched o and
the product taken out.
The ice condenser can be allowed to derost at room
temperature, or warm water can be used to speed up the
process i necessary. The ice condenser chamber should not be
more than hal ull o water. When derosting the ice condens-
er in this way it is important to make sure that no water nds
it way into the connecting pipes to the vacuum pump and the
pressure gauge!
Condensation and derosted water is drained o into a
container through the drain valve. Beore starting a new
process any residual water in the system should be removed.
The drain valve and aeration valve are then closed and the
system can be loaded with the next batch.
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
13/54
12
4.2 Freezing
The reezing phase determines the microstructure ormed by
the solidied solution and thus also that o the dried product.
A distinction is made between two dierent structures o
rozen materials: the crystalline orm is characterised by the
presence o ice crystals with denite crystal boundaries. This is
the case or most aqueous solutions with a low proportion osugars or proteins. I the reezing is carried out slowly enough
the mixture will separate out gradually until the nal drop o
liquid solidies at the lowest possible temperature, the
so-called eutectic temperature. In many cases the system does
not keep to the thermodynamic equilibrium and the liquid
becomes supercooled, possibly by as much as 1020C.
Crystallisation can then be initiated suddenly by shaking or
the introduction o a nucleus o crystallisation, and in this case
the solid phase will not have a eutectic composition.
In contrast, amorphous substances do not have any crystal
boundary, similar to a supercooled melt, e. g. window glass.
Heating such a congealed solution does not lead to a sudden
melting, but rather the material which has become soter
begins to fow away. This is thereore reerred to as the
collapse temperature TC. The glass transition temperature T
G
reers to the solidication point rom the liquid to the
amorphous and is usually a ew Kelvin lower than thecollapse temperature.
In the pharmaceutical industry amorphous matrices are
preerred or embedding sensitive biomolecules because the
active substance can be stabilised better. Conversely, crystalline
products can be reeze-dried quicker and more easily because
the grain boundaries avour the transport o water vapour.
While the melting o a crystalline product during drying can
lead to spattering and the risk o cross-contamination, with
amorphous, honey-like substances there is at rst only a loss
o structure. Although the product may not be impaired, anycustomer would object to being oered sticky crumbs. Many
substances in the pharmaceutical sector have a longer shel
lie i they are embedded in an amorphous matrix.
The key aspect when determining the necessary shel
temperature and pressure during primary drying is the
solidication temperature (= reezing point) o the material
being dried. In addition to being dependent on the product
in question, this is also dependent on the rate o reezing.
As an example, the table in Figure 4.4 shows the wide range
o eutectic points o microbiological culture media.
The eutectic point is the point in a constitutional diagram
at which an homogeneous eutectic alloy or mixture solidiies
directly rom liquid to solid state without orming a mix
o phases.
Figure 4.3 Determining the reezing point with CHRIST Lyocontrol
10-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
C
2 3 4 5
Shel 1
Product 1
Product 2
Lyo Temp
Shel 2
Icecondenser
Stopper
Sensor
Product
CHRIS-Lyocontrol LC-1
Freezing point
Rx
t / h
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
14/54
13
Sample Eutectic Temperature/C
Tab water -1.0
Super pure water 0.0
UHT-Milk -11.7
Skim-Milk -11.0
Lactose 5 % -1.0
Lactose 10 % -2.0
mod. pc-med. (3 % NaCl) -45.0
Litmus milk -12.0
Hgl -12.0
ba bouillon -29.0
Glucose bouillon -6.5
Malt extract bouillon -6.5
Yeast water -1.5
ygc -15.0
Mrs bouillon -20.0
M 17 -15.5
Basic medium streptococcus -15.0
Figure 4.4 Eutectic point o various nutrient
media [1]
Figure 4.5 With a less rapid rate o increase o the Rx-value during
solidiication, the solidiication point should be taken as the product
temperature determined according to this igure.
The reezing point can be determined by means o
the theoretical thermodynamic value
(source: chemistry manuals, technical literature
[e. g. VDI Thermal Atlas], reerences)
Cryo-microscope
DSC (Dierential Scanning Calorimetry)
measurement o temperature and resistance
during the reezing phase
The electric resistance o the product being dried almost
always rises dramatically with the transer rom the liquid to
the solid state due to the reduced mobility o 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 reezing point.
Because there is usually a very abrupt rise in resistance,
the intersection o the Rx- and T-curves can be taken as the
reezing point with a very high level o accuracy. This has been
conrmed by numerous measurements with various solutions.
p r o c e d u r e s
Lyo product Calc.-Tmp.
Freezing point -21.6 C
Pressure according to vapour-pressure 0.884 mbar
Proposed drying pressure 0.538 mbar
0
10
20
30
40
50
60
70
80
90
100
(%)
00:25 00:26 00:27 00:28 00:29 00:30 00:31 00:32 00:33 00:34 00:3509:24 09:25 09:26 09:27 09:28 09:29 09:30 09:31 09:32 09:33 09:34
-100
-100
-80
-70
-60
-50
-40-30
-20
-10
0
10
20
30
40
50
60
70
80
90
100
(C)
Duration
Upper Rx-asymptote 96.9 %
Point o infection Rx 40.4 %
Freezing point -21.6C
Lower Rx-asymptote 96.9 %
Intersection with asymptote -96.9 %
Lyo Rx Lyo RxCalc Tangent Limits
8/22/2019 Christ Theorie Katalog en Web
15/54
14
With Christ pilot and production systems it is possible to
speciy an Rx minimum value in advance. Below this, the
systems reverts to reezing mode, so that any o the product
which has thawed out will be rozen again. The Lyo-Control
System is able to accurately detect the reezing point o the
solutions which solidiy in a crystalline orm, but is less good
at reading o the collapse temperature o the amorphous
substances used in the pharmaceutical sector. The rate o
reezing has a considerable impact on the morphology o
crystalline systems (see Figure 4.8).
Figure 4.6 Plot o Lyo-Rx or a non-sensitive product
Figure 4.5 shows the determination o the eutectic point or
more generally the reezing point. For a less steep rise o the
Rx-value during the solidication then the solidication point
should be taken as the product temperature at which the
Lyocontrol resistance no longer changes.
The resistance is recorded as a percentage because it
can vary over several orders o magnitude and the actual
Ohm-value is not relevant or determining the reezing point.
A urther advantage o the Christ Lyocontrol system it the
opportunity it oers to monitor the process. During primary
drying the product can melt, leading to splattering, cross-
contamination and possibly the loss o the batch, but this can
be avoided by checking the Lyo-Rx level. The resistance can
break down i the product is heated up too quickly. Figure 4.6
and Figure 4.7 show graphs or a non-sensitive product
(resistance value always near 100 %) and or a very sensitive
product which thawed out ater only a ew hours o primary
drying.
Amorphous substances e. g. glass have no crystalline boundary
and behave like a rozen liquid. At the glass transition temperature TG,
the product starts to behave like elastic rubber and urther begins
to low (collapse temperature TC).
