Melt Extrusion: Shaping Drug Delivery in the 21st Century - Pharmaceutical Technology

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Melt Extrusion: Shaping Drug Delivery in the 21st Century
The authors provde a review of melt extrusion's evolution and applications in the pharmaceutical industry. This article is part of a special Drug Delivery issue.

Pharmaceutical Technology
pp. s30-s37

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.

Figure 1: Representative schematic of melt-extrusion processing as a function of pressure. (FIGURE 1 IS COURTESY OF THE AUTHOR)
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.


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