This article is part of a special issue on Drug Delivery

Melt extrusion has been an established industrial manufacturing technology for more than 50 years and has been applied to the production of everything from layered trash bags and space-shuttle parts to synthetic wine corks. During the past decade, the technology has emerged as a viable platform for pharmaceutical development. Today, melt-extrusion applications for pharmaceutical production range from controlled-release systems to oral bioavailability enhancement and show potential for small molecules and therapeutic peptides.

Pioneering development activities in the late 1980s and 1990s spawned several amorphous compositions, including Sporanox (Janssen Pharmaceuticals, Titusville, NJ), Prograf (Astellas Pharma, Deerfield, NJ), and Rezulin (Parke-Davis*), leading to the general acceptance of solid dispersions (1–3). Driven by the continuing development of new chemical entities with limited solubility and industrial aims at continuous commercial manufacturing, melt extrusion has gained acceptance for improving bioavailability and increasing manufacturing efficiencies (4, 5). The emergence of novel drug-delivery systems and routes of administration also have allowed for the expansion of melt-extrusion applications within the pharmaceutical industry. This review article presents an overview of the processing technology, covering four major areas of application: bioavailability enhancement, oral controlled release, melt granulation, and the production of advanced controlled-release dosage forms.

Twin-screw extruders (TSEs) process materials in channels bounded by screw flights and barrel walls, and are therefore referred to as small-mass continuous mixers. The motor inputs energy into the process through rotating screws. Process-control parameters include screw speed (rpm), feed rate, temperatures along the barrel and die, and vacuum level (6). Typical monitoring parameters for in-line quality measurement include melt pressure, melt temperature, motor amperage, and near-infrared (NIR) sensors.

Table I: Oral bioavailability of itraconazole solid-dispersion formulations in healthy volunteers (n = 8). Adapted from Six et al. (Ref. 14).

TSEs are starve-fed, with the output rate determined by the feeder(s), which can meter pellets, liquids, powders, and fibers into the process section (8). The TSE screw speed is independent from the feed rate and used to optimize compounding efficiencies. Because the pressure gradient in the extruder process section is zero for much of the process, materials can be introduced into downstream barrel sections to facilitate sequential feeding (7). For instance, a shear-sensitive active pharmaceutical ingredient (API) can be metered in the latter stages of the process section.

TSE processing offers advantages over batch manufacturing techniques. Polymers are specified to function as thermal binders and act as drug depots and drug-release retardants upon cooling and solidification. Solvents and water are generally not necessary for processing, which reduces process steps. Expensive drying equipment is eliminated as well, along with time-consuming drying steps.

The intense mixing associated with the short interscrew mass-transfer characteristics inherent in a TSE small-mass continuous mixer results in highly efficient distributive and dispersive mixing that leads to a more uniform product compared with large mass-batch mixers (7). Entrapped air, moisture, and volatiles are also removed by vacuum venting during the extrusion process. The short residence time associated with a TSE process compared with a batch process is beneficial for many heat and shear-sensitive materials because the TSE can be designed to limit exposure to elevated temperatures to a few seconds.