Figure 4.7 Plot o Lyo-Rx or a sensitive product which thaws out
in the course o primary drying
-1000
0 402010 305 452515 35 (h)
0.001
0.001
0.100
1,000
10,00
100,0
Atm.(mbar)
-905
-4030
1055
6080
-8010
-3035
2060
7085
-7015
-2040
3065
8090
-6020
-1045
4070
90
(C)
100
95
(%)
100
-5025
050
5075
-1000
0 4020 6010 5030 705 4525 6515 5535 75 (h)
0.001
0.001
0.100
1,000
10,00
100,0
Atm.(mbar)
-905
-4030
1055
6080
-8010
-3035
2060
7085
-7015
-2040
3065
8090
-6020
-1045
4070
90
(C)
100
95
(%)
100
-5025
050
5075
Vacuum Lyo RxShel Icecond. Product 1 Product 3 Lyo Temp
Vacuum Lyo RxShel Icecond. Product 1 Product 3 Lyo Temp
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
16/54
15
Crystal ormation at -2 C
Freezing too rapidly and to a too low temperature leads to a changed
drying rate (lower pore diameter, crack-ree surace structure)
longer primary drying
Figure 4.8 Crystal ormation (vertical cross-section)
when reezing 100% mannitol solution [3]
Fast freezing
(in liquid nitrogen LN2,
cooling rate approx.
50 C / min)
Slow freezing
(cooling rate
approx. 0.14 C / min)
Moderate Freezing
(e. g.: cooling rate
11.5 C / min)
Annealing
(e. g.: cooling rate
approx. 1.5 C / min,
5 h storage at -10 C)
Crystal morphology (vertical cross-section) 10 % mannitol
Crystal ormation at - 8 C
On the let a 10 % mannitol solution was slowly cooled
to - 2 C, and then crystallised out. The section on the right
show the result o rapid cooling with crystallisation at -8 C.
Rapid reezing leads to a longer primary drying duration due
to the lower pore diameter with ewer ssures in the surace
structure. Slow reezing (classication see Figure 4.8) leads
to so-called reezing concentration.
- 40C
t
+10C
Figure 4.9 Classiication o possible cooling rates [4]
As an example, a sodium chloride solution orms two separate
types o crystal during reezing, namely an NaCl-poor ice phase
and a second, highly NaCl enriched phase. The last drop
solidies at the lowest possible temperature, the so-called
eutectic temperature.
For practical purposes, a rate o reduction o temperature
o 12 Kelvin per minute (moderate reezing) is best or
avoiding reezing concentration on the one hand, while on
the other hand allowing the ormation o suitable crystal
structures.
A starting material containing solvent, or a material with
high salt concentration may thaw during the drying process
(usually clearly visible because o oaming). It is then necessary
to reeze the material to the lowest possible temperature, e. g.
in liquid nitrogen.
I the starting material has a high solvent concentration or
contains acidic material it cannot be dried without protective
measures and special apparatus, e. g. additional LN2
cooling
traps to protect the vacuum pump (in case o doubt consult
us). Alternatively, Vacuum Hybrid pumps (e. g. RC-6) can be
used which are resistant to chemicals.
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
17/54
16
E I N F H R U N G
Sublimation in thermodynamics is when a substance transers
directly rom the solid to the gaseous state without the
intermediate ormation o a liquid.
Ideal gas law
p x V = m x Rm
x T = const.
p = gas pressure [Pa], 105 Pa = 1 bar
V = volume [m3]
m = mass [kg]
rm
= r / M, r = ideal gas constant = 8.314 J / mol x K,
M = mol mass [g / mol], M(H2o) = 18 g / mol
t = temperature [K]
1.0 gram o ice at a pressure o
1.0 mbar produces 1 m3 o water vapour
0.1 mbar produces 10 m3 o water vapour
0.01 mbar produces 100 m3 o water vapour
P = 10 5 Pa = 1bar P = 10 4 Pa = 0,1bar
A very low pressure would lead to the production o an enormous
volume o water vapour, but not necessarily to a rapid reduction in
the water content o the sample!
However, i the pressure is too low this is counterproductive:
It is very important to select the correct pressure.
This can be explained with reerence to the ideal gas law:4.3 Primary drying and secondary drying
Following on rom the necessary warm-up / cool-down
phase already mentioned (warming up the vacuum pump
and cooling the ice condenser) the pressure in the system is
reduced to a specied working vacuum, and this is then
generally maintained during the primary drying. As soon
as the sublimation o the ice in the rozen material begins,heat energy is extracted rom the material and it is thereore
urther cooled.
At the same time the stepwise increase o the shel
temperature supplies the necessary sublimation energy to
the product.
The duration o the reeze drying process can range rom at
least 12 hours or simple products through to several days
or products which are more dicult to dry, such as a vaccine
with a low solidication temperature. Drying voluminous
archaeological nds may take weeks.
The vapour extracted when drying under vacuum reezeson the suraces o the very cold ice condenser, so that the ice
condenser eectively acts as a vapour pump. The vacuum
pump serves only to extract the air rom the drying chamber,
but not to pump out the water vapour (gas pump).
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
18/54
17
E I N F H R U N G
Figure 4.10 Inluence o the working pressure
on the rate o sublimation [5]
-1.0
0:00 5:00 10:00 15:00 20:00 25:00 30:00 35:00 40:00 45:00
0,0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Rate o sublimation [mg / min]
Protein solution
Time (hh:mm)
Rate o sublimation with shel temperature -10 C and 0.1 mbar
Rate o sublimation with shel temperature 0 C and 0.1 mbar
Rate o sublimation with shel temperature 0 C and 0.05 mbar
The longer drying times or very low pressures deduced rom
the vapour-pressure curve and the ideal gas law have been
conrmed in many experiments. For example. Fig. 4.10 shows
the rate o sublimation which can be achieved or various
chamber pressures and shel temperatures [This result was
obtained using a Christ micro-balance].
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
19/54
18
Example
Eutectic temperature teu
= -10C
Drying temperature tdry
= -20C
Drying vacuum pdry
= 1.030 mbar
Saety temperature tsae
= -15C
Saety vacuum psae
= 1.650 mbar
Alarm temperature talarm
= -13 C
Alarm vacuum palarm
= 1.980 mbar
Figure 4.11 Freeze drier with saety pressure unction
Figure 4.12 Freeze dryer with additional alarm pressure unction
In view o the dominant infuence o the apparatus
vacuum on the product temperature, CHRIST has integrated a
so-called saety-pressure unction to protect the products. I
the pressure in the drying chamber rises until it exceeds thesaety pressure limit, then the energy supply to the shel is
interrupted and the sublimation process slows down. This
prevents the product rom melting and avoids the risk o
cross-contamination and the alteration o the product
properties. The saety temperature should be 5 C below the
melting point, i. e. between the drying temperature and the
melting point:
Example
Eutectic temperature teu
= -10 C
Drying temperature tdry
= -20 C
Drying vacuum pdry
= 1.030 mbar
Saety temperature tsae
= -15 C
Saety vacuum psae
= 1.650 mbar
In larger units with liquid temperature control or the shel
it is possible to work with an additional alarm pressure. I the
pressure in the drying chamber rises to a selected alarm value
despite the energy supply being interrupted, the shel is
cooled down as quickly as possible to the reezing tempera-
ture. The alarm temperature should be about 3 C below
the melting point.
