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A Discussion of the Effect of Chamber Pressure on Heat and

Mass Transfer in Freeze-Drying
R. G. Livesey and T. W. G. Rowe

PDA J Pharm Sci and Tech 1987, 41 169-171

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RESEARCH ARTICLE

A Discussion of the Effect of Chamber Pressure on Heat and Mass Transfer in

Freeze-Drying

R. G. UveseyA and T. W. G. Rowe

Edwards High Vacuum, Crawley, Sussex, England

ABSTRACT: There have been many reports concerning the influence of chamber pressure on primary drying
times and sublimation rates offreeze-dried materials. However, there is disagreement about the mechanisms
responsible/or the observed effects. The complex interaction between system parameters and product nature,
which may lead to the contradictory views expressed in the literature, are discussed. In particular, it is
considered by the present authors that results derived from pure ice are not applicable to product in which a
cake of residual solids is formed.

Observations of Pressure Effects
In 1962, when using a vapor pressure method to deter-
mine the average temperature of the freeze-drying front
in food pieces, Neumann and Hackenberg (1) found that
the sublimation phase of freeze-drying was shortened
when conventional wisdom would have expected it to be
extended. The explanation was that an intermittent in-
crease in the pressure of water vapor in the pores of the dry
cake increased simultaneously the thermal conductivity of
the cake and briefly raised the temperature of the inter-
face. When the ambient vapor pressure was lowered the
sublimation rate increased for a short period until the
temperature of the interface fell due to evaporative cool-
ing. The process was, therefore, intermittently trans-
formed from one which was rate limited by heat transfer,
where the normal penalty of increasing the heat supply to
the product was scorching at the surface (not melting or
collapse at the interface), to one which was limited by
vapor transfer.
About the same time a procedure known as accelerated
freeze-drying (2), in which food pieces were sandwiched
between sheets of expanded metal pressed into thermal
contact by moveable heated platens, used a vapor-stifling
method to effect a compromise between heat and mass
transfer. This led to a number of mathematical treatments
(3-5) of the problem to determine whether cycling or
quasi-steady but increased pressures in vacuum freeze-
drying gave optimum results.
Initially there was little expectation that these tech-
niques would be significantly useful when applied to the
freeze-drying of liquids frozen in trays or vials as, in such
cases, only one-fifth of the total heat of sublimation, at
most, was known to be transmitted through the residual
cake.
Received September 15, 1986. Accepted for publication July 15,
1987.
A
Author to whom inquiries should be directed.
At this time there was very little published work on the
effects of system pressure. However, verbal reports began
to reach the authors from various sources that raising the
ambient pressure in the freeze-drying chamber could sig-
nificantly shorten the sublimation phase in vial-contained
materials. The authors and their colleagues have also
witnessed the converse: namely an increase in sublimation
(primary drying) time when water vapor condensers (op-
erating at —40 °C) in older equipment were replaced by
condensers working below —50 °C, which lowered the
partial pressure of water vapor in the system.
The inference was that in freeze-drying the heat trans-
mitted from a supporting shelf at a given temperature to
the base of a vial at a lower temperature varied, within
limits, according to the pressure in the system, although it
was not clear what the atmosphere consisted of. The effec-
tive upper limit to the pressure would be that at which
heat transfer in the gap between shelf and vial ceased to be
pressure dependent (that is when molecular flow condi-
tions in the gap ceased to prevail) and this would depend
on the average thickness of the gap. The limiting lower
pressure would be that below which any further pressure
reduction would produce a negligible change in heat
transfer.
In practice there would be a constraint on the upper
limit of ambient pressure so as to avoid melting the frozen
product or causing collapse of the cake structure.
It might be thought that an increase in product tem-
perature could follow from a reduction in the rate of
sublimation (due to the increase in environmental water
vapor pressure) when excess energy would appear in the
form of sensible heat. However, an increase in product
temperature would cause an increase in the saturated
vapor pressure at the sublimation front which would tend
to increase the sublimation rate. Note that an increase in
the product temperature reduces the difference in tem-
perature between it and a heated shelf so that the interac-
tion between heat and mass transfer begins to look more
complex than might at first be supposed.

