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The "adjustment" of the profile showing T
s
over time (averaging of the SMART shelf-temperature settings during primary drying to obtain a constant shelf temperature
over time) and P
c
setting (increase of P
c
from 52 to 62 mTorr) was conducted to further improve the recipe and to facilitate scale-up (see Figure 2) (10). T
p
and R
p
profiles over time for this modified cycle were found in very good agreement to the initial SMART cycle with a maximum temperature
of –34.8 °C during the run (see Figure 3 and Table I). Total primary drying time was 1190 min, or about 5% longer than the
initial cycle recipe. It is important to note that the product processed in both cycles showed no indication of shrinkage
or collapse (see Figure 5a).
Figure 3
Impact of Tsand Pc variation on product temperature. For 50 mg/mL sucrose, variation of shelf temperature of ± 5 °C had very little influence on the profile of T
p
over time (see Figure 3). However, an increase in P
c
from 52 to 200 mTorr led to a significant increase in T
p
(>3 °C), thereby exceeding T
c
. In contrast, an increase in solid content to 200 mg/mL and use of identical process conditions revealed only an increase
of 1 °C in T
p
.
Theoretical modeling of the freeze-drying cycle is an alternative method to gain a better understanding of the impact of process
variables on the product-temperature profile. A one-dimensional steady state of the freeze-drying process was used to simulate
the influence of T
s
and P
c
variations on T
p
for the 50 mg/mL sucrose solution. Note that T
s
and P
c
parameters were used according to the experimental design described above (see Figure 3 and Table I). During primary drying,
the system is in a "pseudo steady state" and the following equation can be applied to predict product temperature (3, 11):
Henning Gieseler, PhD, works in the Department of Pharmaceutics at the University of Erlangen, Erlangen, Germany 91058.
tel. +49 9131 85 29545, gieseler@freeze-drying.eu.
Articles by Henning Gieseler, PhD
