After 15 min on a precooled freeze-dryer shelf, only the TBA peak can be seen in the Raman spectrum (see Figure 2). This indicates
that at this stage of the process, the solvents were still in the liquid state and that the solutes were still dissolved in
these solvents. After 75 min, the intensity of the peak corresponding to ice increased, and the width of the TBA peak decreased.
However, no significant change in the relative intensities of either fenofibrate or mannitol peaks could be seen, which shows
that during the freezing step, the solvents crystallized and that, importantly, the solutes did not. During equilibration
at –50 °C the solutes still did not crystallize.
Figure 3: Dissolution profiles of fenofibrate from tablets composed of physical mixtures (open symbols), dispersions prepared
by the batch process (black symbols), and dispersions prepared by the semicontinuous process (gray symbols). The tablets contained
30% (circular symbols) and 40% (square symbols) w/w fenofibrate in mannitol. (n=3–6; mean). (FIGURE 3 IS COURTESY OF THE AUTHORS)
However, when the temperature was increased to –25 °C and maintained for 500 min, mannitol and fenofibrate peaks increased.
This increase in intensity finished well before the drying step was initiated, indicating that crystalline mannitol and crystalline
fenofibrate were formed during the crystallization step and that this crystallization was finished before drying started.
To initiate drying, the pressure was decreased at 2963 min. The intensity of the water peak decreased and the width of the
TBA peak increased thus indicating that sublimation of the solvents had begun. In summary, upon freezing, only the solvents
crystallized, while the solutes did not crystallize until the temperature in the freeze-dryer was increased. Crystallization
of the solutes finished before drying started.
From freeze-drying to spray freeze-drying using a three-way nozzle.
Because only small quantities can be prepared in vials in the initial experiment, this freeze-drying process is not suitable
for large-scale production. Therefore, a three-way nozzle was tested to determine if it could convert the small-batch freeze-drying
process into a semicontinuous spray freeze-drying process for scale-up.
Solid dispersions prepared by freeze-drying (freezing in liquid nitrogen) and spray freeze-drying were compared. The dissolution
rate of fenofibrate from dispersions prepared by the semicontinuous spray freeze-drying process was faster, especially at
a higher drug load, than that of dispersions prepared by the small-batch freeze-drying process (see Figure 3).
Because dispersions obtained from the different processes were all fully crystalline, the differences in dissolution rate
should be attributed to differences in drug crystal size. Indeed, the SEM pictures indicate that crystals obtained from the
semicontinuous process were smaller than those obtained from the batch process (see Figure 4). However, in-line Raman spectroscopy
measurements showed that the solutes did not crystallize upon freezing, but after the temperature of the freeze-dryer shelf
Figure 4: Scanning-electron microscopy pictures of controlled crystallized dispersions prepared by freeze-drying (top) and
spray freeze-drying (bottom). (FIGURE 4 IS REPRINTED FROM H. DE WAARD ET AL.,EUR. JRNL. OF PHARM. SCI. 38, 224–229 (2009),
WITH PERMISSION FROM ELSEVIER.)
Therefore, the difference in drug crystal size can be explained by the difference in freezing rate (11). During the batch
process, vials containing 2 mL solution were immersed in liquid nitrogen, whereas during the semi-continuous process very
small droplets were sprayed into liquid nitrogen. Because the volumes of the individual droplets were smaller than the volume
of liquid in the vial, rapid freezing rates could be achieved by spray-freezing into liquid nitrogen (12).
A higher freezing rate leads to the formation of smaller solvent crystals, and therefore smaller interstitial spaces (containing
the freeze-concentrated fraction) between the solvent crystals (13). Because the drug and matrix crystallize in the freeze-concentrated
fraction, the size of the drug crystals is limited to the size of these interstitial spaces. Thus, when smaller interstitial
spaces are formed, the final drug crystal size is smaller (see Figure 5).
Figure 5: A diagram of the controlled crystallization process. The white areas represent the solvent crystals, the grey areas
the freeze concentrated fraction, and the black squares the drug nanocrystals. (FIGURE 5 IS COURTESY OF THE AUTHORS)