The comparison o the red and blue curves shows that even a
slight increase in the pressure rom 0.05 mbar to 0.1 mbar with
the same energy supply can lead to a signicant increase in the
sublimation rate, with the result that the primary drying phase
is about 4.5 hours shorter. This phenomenon is also used in
industrial reeze drying. For example, when reeze drying
ceramic suspensions, which have a reezing point near 0C,
a pressure o 2 to 4 mbar is used, that is near the triple pointo water, but producers o vaccines operate at 0.04 to
0.12 mbar. This is because the reezing point o such solutions
is oten very low.
Another inhibiting actor in the pharmaceutical sector
is the amorphous structure o the materials (no crystal
boundaries or water vapour transport).
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
20/54
19
Figure 4.13 Production unit with so-called liquid-controlled shel
temperature (with silicone oil) and alarm pressure unction
The secondary drying is an option which can be used i the
goal is to retain the minimum amount o residual moisture.
This in act involves the physical process o desorption, i. e.
the removal o absorbed residual solvent. An ice phase should
not longer be present. The secondary drying is carried out at
the lowest possible nal pressure in the system, as a rule
supported by a raised shel temperature (e. g. rom +20 C to
+30 C) in order to make it easier to outgas the thin layers o
solvent molecules on the pore suraces.
The lowest-possible nal pressure in the drying chamber
or the most eective desorption depends on the ice condens-
er temperature in accordance with the vapour-pressure curve
over ice and the rating o the vacuum pump.
In order to be certain o avoiding a melting o the product
during the drying, we recommend working at approx. 10 C
below the solidication temperature (eutectic point or
glass-transition temperature). This approach is described
in more detail on page 18.
Where eciency and speed are key production actors, e. g.
or active pharmaceutical substances, then the aim is usually to
work as closely as possible to the solidication point (perhaps
only 2 C below this). These processes require good knowledgeo the product and extensive pilot tests as preparation.
In order to start the sublimation process, the energy must
be provided or the product in some orm. Energy is received
rom the much warmer surroundings (direct contact heat)
when drying in round-bottomed fask, wide-necked fasks, etc,
or by ambient thermal radiation in the case o an unheated
shel, or directly rom a temperature-controlled shel.
Figure 4.14 Properly dried product (let) and melted, splattered product
(right)
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
21/54
20
Figure 4.15 Temperature proile in a beaded-rim lask
during primary drying
melting
triple point
evaporationsolid
gaseous
10-5
100 -80 -60 -40 -20 0 20 40 60 80 100 C
p
10-4
10-3
10-2
10-1
100
101
102
103
sublimation
solidiication point tr
= -15 C
drying temp. tdry
= -25 C
drying vacuum pdry
= 0.630 mbar
temperature C
-25 -15 -5 +5 +15 +25
heated shel
radiation heat
stopper not tight
dried layer
rozen layer
sublimation ront
thermal transmission
and convection
Figure 4.15 shows the temperature prole at a
beaded-rim fask during primary drying.
The thermal insulation provided by the vial material and the
geometry o the base o the vials lead to a very high tempera-
ture drop rom + 25 C on the shel to -15 C at the base o the
vessel and the rozen product on it. The comparatively good
thermal conductivity o the rozen solid leads to a lower
temperature gradient rom the fask base to the sublimation
ront. The heat transer is given by the equation:
This provides a direct relation to the heat transported
to the ice surace where it is required or sublimation.
The ice temperature at the sublimation ront is determined
by the water vapour pressure curve o the material, which
is ideally aqueous. The temperature gradient in the dried prod-
uct cake above this is determined by the radiant heat and by
the cooling eect o the water vapour fowing through it.
Lyophilisation can be described mathematically as a complex
heat and material transport problem. This can only be solved
by making certain simpliications.
Q = Q = k A T
Q: heat low [W = J ]
Q: heat quantity [J]
t: time [s]
k: heat transport resistance [ W ]
A: cross-sectional area or the heat transport [m 2]
T: temperature dierence [K]
t
.
.
S
m2K
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
22/54
21
Figure 4.16 Freeze drying process in a product dish
shel
contact:
heat transer
product
sublimation zone
t < collapse
temperature
vessel
ice core
thermal radiation
thermal radiation
water vapour
~ + 30C
The second way to infuence the speed is using the tempera-
ture-control o the shel. Figure 4.17 presents the results o
a laboratory drying experiment using pure water with and
without shel heating. In practical application the shel
temperature has less infuence because the pressure will oten
be lower and normally a product matrix will impede the water
vapour fow and reduce the rate o drying.
- 30
- 25
- 20
- 15
- 10
- 5
- 0
- 5
10
15
20
25
30
product temperature in C
time / h
heated shelves (T = 20 C)
unheated shelves
drying time = (T)
product quantity: 5 x 200 ml water
layer thickness: 0.8 cm
vacuum: 1.03 mbar
end o drying end o drying
0 5 10 15 20 25
The reeze-drying o rozen liquids, slurries, suspensions etc.
in dishes should be carried out in systems with heated shelves.
But this is not necessary with materials in pieces or irregular
orms, e. g. plants, ruits, archaeological nds, because the
contact area or heat exchange would be in any case too small.
As in the case o fask drying, the necessary energy here is
provided by ambient thermal radiation through the trans-
parent plexiglass hood. It is hardly possible to regulate the
energy supply. I the product begins to melt (= too much
radiation) then the hood or glass fask can be insulated,
e. g. with aluminium oil.
Figure 4.17 Inluence o shel heating on the
drying rate (pure water) [6]
p r o c e d u r e s
The situation in practice is illustrated in the ollowing
graphic.
8/22/2019 Christ Theorie Katalog en Web
23/54
22
In summary, the product temperature during the drying is
mainly determined by the vacuum level which is chosen, and
less by the shel temperature.
In the rst quarter o the primary drying accounts or 50 % o
the water content, the next quarter or 50 % o the remaining
water content, and so on until the drying curve asymptotically
approaches the time axis. This is due to the act that the
sublimation level withdraws into the product and the water
vapour then has to nd its way through the dry layers and the
resistance becomes increasingly greater. The drying process is
determined mainly by the supply o sublimation heat and therate o transport o water vapour. In order to increase the
special thermal conductivity o the material to be dried and
to generate the smallest possible volumes o water vapour,
the drying should be carried out as near as possible to the
solidication point (eutectic temperature or glass transition
temperature).
The closer the pressure is to the solidication point
according to the vapour-pressure curve over ice then the
shorter is the primary drying time.
Figure 4.18 Asymptotic drying
0
0
50
100
10 20 3024
time (h)
water (%) primary drying secondary drying
The drying o a substance with a solids content o approx. 10 %
is shown in gure 4.18.
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
24/54
23
p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
25/54
24
A virtual leak is a phenomenon whereby liquid which has remained
in a reeze drier rom the previous drying process gradually evaporates,
so that (as with a real leak) the pressure does not all as low as would oth-
erwise be possible.
