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

Modern drug-discovery techniques are rapidly increasing the number of lipophilic drugs (1). This lipophilicity and consequent slow dissolution rate results in poor bioavailability after oral administration. However, these drugs are easily absorbed from the gastrointestinal tract once dissolved (2). Therefore, the bioavailabilities of these drugs can be improved by increasing dissolution rate (3).

The formation of drug nanocrystals is one of many strategies to increase dissolution rate. Drug nanocrystals are crystalline drug particles with a diameter below 1 m. Because of their small size, the saturation concentration around these particles is increased (Ostwald–Freundlich, see Eq. 1), the boundary layer thickness is decreased (Prandtl, see Eq. 2), and the specific surface area is increased (4). All these effects contribute to an increased dissolution rate (Noyes–Whitney, see Eq. 3) as shown below (5).



where, C s,curved is the saturation concentration around the curved surface, C s,flat is the saturation concentration at a flat surface, γs is the interfacial surface tension, M d is the molecular weight of the drug, R is the gas constant, T is the temperature, ρd is the density of the drug, and r is the radius of curvature of the drug.



where, h is the hydrodynamic boundary layer thickness, k is a constant, L is the length of the surface in the direction of the flow, and V is the relative velocity of the flowing liquid versus the flat surface.



where, dm/dt is the dissolution rate of the drug, d is the diffusion constant, A is the specific surface area, and C is the concentration in the bulk.

Current methods to prepare drug nanocrystals can be divided into bottom-up and top-down methods. Top-down methods (e.g., ball milling and high pressure homogenization) have disadvantages, such as the use of surfactants, low process yields, and the difficulty in achieving uniform-size distribution (6, 7). Bottom-up methods are generally precipitation-based but also have disadvantages, such as difficulty in controlling crystal size and the need to use toxic organic solvents.

To overcome these disadvantages, controlled crystallization during freeze-drying (CCDF) was developed as a novel method to prepare drug nanocrystals (8). First, two solutions are prepared: lipophilic drug in tertiary butyl alcohol (TBA), and matrix material in water. The two solutions are mixed and immediately frozen. The temperature in the freeze-dryer is then increased to –25 C and this temperature is kept constant for a few hours. Finally, the frozen mixture is freeze dried at this relatively high temperature.

Because the mixture of drug, matrix material, TBA, and water is thermodynamically unstable, the drug and matrix material can either crystallize upon freezing or after the temperature in the freeze-dryer is increased (9). Therefore, the first aim of the study was to elucidate when the four different components crystallized during the production process by placing a Raman probe in the freeze-dryer above the sample. By using this in-line analytical tool, the crystallization of the individual components was monitored.

The second aim of the study was to modify the freeze-drying process to ensure its suitability for large-scale production. Because the thermodynamically unstable mixture must be frozen immediately after mixing, at laboratory-scale, only small quantities were mixed in glass vials and subsequently frozen on a freeze-dryer shelf or by immersion in liquid nitrogen. At production scale, it is difficult to mix and freeze large quantities sufficiently fast, so a three-way nozzle was evaluated for its ability to solve this technical problem. The three-way nozzle used in this study allows two liquids to flow separately through the nozzle; the two solutions are mixed just outside the nozzle by an atomizing airflow from a third channel and sprayed into liquid nitrogen, thus achieving high freezing rates. To investigate whether this three-way nozzle could modify the small batch freeze-drying process into a semicontinuous spray freeze-drying process, the crystallinity, particle size, and dissolution rate of the obtained products were determined.


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