Vol. 41, No. 5/September-October 1987 169

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Influence of System Control
Attempts to demonstrate or explain the effects of vary-
ing the pressure in a freeze-drying system have often
failed to take into account built-in autoregulation. For
example, with a given power input (neglecting for a mo-
ment the thermal inertia of the shelf), the shelf and prod-
uct temperatures will adjust themselves to balance the
transfer of heat to the product and its transformation into
water vapor. Let us suppose that the product temperature
is at an optimum; that is to say a higher temperature
would damage the product and a lower temperature would
not give the highest practical rate of sublimation. Imagine
that the thermal resistance between shelf and product is
reduced by increasing the ambient pressure. An increased
heat supply to the shelf is now required to maintain its
temperature constant. The increased heatflow raises the
product temperature which is now above the optimum and
the product is damaged. The sublimation rate increases, in
spite of the tendency of the increased environmental pres-
sure to reduce it, because the saturated vapor pressure at
the sublimation front is an exponential function of tem-
perature. If, as is usual, a temperature limiting device in
the product operates to reduce the power input to the shelf
to safeguard the product, then the rate of sublimation is
reduced. In these conditions an increase in chamber pres-
sure leads eventually to a reduction in the rate of sublima-
tion through the intervention of a control system.
In an alternative scenario the shelf is automatically
maintained at a constant temperature. As the system pres-
sure is increased, and the heat transfer improved, the
product temperature rises and the shelf temperature tends
to fall demanding an increase in power input to maintain it
at constant temperature. This increased power input is
matched by an increased heat loss in the form of sublimed
vapor.
The only unambiguous statement which can be made,
therefore, about varying the pressure in a freeze-drying
system under the conditions described is that it can pro-
duce corresponding variations in the rate of heat transfer,
for a given temperature difference, between a heated shelf
and a product. Such a variation can also be produced by
changing the shelf temperature. In particular, faster dry-
ing can be achieved simply by increasing the shelf tem-
perature and this can produce marginally shorter subli-
mation periods than increasing the system pressure. The
reason why this method is not preferred is that to obtain
the greatest reduction in sublimation time very high initial
shelf temperatures are required. From mathematical
models simulating typical conditions we find (in work to
be published shortly) that initial shelf temperatures great-
er than 500 °C would be necessary to maintain the maxi-
mum sublimation rate (while allowing the product tem-
perature to remain below chosen, typical collapse and
melting limits). The required temperature reduces as the
sublimation front withdraws from the outer cake bound-
ary. Even so, high initial temperatures can endanger the
product because of the thermal inertia of shelves and their
associated heat transfer fluids. The consequent sluggish
response to temperature control, compared with the rela-
tively rapid response to pressure control, can allow the
product to reach excessively high temperatures.
This has led to cases in which considerably shorter
freeze-drying times have been claimed with nitrogen
bleeds. In such cases it is usually found that routine
freeze-drying (without nitrogen bleed) had been carried
out at a substantially constant shelf temperature. This
means that if the shelf temperature had been at a safe,
relatively low, value near the end of sublimation it was
grossly inadequate at the beginning. During freeze-drying
the process changes from one which is rate limited by heat
transfer, requiring a relatively high rate of heat input, to
one which is limited by vapor transfer which requires a
much lower rate. In the early stages of freeze-drying the
sublimation rate can be very high but is ultimately limited
by heat transfer to the frozen product. Under these condi-
tions increasing the system pressure to improve the heat-
flow will increase the sublimation rate and thus reduce
overall drying time. When the dry cake has increased in
thickness the impedance to vapor flow reduces the subli-
mation rate and the corresponding heatflow can be
achieved by a relatively low shelf temperature and low
system pressure.
Freeze-Dried Product vs. Pure Ice
We have argued that the reduced drying times observed
when system pressure is increased, in vial freeze-drying,
are a consequence of improved heatflow between the shelf
and vial base (a number of authors have previously ex-
pressed a similar opinion). In this connection the observa-
tions of Jennings (6) are of some interest, since he found
that the sublimation rate of pure ice is reduced when the
system pressure is increased and argues that this is the
case for frozen solutions. He then goes on to explain the
increase in sublimation rate observed by Nail (7) and
Pikal et al. (8) in terms of loss of contact with the vial
walls and the resultant exposure of a larger surface area of
ice to sublimation. While this may explain the particular
case he studied, when subliming pure ice other aspects
must be considered.
First an increase in sublimation rate can only result
from a corresponding increase in the rate of heat supply.
The rate of sublimation is given by:
where:
Rs = rate of sublimation, kg/m/sec
Pv = S.V.P. of ice, Pascal
Pa = partial pressure of water vapor above ice surface,
Pascal
a = accommodation coefficient (very close to 1 for
ice)
M' — molar weight of ice [= molecular weight
(A0/1000],kg/mol
T — absolute temperature
R - gas constant = 8.314 J/K/mol
Expressing rate in g/cm2/sec, pressures in torr and
taking a = 1 this becomes:
.lournal of Parenteral Science & Technology
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When T = —47 °C the corresponding vapor pressure Pc
= 0.0425 torr and when Pa = 0.002 torr (corresponding to