5 Practical aspects
5.1 Warm up / cool down phase
With systems tted with a pressure control valve, the
opportunity should be used to warm up the vacuum pump.
It is better or the working lie o the vacuum pump i this is
only subjected to the vapours ater the operating temperature
o the pump has been reached, to avoid condensation.
The vacuum pump can be started up during the reezing
and the pressure control valve kept closed. The vacuum pump
should be allowed to warm up or at least 15 minutes, or be
switched on beore the start o primary drying.
In some cases, it is possible that during the primary drying
the pressure in the ice condenser chamber or in the drying
chamber will drop (e. g. rom 0.63 mbar to 0.47 mbar), even
though the valve to the vacuum pump has been closed.
This is due to the pumping eect o the ice condensers
(Cryo-Pumping Eect).
5.2 Shell-reezing and spin-reezing
I liquids are to be dried in fasks in a layer more than 1 cm
thick, then we recommend using a shell- or spin-reezing
arrangement (see Figure 5.2) in a cooling bath. The rotation
spreads the liquid on the inner walls o the fask where it
reezes. The reezing process produces a thinner layer
and increases the potential area or sublimation, which
considerably reduces the overall drying time.
Figure 5.2 Spin-reezing in an inusion lask
Figure 5.1 Shell-reezing in a round-bottomed lask
Layer thickness 70 mm
Surace area 38.5 cm2Layer thickness 9 mm
Surace area 253.3 cm2
70mm
As an example, i 250 ml o substance is introduced in
a 500 ml blood plasma fask, the resultant layer would be
approx. 70 mm thick. By rotating the fask in an upright
position at approx. 1000 rpm, the rozen product liquid is
spread evenly on the inner walls o the fask, so that the
maximum thickness o the layer is approx. 9 mm.
The fask is rotated in a cooling bath. Spin reezing
produces an even, homogeneous layer. Concentration
increases, volume changes and the ormation o varying
crystals o the substances are largely excluded.
155mm
9 mm
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
26/54
25
Figure 5.3 Cooling bath or reezing round-bottom lasks
or wide-necked lasks under rotation (let) and drying lasks
in a laboratory dryer (right)
5.3 Achievable pressure values
The vapour-pressure graph above ice that is the relationship
between ice temperature and the vapour pressure above
this has consequences or daily operations. With single-
stage cooling systems (e. g. ALPHA 14, DELTA 124) the
lowest possible pressure is only 0.021 mbar, because
the ice condenser has a temperature o - 55 C.
The attempt to reduce the pressure urther, e. g. to
0.01 mbar, would be thwarted by the sublimation o ice
rom the ice condenser (secondary vaporisation).
In comparison, the lowest possible pressures with a
two-stage cooling system (e. g. GAMMA 216, EPSILON 26D)
is limited by the nal vacuum o the rotary vane pump which
is usually used this is about 0.005 mbar. The vapour pressure
over the ice condenser at about - 85 C would be an order
o magnitude lower, at 0.0005 mbar.
The theoretical values given here could only be achieved
with a completely dry system. Any residual moisture, e. g. in
an outlet, would increase the achievable nal pressure as a
result o secondary evaporation (virtual leak).
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
27/54
26
A rough statement about the end o drying can be made on
the basis o the pressure and the ice condenser temperature.
Is the ice condenser not longer burdened, it reaches its nal
temperature o approx. - 55 C or -85 C.
The pressure in the drying chamber alls in accordance
with the ice condenser temperature.
Figure 5.4 shows an example o the placement o producttemperature sensors. The drying is also at an end when sample
temperature and shel temperature are well into the positive
range (15 20 C) and do not dier rom one another by more
than 5 K. This indication is more reliable than the observation
o pressure and ice condenser.
Figure 5.5 shows the extent to which the position o the
sensor in the vial infuences the recorded product temperature.
Figure 5.4 Product sensors in a 1 cm high beaded-rim lask illed with an
active substance and in a spongy product
5.4 Determining the end o drying / PAT(Process Analytical Technologies)
The residual moisture in the substance being dried is mainly
dependent on the temperature o the substance during the
secondary drying and the nal pressure achieved during
secondary drying.
The end o the primary drying phase is reached whenthe product temperature and shel temperature are approxi-
mately the same (temperature dierence between shel
and product about 3 K to 5 K). I the absorbed water is to be
removed rom the product, it is then possible to proceed to
the secondary drying phase.
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
28/54
27
A sample can be assumed to dry rom top to bottom, as a
rst approximation, and the upper o the three temperature
sensors shows a rise in product temperature already ater
approx. 7 hours. Due to the cooling eect o the vapour romthe sublimation boundary, the product temperature at the
sensor takes approx. 20 hours to rise above 0. The lowest o
the three sensors shows the most correct value, because it is
directly above the base o the vial or dish where the material
will dry last. The box symbols in the graph show the product
temperatures at the sublimation ront determined using the
relatively new, so-called barometric temperature process o
measurement, a special process which operates with quickly
opening and closing intermediate valves.
In contrast, the pressure increase tests, which have been
in practical use or some time, operate with longer closingperiods or the valve (see Figure 5.6). The principle is based on
a separation o the product chamber rom the ice condenser,
so that the water vapour rom the sublimation cannot escape.
This results in an increase in pressure in the product chamber,
which can be measured. But once the product is completely
dry there will be little or no increase in the pressure.
Figure 5.5 Inluence o the positioning o a temperature
sensor in the product [4]
0 5 10 15 20 25
-30
-20
-10
0
10
20
30
40
T (C)
Time (h)
PT 100
BTM TICE
Figure 5.6 Principle o the pressure increase test
This process is in wide practical use, wherever the reeze dryer
is regularly operated with the same load (number and type o
vials or dishes). The pressure increase test is requently used as
a criterion or switching automatically between primary andsecondary drying as well as or recognising the end o the
drying process.
With sensitive products, the valve must not be kept closed
or very long, i. e. only or a ew seconds, in order to prevent
the rozen material rom collapsing or melting.
The CHRIST microbalance is a unique tool or process
development and optimization in pilot plants.
Flow ovapour romthe sampleto the icecondenser
Vapourenclosed inthe productchamber
Valve open Valve closed
Vacuumpumps
Vacuumpumps
Ice condenser Ice condenser
Productchamber
Productchamber
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
29/54
28
Figure 5.7 The microbalance rom Christ or measuring
vials and small dishes
Figure 5.8 Spectroscopic measurement o the end o drying by recording
the proportion o water vapour in the gas low to the ice condenser
(creating a cold plasma) [7]
Figure 5.9 Principle o the pressure measurement with the
Pirani gauge (let) and with a capacitive sensor (right)
The microbalance works on the principle o electromagnetic
orce compensation. At periodic intervals pre-selected by the
customer, the micro-balance lits the vial and generates a
weight reduction curve with an accuracy o 0.001 g, which
indicates the completion o drying.
