A novel freeze pelletization technique for preparing matrix pellets: a novel and simple freeze-pelletization technique generates immediate- or sustained-release spherical pellets with a narrow particle-size distribution

A novel freeze pelletization technique for preparing matrix pellets: a novel and simple freeze-pelletization technique generates immediate- or sustained-release spherical pellets with a narrow particle-size distribution
October 2004
Sreekhar Cheboyina, Walter G. Chambliss, Christy M. Wyandt
Pharmaceutical Technology
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Pelletization involves the agglomeration of active pharmaceutical ingredients and excipients in spherical beads called pellets. Pellets have numerous pharmacokinetic and biopharmaceutical advantages over tablets (1-3). Pellets provide an alternative for blending incompatible active ingredients, obtaining various release profiles, and developing multidrug controlled-release formulations. As a result of this flexibility, the number of oral drug delivery systems involving pellets has steadily increased during the past 40 years.
Manufacturers produce pellets using techniques such as bailing, extrusion-spheronization, high-speed shear mixing, and drug layering on seeds using coating pans or fluidized-bed equipment (4). These techniques require expensive equipment, labor-intensive processes, and skilled operators. Moreover, their process development and validation are tedious. Other pelletization techniques require introducing liquids or molten solids into a cooling fluid as droplets and freezing or solidifying these into pellets. The cooling fluid is typically either liquid nitrogen or cooling gases from liquid nitrogen. The most widely used process for producing such solid particles is spray congealing, in which a molten solid mass is sprayed into cooling chambers (5-8). This process may not be feasible in some cases because it requires tall cooling chambers for adequate cooling of the molten solids. In cryopelletization, aqueous--organic solutions, suspensions, or emulsions are dropped into liquid nitrogen to form frozen particles. These particles are then freeze-dried or lyophilized to remove water or organic solvents (9-12). A major limitation to this process, however, is that it requires liquid nitrogen, which has a temperature of -196[degrees]C. Moreover, the impact of liquid or semisolid droplets on the surface of the liquid nitrogen create surface irregularities in the pellets. In addition, pellets produced by freeze-drying are highly porous and may not be spherical.
Freeze pelletization
Freeze pelletization is a new and simple technique for producing spherical pellets for pharmaceutical use. In this technique, a molten-solid carrier/matrix is introduced as droplets into an inert column of liquid in which the molten solid is immiscible. The molten solid moves in the liquid column as droplets and solidifies into spherical pellets. The molten-solid droplets can move upward or downward in the liquid column depending on the droplets' density with respect to the liquid in the column. If the density of the molten-solid carrier/matrix is more than that of the liquid in the column, then the droplets are introduced from the top of the column and pellets solidify in the bottom portion of the column as illustrated in Apparatus I (see Figure 1). Conversely, if the density of the molten-solid carrier/matrix is less than that of the liquid in the column, then the droplets are introduced from the bottom of the column and pellets solidify at the top portion of the column as shown in Apparatus II (see Figure 2).