Hot-melt extrusion (HME) technology is prominent in the pharmaceutical industry. Of particular interest is the use of HME to disperse active pharmaceutical ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions. This method is becoming more and more important because the percentage of poorly soluble new chemical entities in drug development is constantly increasing (1). Especially for BCS class II compounds, improved absorption and therapeutic efficacy can be realized by enhancing API solubility (2). An additional benefit of the HME technique is that it is a robust and continuous manufacturing process that can be run in practically any pharmaceutical plant.
However, as with other innovations, numerous obstacles have to be overcome before the technology and resulting dosage forms can be exploited commercially. Compared with other pharmaceutical technologies, such as granulation and compression, hot-melt extrusion is still an emerging method, and its potential has not been explored fully yet. The technology itself can be described as a process in which a material melts or softens under elevated temperature and pressure and is forced through an orifice by screws. Appropriate thermoplastic behavior is a prerequisite of any polymer to be used in hot-melt extrusion. However, the number of such polymers approved for pharmaceutical use is limited.
Purposes of HMEWithin the pharmaceutical industry, HME has been used for the following purposes:
In comparison with other possible processes, HME is, by far, less complex and more cost effective because its manufacturing process requires only a few steps. HME presents the following advantages over solvent-based processes:
Furthermore, the polymeric components used in the extrusion process may function as thermal binders, drug stabilizers, drug solubilizers or drug-release controlling excipients.
The choice of an adequate polymer as a matrix to form stable solid solutions is crucial in HME. Polymers with a high solubilization capacity are particularly suitable because they can dissolve large quantities of drugs. Some features, such as lipophilicity, hydrogen-bonding acceptors, or donors and amide groups, are basic prerequisites for a high solubilization capacity (5). This factor explains why povidone, copovidone, and PEG-VCap-VAc are highly suitable for HME. Copovidone and PEG-VCap-VAc, in particular, are more lipophilic than many other water-soluble polymers containing hydroxyl groups. Therefore, they are best suited to the lipophilicity of poorly soluble drugs (6, 7).
When the drug is incorporated in a supersaturated form, the whole mixture should have a rigid structure to minimize crystallization from the dissolved drug and from amorphous drug particles (8, 9). As a solid solution, the formulation dissolves in gastric or intestinal fluids, thus forming a supersaturated solution of the drug and enhancing dissolution and bioavailability (10).
In extruded drug-delivery systems, the polymer serves as a matrix. Larger quantities of polymer thus are required than when the polymer is used as a binder or coating agent. Consequently, it is crucial that the polymers be nontoxic and approved in various countries at high doses.