The drying process itsel is not interrupted, and thebalance can be placed at any position on the trays in the
chamber. But the shel where the balance is located cannot
be used or sealing. Furthermore, the microbalance cannot
be autoclaved. A dish is provided or the simulation o
bulk-drying.
Lyotrack, developed by Alcatel / Adixen, France does not
examine individual products but monitors the progress o
drying indirectly. At a dened measuring point between the
product chamber and ice condenser, a sample o the vapour
fow is extracted and placed in a so-called Cold Plasma using
a special method. A spectrometric analysis o the radiationreleased provides the ratio o nitrogen to water vapour in the
mixture on its way to the ice condenser at the time o meas-
urement. The urther the drying proceeds, the lower the
proportion o water vapour becomes. Reerence measurements
in comparison with the microbalance show that the Lyotrack is
so sensitive that it not only determines the end o the primary
drying, but can also track the release o water vapour in
secondary drying (desorption).
The composition o the gas fow is also used in methods based
on process monitoring with simultaneous measurement o the
pressure using a Pirani gauge and with the capacitive sensor
(comparative pressure measurement). Figure 5.9 shows both
operational principles.
1
Electrode
Diaphragm
xxxx1
2
3
4
12:00 13:00 14:00 15:00 16:00 17:00 18:00
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Duration o reeze drying (hh:mm)
Plasma versus temperature sensor
Plasmasignal
relativetosaturation
Temperatureof
shelves-/product(C)
-35
-30
-25
-20
-15
-10
-5
0
12:00 18:00 0:00 6:00
Duration o reeze-drying (hh:mm)
Lossofweightmeasured
withthemicro-balance
Plasma versus microbalance
Plasmasignal
relativetosaturation
0 0
0.20.4
0.60.8
1
1.21.4
1.61.8
2
0.10.20.30.40.50.60.70.80.9
11.1
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
30/54
29
0:00 5:00 10:00 15:00 20:00
Time (hh:mm)
Temperature(C)
Pressure(mbar)
Temperature sensor End primary drying
End primary drying
MKs sensor
Pirani gauge
25:00 30:00 35:00 40:00
0.001
0.01
0.1
1
10
100
-100
-80
-60
-40
-20
0
20
40
The Pirani sensor consists o a single wire which loses heat
depending on the pressure o the surrounding gas. The change
o temperature o the wire alters its electric resistance and
thus the current I fowing under a constant voltage V (I = V / R).
The indirect relationship between current and pressure,
I = (pressure) is established by calibration. The heat loss also
depends on the type o gas, and is higher i there is a large
proportion o water vapour.The capacitive sensor is based on the pressure-dependence
o the defection o the membrane o an electrical capacitor,
which is not dependent on the composition o the medium.
Since the Pirani gauge readings are dependent on the type
o gas, and in particular measurements are too high at the
start o drying when a higher proportion o the mixture is
water vapour, whereas the capacitive sensor measurements are
independent o the nature o the gas, when the two measure-
ment curves meet this indicates the end o the primary drying.
Figure 5.10 Pressure measurement with the Pirani gauge and
with a capacitive sensor [5]
p r a c t i c a l a s p e c t s
8/22/2019 Christ Theorie Katalog en Web
31/54
30
E I N F H R U N G
The temperature o the rozen product beore the start o
sublimation should be approx. 10 C below the solidication
temperature. The pressure value or the 10 C lower value
should be chosen using the ice pressure curve.
During the primary and secondary drying, the shel is
heated to provide the necessary energy, but the shel
temperature prole can as a rule only be determinedempirically.
Figure 6.2 shows how the rate o sublimation depends
on both, the pressure and the shel temperature.
This gure only applies or a time point t, because the array
o curves changes with the development o a dried, porous
layer (increasing pressure loss or vapour fow). The determi-
nation o the suitable temperature prole o the shel heating
involves a very complex thermodynamic heat and material
transport problem. In this case, some empirical tests with
temperature sensors and Lyocontrol are preerable to
time-consuming theoretical calculations. Christ provides
recommendations or product applications on its web site
(www.martinchrist.de) and in the ollowing part o this
brochure.
s u M M a r y o f p r o c e d u r e s
Figure 6.2 Dependence o the rate o sublimation on pressure p and
the shel temperature T with the corresponding isotherms o the
product temperature [19]
+30 C
6 Summary o procedures
Figure 6.1 gives an overview o the master parameters or the
design o a reeze drying cycle.
Figure 6.1 Key relationships or the reeze-drying
A key actor is the solidication temperature o the product
in question. As an approximation, it is possible to record the
cooling temperature in the reeze dryer. At the reezing point,
the curve will have a plateau, i. e. the product only cools
urther when the last liquid drop has solidied (Gibbs'
phase rule). Alternatively, the solidication temperature
can generally be determined reliably with the Lyocontrol.
However, this process is less accurate when used withamorphous structures. When such substances are being
handled, or example in the pharmaceutical industry, then
it is better to use other procedures such as dierential
scanning calorimetry (DSC) or cryo-microscopy.
Freezing temperature= (solidiication temperature)
Vacuum = (solidiication temperature)
Lyo-Rx, T-curve, DSC, Lyo-microscope
Shelf temp. primary drying = (time, vacuum)
T-sensor, Lyo-Rx, some tests, Christ application instructions
Process end of primary and secondary dr ying
T-sensor, pressure-rise test, sample thie, micro balance
comparative pressure measurement (igure 5.10)
Pressure p (primary drying)
Product temperature
ShelftemperatureT(primarydrying)
Rateofsubli
mation
-10 C
-40 C
-35 C
-30 C
-25 C
-20 C
0 C
+10 C
+20 C
8/22/2019 Christ Theorie Katalog en Web
32/54
31
E I N F H R U N G
The end o the primary drying process can be determined
by a temperature sensor, the pressure rise test or the micro-
balance. In order to determine the end o secondary drying,
the pressure rise test is a suitably sensitive process and is
preerable because the product temperature no longer
changes and the balance is not always sensitive enough or
measurements during desorption. Alternatively the detection
o the residual water vapour in the chamber is a suitablemethod (Lyotrack by Adixen). O course it is also possible to
use manipulators or sampling equipment to take samples
during the process or the chemical analysis o the residual
moisture content.
s u M M a r y o f p r o c e d u r e s
8/22/2019 Christ Theorie Katalog en Web
33/54
32
f u r t H e r l i t e r a t u r e
7 Further literature
1 Bockelmann, WilhelmGeriertrocknung und Lagerung
von Mikroorganismen. Christ-Geriertrocknungsseminar,
3rd 4th o march 2009, Osterode.
2 Hudel, Klaus Probetrocknung im Versuchslabor der
Fa. Christ, 12 / 2006.
3 Gieseler, H.; Lee, G.Inuence o Dierent Cooling
Rate on Cake Structure o Freeze Dried Samples Measured
by Microbalance Technique. Poster presentation, Controlled
Release Society German Chapter Annual Meeting,
Mnchen (2003).
4 Gieseler, HenningGeriertrocknung von Pharmazeutika
Grundlagen der Formulierungs- und Prozessentwicklung.
Christ-Geriertrocknungsseminar, 25th o june 2003.
