Controlled Crystallization During Freeze-Drying - Pharmaceutical Technology

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Controlled Crystallization During Freeze-Drying
The authors discuss the preparation of lipophilic drug nanocrystals by controlled crystallization during freeze-drying.


Pharmaceutical Technology
Volume 35, Issue 8, pp. 58-62

Results and discussion


Figure 1: Dissolution profiles of tablets composed of a physical mixture (open symbols) and controlled crystallized dispersions (black symbols) of 35% w/w fenofibrate in mannitol. (n = 3–6; mean standard deviation). (FIGURE 1 IS COURTESY OF THE AUTHORS)
In-line Raman spectroscopy. The dissolution rate of the solid dispersion, which had been frozen on a precooled freeze-dryer shelf, was higher than the dissolution rate of the physical mixture (see Figure 1). Because the freeze-dried sample was fully crystalline (as determined by differential scanning calorimetry and X-ray powder diffraction, the difference in dissolution rate was likely caused by differences in drug crystal size. Therefore, the drug crystals in the controlled crystallized dispersion were smaller (probably in the nanosize range), than the drug crystals in the physical mixture (x50 = 13 m, determined by laser diffraction).

Although both components in the solid dispersion were fully crystalline, it was not clear at what point during the process the drug and matrix material crystallized. Therefore, in-line Raman spectroscopy was used to measure crystallization during the freeze-drying procedure. The Raman spectra clearly show peaks corresponding to water (208–226 cm-1 ), TBA (725–763 cm-1 ), δ-mannitol (865–895 cm-1 ), and fenofibrate (1580–1610 cm-1 ).


Figure 2: Raman spectra during freeze-drying of the rapidly frozen sample during freezing (15 and 75 min), after the temperature was increased to –25 C (500 min), and during drying (2963 min). The gray bars indicate the characteristic peaks of water (208–226 cm-1), tertiary butyl alcohol (725–763 cm-1), d-mannitol (865–895 cm-1), and fenofibrate (1580–1610 cm-1).
These peaks are clearly separated from each other (see Figure 2), so the crystallization of the individual components could be monitored throughout the process. To determine crystallization, the relative intensities of the individual peaks of fenofibrate, mannitol, and water were determined. An increase in the peak intensity indicates the formation of crystals of the corresponding component. Peak intensity cannot be used to determine crystallization of TBA because liquid TBA already shows a peak with a high intensity. Therefore, the width of this peak was used to determine the onset and end of crystallization (10). A narrowing of the peak indicates the start of the TBA crystallization.


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