A variety of downstream systems, including die face cutters and belt pullers, are available postextrusion. Pellets or shapes
may be produced. Film and lamination systems are often used for transdermal and dissolvable film applications, and unique
shapes are also possible.
Pelletization is one such downstream process in which the melt stream is pumped through the die, cooled, and formed into a
pellet, typically between 0.5 and 5 mm. In strand pelletization, "spaghetti" strands are extruded and cooled on a stainless
steel or a US Food and Drug Administration approved plastic belt conveyer (9). The feedrolls of the pelletizer pull the strands
and push them into the cutting assembly. Die-face pelletization is also common. In this process, pellets are cut at the die
face and conveyed and cooled using equipment such as chilled air chimneys and vibratory towers (10). Smaller pellets can be
used for direct capsule filling, whereas larger pellets are typically milled.
To extrude a flat film or sheet, the melt is distributed in the die and cooled on rolls. The roll surface is maintained at
the desired temperature by pumping a liquid through internal cooling channels. The molten material solidifies onto the roll
while it cools.For some flat products, the nip force across the roll face is used to "squeeze" the extrudate between the rolls.
Unwind stations can laminate the film onto a substrate. The final product is then either wound or cut to length (11).
Shape extrusion involves extruding the process melt directly into a part with specific dimensions. The extrudate can be a
simple rod or a complex shape, referred to as a "profile." The extruded profile is formed in the die, sized using calibration
tooling, and conveyed and supported through air-cooling devices. A belt puller feeds the product to an on-demand or flywheel
cutter. In this manner, for example, a 3-mm diameter by 3-mm length tablet can be produced (9, 12).
Bioavailability enhancement. Discovery programs have experienced substantial reductions in new chemical entity solubility, with some reports indicating
that approximately 70% of developmental compounds exhibit solubility limitations (13). Dissolution rate and solubility play
a role in absorption and oral bioavailability. Because these limitations can play a crucial role in drug absorption of orally
administered compounds, new strategies have been developed to improve dissolution rates and enhance metastable solubility.
The development of amorphous solid dispersions using melt extrusion represents one of the most effective technologies for
oral bioavailability enhancement (4). When compared with its solvent-based counterpart, melt extrusion provides unique advantages
in terms of the reduced component nature and improved product density.
The literature provides several examples that demonstrate melt extrusion's ability to improve oral bioavailability of poorly
soluble compounds through the production of amorphous solid dispersions. In these systems, the benefit for bioavailability
enhancement is derived from three crucial aspects associated with the formulation: 1) improvement in dissolution rate, 2)
increased metastable solubility leading to supersaturation and, 3) prolonged duration of supersaturation. The enhancement
in dissolution rate is the result of the reduction in specific surface area to the molecular level in combination with the
change in enthalpy associated with the absence of a drug substance crystalline structure. Utilization of melt extrusion to
disperse the drug into the carrier phase by either melting or dissolving the drug substance in the carrier under elevated
temperatures has been extensively reported and is currently used in the commercial manufacturing of Kaletra (Soliqs, Ludwigshafen,
Germany) along with many other companies using melt-extrusion products in late-stage development.
Figure 1: Representative schematic of melt-extrusion processing as a function of pressure. (FIGURE 1 IS COURTESY OF THE AUTHOR)