5 Presser, IngoGeriertrocknung von Pharmazeutika
Stabilisierungsverahren r empfndliche Arzneistoe.
Christ Seminar Geriertrocknung mit System,
23rd o november 2005.
6 Knerr, Petra Probetrocknung im Versuchslabor der
Fa. Christ, 3 / 2008.
7 Diverse Lyotrack presentation or reeze drying, given
at company Martin Christ, Alcatel / Adixen 8 / 2006.
8 Franks, FelixFreeze-drying o bioproducts: putting
principles into practice. European Journal o Pharmaceutics
and Biopharmaceutics 45, 221229 (1998).
9 Mi, J. Protection Mechanisms o Excipients on Lactat
Dehydrogenase during Freeze-Thawing and Lyohilisation.
Doctoral Dissertation (2002).
10 Allison, S. D.;Chang B.; Randolph T.; Carpenter, J.
Hydrogen bonding between sugar and proteins is responsible
or inhibition o dehydration-induced protein unolding,
Arch. Biochem. Biophys., 365, 289298 (1999).
11 Cleland & Langer Formulation and Delivery o Proteins
and Peptides, Chapter 8, Freeze Drying o Proteins by
Pikal M, American Chemical Society, 120133 (1994).
12 Oetjen, G. W.Lyophilisation. Wiley-VcH ,
isbn 3-527-29571-2 (1999).
13 Kramer, M.Innovatives Einrierverahren zur Minimierung
der Prozezeit von Geriertrocknungszyklen Dissertation
Universitt Erlangen (1999).
14 Ramott, R.; Rambhatla, S.; Pikal, M.; The Eect o
Nukleation Temperature on the Process o Lyophilisation.
Oral Presentation at the University o Connecticut School
o Pharmacy (2002).
15 Searls, J.; Carpenter, J.; Randolph, T.Annealing to
Optimize the Primary Drying Rate, Reduce Freeze-Induced
Drying Rate Heterogeneity, and Determine Tg in
Pharmaceutical Lyophilisation, J. Pharm. Sci., Vol. 90,
Nr. 7, 872887 (2001).
16 Milton, N.Evaluation o Manometric Temperature
Measurement as a Method o Monitoring Produkt
Temperature During Lyophilization, J. Pharm. Sci.
and Techn., 57, 716 (1997).
17 Roth, C.; Winter, G.; Lee, G.;Continuous Measurement
o Drying Rate o Crystalline and Amorphous Systems during
Freeze-Drying Using an In Situ Microbalance Technique.
J. Pharm. Sci., Vol. 90, No. 9, 13451355 (2001).
18 Bedienungsanleitung WgesystemcWs 40, Fa. Christ
Geriertrocknungsanlagen, 10 / 1997, 03 / 2000.
19 Pikal, M.; Nail, S. and Tang, XiaolinAutomated Process
Design Through Manometric Temperature Measurement
Design o a Smart Freeze Dryer. Conerence Presentation,
Freeze Drying o Pharmaceuticals and Biologicals,
Breckenridge, CO (2001).
8/22/2019 Christ Theorie Katalog en Web
34/54
33
f u r t H e r l i t e r a t u r e
20 Pikal, M.Lyophilisation. In: Decker, M. ed. Encyclopedia
o Pharmaceutical Technology. 2001: 1299Y1326
21 Fonseca, F.; Passot, S.; Trelea, C.; Marin, M.Impact o
physical properties o bioproducts on ormulation and on
reeze-drying cycle development. Vienna Congess ispe,
Sept 2006
22 Jiang, G.; Akers, M. et al.Mechanist Studies o Glass Vial
Breakage or Frozen Formulations I. Vial Breakage Caused
by Crystallizable Excipient Mannitol. PDA Journal o Pharma-
ceutical Science and Technology. Vol. 61, No. 6, NovDec 2007
23 Jiang, G.; Akers, M. et al. Mechanist Studies o Glass Vial
Breakage or Frozen Formulations I. Vial Breakage Caused
by Amorphous Protein Formulations. PDA Journal o Pharma-
ceutical Science and Technology. Vol. 61, No. 6, NovDec 2007
24 Tang, X.; Pical, M. J.Design o reeze drying or pharma-
ceuticals: practical advice. Pharm. Res., 21(2): 191200 (2004)
25 Carpenter, J. F.; Pikal, M. J.; Chang, B. S.; Randolph, T. W.
Rational design o stable lyophilized protein ormulations:
some practical advice. Pharm. Res. 1997; 14:969Y975.
26 Tang, X. C. M.; Nail, S. L .; Pikal, M. J. Evaluation o
Manometric Temperature Maesurement, a Process Analytical
Technology Tool or Freeze-drying: PartII Measurement o
Dry-layer Resistance. PharmaSciTech 2006; 7(4) Article 93.
27 Chang, B. S.; Fischer, N. L. Development o an Efcient
Single-step Freeze-Drying Cycle For Protein Formulations.
Pharmaceutical Research, Vol. 12, No. 6, 1995.
28 Presser, I.; Denkinger, N.; Hoermann, H.; Winter, G.
New methods in the monitoring o reeze drying processes:
Validation o the microbalance. Central European Symposium
Pharmaceutical Technology Conerence, Vienna 2001
29 Presser I, Denkinger N, Hoermann H, Winter G
New methods in the monitoring o reeze drying processes:
near inrared spectroscopy determination o residue
moisture during reeze drying. Protein Stability Conerence,
Breckenridge, Colorado 2002
8/22/2019 Christ Theorie Katalog en Web
35/54
34
a p p l i c a t i o n s o f f r e e z e d r y i n g
Algae
Procedure (Overview)
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
-35 C, reezing in LN2
is
convenient
-15 to -25 C wide-necked fasks, dishes A and C TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 0.630 0.220 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-10 C / 4 h, 0 C / 4 h, +10 C / 4 h, +20 C / 1224 h 624 h not necessary
Special eatures
watery material (not de-watered or pre-treated),
straggly consistency
very hygroscopic
resh water and sea-water species
have dierent reezing points
Short description o market
Uses o the reeze-dried products /
Typical users
Food industry (inclusion as favour
carrier, protein-rich)
Cosmetics
* Comments
Process A (Freezing and) drying in the ice condenser chamber
Process B Freezing separate (e. g. rerigerator), drying outside the ice condenser,
e. g. with plexiglass hood
Process C Freezing (on liquid-cooled shelves) and drying outside the ice condensers,
e. g. with plexiglass hood or steel chamber (like EPS ILO N-systems)
EPSILON system with rectangular product chamber, ront loader
It is very diicult to model the processes involved in reeze-drying,
because the transport o heat energy and mass involve very
complex phenomena.