the vapor pressure of ice at a condenser temperature of
-70 °C) the mass flow rate Rg = 0.00067 g/cm2/sec
(2.4 g/cm2/hr). This may be compared with typical rates
of 0.1 g/cm2/hr or less for freeze-dried solutions. The
sublimation rates observed by Jennings are very much
smaller than the rates calculated using the above equation
and seem to imply a relatively large water vapor partial
pressure. Pikal et al. (8) have noted that the atmosphere in
the vicinity of vials during freeze-drying is largely com-
posed of water vapor even when the system pressure is
raised using a nitrogen bleed.
While the sublimation rate is reduced as (P0 — Pa)
decreases, and rapidly so as Pa approaches Pv, the impor-
tant point to note is the high rate of sublimation of pure ice
at a given temperature compared with the rate observed
for ice embedded within a dry shell. When pure ice on a
shelf is first exposed to vacuum the sublimation rate is
very high. This high rate is not usually immediately bal-
anced by heat gained from the shelf and the ice tempera-
ture begins to fall (for example, the time taken for a block
of ice 1 cm thick to adjust to a change in temperature of
one of its faces is approximately one minute). The larger
temperature difference between ice and shelf increases
the heat transfer rate. At the same time the reducing ice
temperature lowers the sublimation rate until the heat loss
by sublimation comes into equilibrium with heat transfer
from the shelf. However, as found by Greaves (9), the
sublimation rate can be much greater than the rates typi-
cally observed for frozen product (provided that the heat
input rate is sufficiently high) even though the pure ice
temperature is much lower than the temperature at which
frozen product would stabilize.
We consider that Jennings' model is invalid when ap-
plied to freeze-drying under real conditions when there is
a resistance to vapor flow imposed by the formation of a
cake of residual solids of continuously increasing thick-
ness. At the instant when sublimation begins, vapor evolu-
tion is sensitive to the water vapor partial pressure in the
system. However, the theoretical sublimation rate (de-
scribed by Eq. 1 ) cannot be sustained because, we calcu-
late, a temperature gradient of 470 °C/cm through the ice
would be required to maintain the sublimation front at,
say, —30 °C (for 1 cm thickness). This would require a
shelf temperature of 10,000 °C and a temperature at the
base of the freeze-drying plug of 440 °C which is clearly
absurd. Under practical conditions, therefore, raising the
pressure in the system to a level approaching, but still
below, the S.V.P. of the ice is not going to be a limiting
factor in sublimation rate. However, the pressure increase
will certainly improve heat transfer to the vial base. As the
dry cake grows in thickness its impedance to vapor flow
becomes increasingly significant compared with the sys-
tem pressure which can still be useful in controlling heat
Vol. 41, No. 5/September-October 1987
transfer. As the sublimation rate continues to fall, for a
given constant shelf temperature, the system pressure
must be reduced. Thereafter, it may be necessary to re-
duce the shelf temperature also.
While cake shrinkage may occur during freeze-drying
it is unusual for the frozen plug to lose contact with the
wall of the container and the authors have not observed
shrinkage of the ice core away from the walls while leav-
ing an enveloping cake in contact. If such a phenomenon
should occur the material would sublime partly under the
conditions observed by Neumann and Hackenberg (1),
where heat transfer through the dry layer is significant
and affected by system pressure. But how would addition-
al heat reach the vial walls and where would it originate?
If dry material continued to make contact with the vial
wall there would still be a high restriction to vaporflowin
the cylindrical annulus of dry cake between core and wall.
Thus the local ice temperature would not fall and there
would be no increase in temperature difference between
ice and vial wall which could cause an increased heat flow.
Furthermore, loss of ice contact with the walls could lead
to loss, of contact with the vial base but it is known that
such detachment, which often occurs when solutions are
freeze-dried in trays, prolongs primary drying time.
Concluding Remarks
Jennings' observations of a reduction in sublimation
rate for pure ice with increased pressure is most interest-
ing and merits further investigation. However, we do not
think Jennings' model offers a plausible explanation of the
general freeze-drying phenomena observed by Nail and
by Pikal et al. It is clear that there is a complex interaction
between a number of parameters during vial freeze-drying
and more experimental and theoretical work will be need-
ed before the problems are elucidated. As a contribution
to the debate we are making this interim, nonmathemati-
cal submission as a prelude to a more detailed analytical
treatment which we hope to publish in the near future.
References
1. Neumann. K. H. and Hackenberg, V., "Considerations sur la lyo-
philisation industrielle," Le Vide, 16(91) 25-31 (1961).
2. Hanson, S. W. F., éd., "Accelerated freeze-drying method of food
preservation," HMSO, London, 1961.
3. Mellor. J. D., "Vapour transfer in the course of freeze-drying," Rev,
L. R., ed. in Advances in Freeze-Drving, Herman, Paris, 1966, pp.
75-88.
4. Mellor, J. D., Fundamentals of Freeze Drying, Academic Press,
London, 1978.
5. Litchfield, R. J., Farhadpour, F. A. and Liapsis, A. J., "Cyclical
pressure freeze drying," Chem. Eng. Sci. 36(7), 1233-1238 (1981).
6. Jennings, T. A., "Effect of pressure on the sublimation rate of ice," J.
Parenter. Sci. Technol., 4(3), 95-97 (1986).
7. Nail. S. L., "The effect of pressure on heat transfer in the freeeze
drying of parenteral solutions." J. Parenter. Drug Assoc, 34(5), 358-
368(1980).
8. Pikal, M. J., Roy, M. L. and Saroj Shah, "Mass and heat transfer in
vial freeze-drying: role of the vial," J. Pharm. Sci., 73, 1224 (1984).
9. Greaves, R. I. N., "The application of heat to freeze drying systems,"
Ann. N.Y. Acad. Sci., 85(2), 682-688 (1960).
171
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