Materials and methods
Fenofibrate and TBA were obtained from Sigma-Aldrich Chemie, mannitol (the matrix material) was obtained from Roquette and
Preparation of the controlled crystallized dispersions by freeze-drying.
To prepare the controlled crystallized dispersions, fenofibrate was dissolved in TBA and mannitol (the matrix material) was
dissolved in water (see Table I for compositions). For the small batch freeze-drying process, the aqueous solution and the
TBA solution were mixed in a 6:4 ratio.
Table I: Composition of the different solutions used to prepare controlled crystallized dispersions. The mannitol–water solution
and fenofibrate–tertiary butyl alcohol (TBA) solution were mixed in a 6:4 ratio.
The mixture was frozen in vials on a precooled (–50 °C) freeze-dryer shelf (Christ) or by immersion in liquid nitrogen after
being placed on the precooled freeze-dryer shelf. The temperature of the samples was equilibrated at –50 °C on the freeze-dryer
shelf. The temperature of the freeze-dryer shelf was then increased to –25 °C. This temperature was kept constant for at least
three hours, after which time the samples were dried at the same temperature by decreasing pressure and using a condenser
temperature of –85 °C.
Preparation of the controlled crystallized dispersions by spray freeze-drying.
For the semicontinuous spray freeze-drying process, the aqueous solution and the TBA solution were pumped separately (9 and
6 mL/min, respectively) through the three-way nozzle and sprayed into liquid nitrogen. After the nitrogen was evaporated,
the frozen sample was placed on the freeze-dryer shelf and equilibrated at –50 °C. The temperature was gradually increased
to –25 °C and kept constant for three hours. After this, the samples were dried at the same temperature by decreasing the
pressure and using a condenser temperature of –85 °C.
In-line Raman spectroscopy.
A noncontact probe (Kaiser Optical Systems) was placed immediately above the sample in the freeze-dryer and coupled via a
glass fiber optic cable to a Raman Rxn1 spectrometer (Kaiser Optical Systems) equipped with an air-cooled charge-coupled device
(CCD) detector (back-illuminated deep depletion design). The laser wavelength was the 785-nm line from a 785 Invictus near
infrared (NIR) diode laser. All spectra were recorded at a resolution of 4 cm-1 using a laser power of 400 mW. The HoloREACT reaction analysis (Kaiser Optical Systems) and profiling software package,
the Matlab Software package (version 6.5, MathWorks), and the Grams/AIPLSplusIQ software package (version 7.02, Thermo Scientific)
were used for data collection, transfer, and analysis. Spectra were preprocessed by baseline correction using Pearson's method.
Spectra were collected every minute during freeze-drying, and the exposure time was 30 s.
Scanning electron microscopy (SEM).
SEM pictures were taken with a JEOL JSM 6301-F microscope (JEOL) using an acceleration voltage of 5 kV. The samples were
dispersed on top of double-sided sticky carbon tape on metal disks and coated with a thin layer of gold–palladium in a Balzers
120B sputtering device (Balzers Union).
Tablets of 100 mg were prepared on an ESH compaction apparatus (Hydro Mooi) at a compaction rate of 5 kN/s to a maximum compaction
load of 5 kN. The tablets were stored for at least one day in a vacuum desiccator over silica gel before further processing.
The dissolution rate of fenofibrate from the tablets was tested in 1 L of 0.5% w/v sodium dodecyl sulfate solution (Fagron)
at 37 °C in a USP dissolution apparatus II (Rowa Techniek) with a paddle speed of 100 rpm. The concentration of fenofibrate was determined
spectrophotometrically by a UV–Vis spectrophotometer (UV-1601, Shimadzu) at a wavelength of 290 nm.