8/22/2019 Christ Theorie Katalog en Web
36/54
35
a p p l i c a t i o n s o f f r e e z e d r y i n g
Books, archaeological nds
Procedure (Overview)
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
books: reezing in the
deep reezer at -10 C,
arch. nds: -30 C
approx. 0 C to -3 C steel cabinet / chamber,
plexiglass tubes
B or C (tempered stainless
steel tubes)
TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 2.560 1.980 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-30 C / 10 h, increase by 5 C every 10 h, i shel
heating is not possible, inrared heating may
be possible (no reports available). Do not dry
too much, books are then placed in the climate
chamber
t = 38 days per object, (or archaeological
nds also some weeks)
end o drying by measuring pressure increase
or weight loss
or books no secondary drying
Special eatures
Books must stand vertically (rack), because
otherwise water vapour cannot escape
Heat transport also possible in sae,
operate close to the eutectic point!
Heating is bad or books (deormation
due to uneven drying because the book
is only warm at the bottom), inrared heating
would be possible (heater at the back o the cabinet)
As ar as possible, objects should be o similar size
so that they dry at the same rate (or example arch les)No temperature prole necessary and not
possible without heated shel
Other application in a vacuum cabinet
(pharmaceutical industry):
Aventis Pharma, Frankurt reeze dries Erlenmeyer
fasks in such cabinets with heated shelves,
giving even heat transer!
Uses o the reeze-dried products
Restoration, or example: wet planning
permission documents ater a food
Typical users
Libraries, museums, public authorities
e. g. wood, textiles, leather
Freeze-dryer or book drying with
2 rerigeration units and heated shelves
Special dryer or archaeological
inds, here treating a Viking boat
It is usually advisable to carry out optimization tests with a
product irst. Some examples o applications ollow to oer
a basis or this.
8/22/2019 Christ Theorie Katalog en Web
37/54
36
Bacteria, viruses, ungi, vaccines
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
-50 C and below -40 C and lower beaded-rim fasks, vials,
ampoules, dishes
A or EPSILON (process C) in
the production range
TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 0.040 mbar and below
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-50 C / 5 h, increase every 5 h by 5 C (4 or
5 times), then reduce to time interval to 3 h
and 1.5 h, Lyocontrol highly recommended
2448 h only in exceptional cases
Special eatures
In laboratories: Disinection and gas sterilisation possible:
Ethylene oxide (highly toxic, outdated), paraormaldehyde,
H2O
2, (increasingly common)
Chemically-resistant CHRIST systems can be provided
Disinection / decontamination: Liquid cleaning (alcohol, etc.),
germs may still be present, special cleaning agents are
recommended or plexiglass (e. g. Incidur)
It is usually necessary to steam-sterilise systems
or production purposes
Sterilisation: with steam > 121 C, complete elimination o germs
Operating in accordance with GMP (Good Manuacturing Practices)and FDA (Food and Drug Administration) requirements
Uses o the reeze-dried products
For human and veterinary vaccination
Ampoules are sealed under vacuum
Vials are closed under vacuum or N2-atmosphere
using special accessories
(pressure o 800 mbar avoids excessive air
diusion into the closed vial in storage and
is enough to keep the sample sterile)
Various bacteria cultures under
vacuum in tightly-sealed
injection vials
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
38/54
37
Plants, sh
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
reezer: -35 C,
eutectic range can
only be determined ater
homogenization
to -15 C see books,
large chambers
B TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 0.630 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying Duration o secondary drying
not applicable, see books 1 d to 1 week (depending on
object dimensions)
minimal 3 h10 h
Special eatures
No temperature-prole requiredFish: remove sh entrails in order to reduce
the layer thickness
Flowers: hang upside down in holders
Note: tissue (bodily fuids) o aquatic animals
contains CaCl2
and so the reezing points are very low
Specialist publication Restoration available rom us
Short description o market
Uses o the reeze-dried products
Fish: anglers, works o art, teaching demonstrations
Plants with very high water content (aquatic plants)or decoration purposes
Typical users
Fish: taxidermists, anglers
Flowers: Garden centres, biological institutes,
generally smaller companies
Freeze-dried sh with a protective
surace coating
Flower seeds ater reeze drying
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
39/54
38
Collagen, tissue samples, thymus
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
pre-cooled in LN2
or
on the shel
Collagen: -45 C
Collagen: about -35 C,
Tissue samples: -56 C
(contain CaCl2)
special dishes,
Special ormats
(L x W, indentation)
A and C TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 0.070 mbar to
0.0047 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-30C / 5 h, increasing rst by 5 C every 5 h
(56 x), then reduce the time interval to 2 h
36 h necessary to remove capillary water,
lowest pressure o pump (10-3mbar)
Special eatures
Rate o rerigeration 1 C / min
Avoid damage to cell walls with non-reezing mixture
(cryo protectants, displace water in the cell wall
and prevent denaturation)
Only heat moderately so that cells do not derost and burst
Short description o market
Uses o the reeze-dried products
Collagen or skin cosmetics (moisturiser, cell rejuvenation)
Cell tissue, bone, arteries, scalp tissue, or aorta valves or
transplantation can be lyophilised
Typical users
Doctors, clinics, increasingly also beauty arms
Collagen plate during test drying
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
40/54
39
Fruits, vegetables, meat
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
ruits, vegetables: -35 C;
meat: -40 C
-25 C dishes B TICE
= TEP
-10 C (= -35 C)
pHT
= (TICE
)
ice pressure curve
= 0.220 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying Duration o secondary drying
ruits, vegetables:
0 C / 4 h, 10 C / 4 h, 20 C / 1624 h)
meat:
-10 C / 4 h, 0 C / 4 h, +10 C / 4 h,
+ 20 C / 1224 h
2436 h a question o cost, not usually
needed
optional
Special eatures
Meat is diced with a side length o about 1 cm
The packaging or reeze-dried products must be
impermeable to air, water vapour and gases
Additional inormation
Freeze drying is viable i the price is more
than Euro 10 / kg (market price)
Freeze-drying plants have an amortisation
period o at least ten years
Doubling the capacity reduces specic
production costs by 10 to 20 percent
A reeze dried product has ten times the aroma
intensity o the same amount o resh product
Uses o the reeze-dried products
Fruits: Baby ood, milk industry
(adding aroma to milk products),
Vegetables: Kitchen herbs
Meat: only as favour carrier (deep-rozen
granules, or ground in a mill)
Typical users
Food industry
Drying specialists
Freeze-dried tropical ruits Arillen
External reezing o trufes
in a reezer
A wide range o oodstus
can be reeze-dried
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
41/54
40
Gelatine
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
-25 to -30 C below -20 C dishes A TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= less than 0.370 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
sensitive, stepwise warming needed -10 C / 4 h,
0 C / 4 h, + 10 C / 4 h, + 20 C / 1224 h
2448 h no
Special eatures
Viscous material, can orm skin,
aecting process
Hygroscopic
The resultant cake is ground
Short description o market
Uses o the reeze-dried products /
Typical users
Intermediate products or the pharmaceutical
industry (carrier, ller), oodstus sector
(binding agent)
Freeze-drying o Lecithin with
tendencies o orm surace skin
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
42/54
41
Royal jelly, honey
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
