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.
TSEs use segmented screws that are assembled on high torque shafts. Barrels are modular and integrate internal bores for cooling.
Segmented screws/barrels, in combination with the controlled pumping and wiping characteristics of corotating, self-wiping
screws, allow screw and barrel geometries to be matched to the process tasks (6, 7). The counter-rotating intermeshing twin
screw mode is also used in the pharmaceutical industry. Solids convey and melt during the first part of the process section.
Screw elements for mixing and devolatilization are used as dictated by the process. Discharge elements help to build and stabilize
pressure (see Figure 1).
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
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.