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 HME
Within the pharmaceutical industry, HME has been used for the following purposes:
- To increase the drug's dissolution rate and bioavailability
- To control or modulate drug release
- To mask the drug's taste
- To stabilize the API
- To create parenteral depots and topical delivery systems.
Personnel can increase the dissolution rate and bioavailability of poorly soluble APIs through HME by forming a solid solution
(i.e., solid dispersion) of a drug within hydrophilic excipients. The solid solution is the ideal type of solid dispersions
for increasing drug release. In such a matrix, the drug is molecularly dissolved and has a lower thermodynamic barrier for
dissolution compared with solid dispersions with crystalline drugs (see Figure 1) (3). Extruded solid solutions offer higher
thermodynamic stability than those prepared by alternative processes, such as spray drying, solvent evaporation, and other
hot-melt methods (4).
Figure 1: Relevant types of solid dispersions. (ALL FIGURES ARE COURTESY OF THE AUTHOR)
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:
- It eliminates the need to handle explosive solvents
- It does not produce residual solvents
- It enables continuous processing
- It entails few process steps
- It yields high product density
- It produces nondusty pellets
- It is a water-free process
- It can be accomplished through small-scale equipment
- It requires a low investment in equipment.
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.