Continuous Mixing of Solid Dosage Forms via Hot-Melt Extrusion

The author describes the benefits, processes, and practicality of using hot-melt extrusion to mix active pharmaceutical ingredients with pharmaceutical-grade polymers.
Oct 02, 2008

Extrusion technology is a highly advanced, standard manufacturing methodology that has been used for more than 70 years. Twin-screw extruders are used in the plastics industry to mix polymers with additives and fillers for nearly every plastics product we encounter, including plastic pipes, garbage bags, and carpet fibers.

In recent years, the continuous extrusion process has been applied successfully to pharmaceutical formulations by downsizing sound, established continuous manufacturing techniques. In addition to being a proven manufacturing process, continuous extrusion meets the goal of the US Food and Drug Administration's process analytical technology (PAT) initiative for designing, analyzing, and controlling the manufacturing process through quality control measurements during processing.

Twin-screw extruders are also used to process complex mixtures for a variety of controlled-release products with pharmaceutical polymers matched to the thermal sensitivity of the drug. Hot-melt extrusion (HME), in particular, involves melting materials, mixing them with active pharmaceutical ingredients (APIs), pumping them through a die, and sizing/cooling them into a shape.

Interest in pharmaceutical HME has greatly increased since the early 1980s as demonstrated by a steady increase in related patents. But it has only been in the past 10 years or so that the pharmaceutical industry has begun to influence twin-screw extruder designs by prompting equipment modifications for regulated manufacturing environments. As the technology is understood, embraced, and applied in this new application arena, extrusion is being recognized as a better approach as compared with traditional batch methods. An HME system is tailor-made for designing, analyzing, and controlling a manufacturing operation through on-line measurement to ensure final product quality, which makes it ideally suited for PAT.

Benefits of HME include the absence of solvents, fewer processing steps, and lower manufacturing costs. Without exception, if the formulation is amenable, the continuous extrusion process is also more consistent and repeatable compared with batch processing.

HME offers advantages in techniques as well. Molten polymers are specified to function as thermal binders and act as drug depots and/or drug-release retardants upon cooling and solidification. Solvents and water are generally not necessary for processing when using HME, which results in fewer processing steps. Expensive drying equipment and time-consuming drying steps also can be eliminated with HME. In addition, a twin-screw extruder acts as an efficient devolatilization device and can be configured to remove more than 40% of volatiles during processing.

The intense mixing associated with the inter-screw mass transfer characteristics inherent with twin-screw extrusion results in highly efficient distributive and/or dispersive mixing, and therefore a more uniform product. The molecular level mixing often achieved by HME has improved the bioavailability of many drug substances, especially for those with low water solubility.

The short residence time associated with HME, as compared with a batch process, is beneficial for many heat- and shear-sensitive compounds. The HME process can be designed to limit exposure to elevated temperatures to just a few seconds to avoid the degradation associated with both time and temperature. Downstream feeding of APIs also avoids the shear effects associated with melting the polymer, which is the highest shear region in the HME process section.

Extrusion machinery and design

The major differences between pharmaceutical and plastics extrusion machinery is that the metallurgies for parts that wet the materials are specified to be nonreactive, nonadditive, or nonabsorptive with the pharmaceutical product. In addition, the equipment used for pharmaceutical extrusion is configured to meet cleaning and validation requirements associated with a good manufacturing practice (GMP) environment. Otherwise, the unit operations performed for pharmaceutical and plastics processes are identical.