process A or C,
pre-cooled shel,
shock reezing
usually at -40 C
to -40 C dishes A, C TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= to 0.040 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-30 C / 5 h, rst increase by 5 C every 5 hours
(5 to 6 x), then reduce the interval to 2 hours
2436 h as appropriate
Special eatures
Product is very hygroscopic, must be packed quickly
Substances containing aroma additives and sugar
tend to orm skin during the drying process
Short description o market
Uses o the reeze-dried products
Drugs, ood additives
Typical users
Pharmaceutical companies, private companies
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
43/54
42
Ceramic powders
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
to -20C, separately or in
system
below -10 C
(that is 0 to -10 C)
dishes or modules A TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 1.030 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-10 C / 4 h, 0 C / 4 h, +10 C / 4 h, +20 C /
1224 h, stepwise, rapid drying
possible up to +80 C
224 h no
Special eatures
Initial material is ceramic powder and binding agent
(coating grains), this binder is preserved by reeze-drying,
it would be broken up by thermal drying)
Short description o market
Uses o the reeze-dried products /
Typical users
Use as ceramic base structure or compound materials
Small-scale (Lab): KFA Jlich (Inst. For Materials Testing),
BAM, Berlin
Cylinder rom porous special
ceramics (not a nished product)
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
44/54
43
Sewage sludge, soil samples
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
at about -35 C -25 C dishes, with sieves to hold
back very ne silt particles
A, B, C possible TICE
= TEP
-10 C (= -35 C)
pHT
= (TICE
)
ice pressure curve
= to 0.220 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying Duration o secondary drying
0 C / 6 h, 30 C / 18 h slurry: 24 h
soils: 2436 h
not necessary not applicable
Special eatures
Material o dishes: Aluminium (less rigid) or stainless steel,
can be tefon-coated or heavy-metal analysis
Product sieve or ne-grained soils
German standard DI N 3841 4/22 (Sample preparation)
gives details o eective working pressure, sae pressure,
the pressure control valve, the heatable shel and
sample preparation)
Short description o market
Uses o the reeze-dried products
Analytical laboratories, environmental
departments o industrial companies
Assessing soil contamination levels
Typical users
Environmental oces, analytical laboratories,
sewage treatment plant, water management associations
Lab reeze-drier or up to 4 litres
o slurry or soil samples
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
45/54
44
Microbiological products, ermented products
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
200500 ml spin reezing
(in vertical fasks, with
corresponding cooling
baths
-13 to -35 C 5500 ml fasks,
dishes (albumin)
A and C,
EPSILON systems
(Soletemp.)
TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= to 0.770 0.070 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying Duration o secondary drying
-30 C / 5 h, increase temperature
initially by 5 C every 5 h (e. g. 3 x),
then reduce the time interval to
2 h
24 h (at 1 cm) not at max. vacuum; set or
residual moisture content o
25 %, (customer expertise)
24 h
Special eatures
Lyo-Control recommended or reezing process,
Max. product temperature 30 C (denaturation above 37 C),
Close under vacuum, but risk o air diusion internally
(better to close in an N2atmosphere)
Short description o market
Uses o the reeze-dried products
Blood derivatives or injection purposes, now used instead o ull
plasma transusions (blood substitute = saline solution and plasmacomponents dissolved in bi-distilled water; allows aster uptake o
key components)
Typical users
Red Cross, pharmaceutical companies
e. g. proteins, enzymes, blood serum, plasma, other blood derivatives (albumin, fbrinogen, actor 8 and 9).
Freeze-dryer with temperature-
regulated shel and system or
closing fasks under vacuum
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
46/54
45
Milk products
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
Shell-reezing (round-bot-
tomed fask) Spin-reezing
(cylindrical fasks),
minimum -25 C
-13 C (cow's milk) dishes,
round-bottomed fask,
wide-necked fasks
B, possibly C TICE
= TEP
-10 C (= -23 C)
pHT
= (TICE
)
ice pressure curve
= 0.770 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
0 C / 5 h, then increase to between
+25 and + 30 C
24 h not necessary
Special eatures
non-sensitive product,
Single-chamber systems highly suited or
production applications
Short description o market
Uses o the reeze-dried products
Mare's milk (health ood, valuable vitamins),
goat's milk, camel milk (Emirates), mother's milk
Typical users
Mare's milk arms, pharmacists who wish to
supply to wider areas (rozen then not possible,
thereore reeze-dried); mare's milk goes o
very easily i not reeze dried
Drink yoghurt and reeze-dried
yoghurt
Drying yoghurt in stainless
steel trays
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
47/54
46
Nucleic acids, peptides
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
to -40 C to -30 C nucleic acids: fasks
peptides: dishes, fasks,
vials, ampoules
A (nucleic acids)
A and B (peptides)
TICE
= TEP
-10 C
pHT
= (TICE
)
ice pressure curve
= 0.120 mbar
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
-30 C / 5 h, increase temperature by 5 C every
5 h (56 x), then reduce the time interval to 2 h,
more rapid heating oten possible i no
problems are encountered
2436 h as required
Freeze-dried peptides in
injection vials
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
Special eatures
Material is hygroscopic
In production plant with automatic cleaning (CIP),
steam sterilisation in some cases
Short description o market
Uses o the reeze-dried products /
Typical users
Pharmaceutical companies (additives)
8/22/2019 Christ Theorie Katalog en Web
48/54
47
Organic solvent
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
rst evaporate solvent
with RVC
below -50 C possible dishes
in part also fask drying
(particularly ACN-water
mix)
A corresponding to the xed
point (Ice pressure curve
or water not applicable)
Temp. o the shelves during
primary drying (TSF
/ t)
Duration o primary drying Vacuum or secondary drying
TFp.
-10 C, note: avoid partial derosting
i the pore structure o the sample is important
must be determined experimentally or
a wide range o substances (see below)
depends on product
Special eatures
Examine vapour-pressure curve o the solvent,
Ice pressure curve or water is oten not applicable
An indication o the drying time relative to water (1 cm layer
o ice in 24 h) is given by comparing the vapour pressure
or better sublimation pressure o the substance with that o H2O
Check state o system (rubber seals, acrylic doors / hoods)
With processes A and C, reeze-drying systems can also
be used or vacuum drying or conditioning processes
(creating a product oam). At a low pressure, careul increase
o the heating temperature causes a controlled boiling process.
Short description o market
Uses or the reeze-dried products
Special market, preparation processes in the
pharmaceutical industry, extracting natural substances
Solvents with high-boiling points can also be used
(the key is the solubility o the relevant substances)
Typical users
Chemical and pharmaceutical industry, growing
markets or special applications
Comments
A special presentation is available on this
with details o applications
Laboratory system or fask drying
rom solvent
Rack with sieve cover or drying
rom solvent (avoidance o
cross-contamination)
a p p l i c a t i o n s o f f r e e z e d r y i n g
Procedure (Overview)
8/22/2019 Christ Theorie Katalog en Web
49/54
48
Vegetable materials
Freezing Solidication range,
Solidication point
Container or FD Process
A / B / C *
Vacuum primary drying
-10 C (sometimes down
to -40 C) A and C, reezer
cabinet, rarely with LN2
-10 C (in some cases
to -30 C)
dishes, shelves A and B
TICE
= TEP
-10 C
pHT
= (TIC