Polymer combinations have been shown in numerous studies to yield amorphous solid dispersions while providing enhanced dissolution
rates that led to improved oral bioavailability. There are, however, some examples where increasing the dissolution rate failed
to substantially improve oral bioavailability. In a series of studies using itraconazole as the model compound, dissolution
rates were improved in vitro (see Figure 2) but failed to provide a substantial improvement for oral bioavailability (see Table I) (14). Subsequent research
has shown that the oral bioavailability of itraconazole is associated with an increase in metastable solubility and the ability
to maintain supersaturation. Through the combination of poorly soluble drugs with concentration enhancing polymers to prepare
amorphous solid dispersions, substantial increases in oral bioavailability can be achieved. Such strategies have shown benefits
not just in academic settings but also in industrial applications.
Table II: Comparison of melt-granulated systems with conventional dry-granulation systems. Adapted from Kowalski et al. (Ref.
As part of a Pfizer-Bend Research collaboration, Curatolo et al. studied the utility of 41 materials for the concentration
enhancing benefits provided to nine proprietary and model drug substances (15). Their results demonstrated broad effectiveness
of hypromellose acetate succinate (HPMCAS) to provide superior concentration enhancing behavior. Similar concentration enhancing
behavior of HPMCAS has also been demonstrated using hot melt extrusion and the excellent melt properties of the polymer make
it an appropriate material for use as a carrier in melt extrusion. HPMCAS, however, is not a universal solution to solubility
enhancement. Other commonly used pharmaceutical polymers such as Kollidon VA 64 (BASF, Florham Park, NJ), Eudragit L100-55,
and Eudragit E PO (Evonik, Parsiappany, NJ) have been shown to provide application for bioavailability enhancement.
With regard to selecting a processing technology for oral bioavailability enhancement, the literature shows that the technology
used contributes to the observed dissolution rate of a solid dispersion. Patterson et al., showed in a comparative study that
the distribution obtained by melt extrusion was more homogeneous than that obtained by spray drying, which exhibited some
drug rich regions within the matrix (16).
There are some perceived limitations to using melt extrusion, specifically with regard to elevated-temperature processing.
Although melt extrusion may not be an obvious choice for the production of extremely thermally-labile drug-substance solid
dispersions, it has shown significant utility with high melting point compounds. Literature reports have shown the ability
to process at temperatures almost 50 °C below drug substance melting points and still achieve amorphous material with a drug
loading of more than 30% (17). Additionally, the development of analytical technologies to characterize pharmaceutical polymer
stability has further improved control over the processing variables. By developing an understanding of processing variable
impact on polymer stability, one can more appropriately control the manufacturing process to ensure appropriate critical product
attributes. Through careful consideration of critical processing parameters during melt extrusion, it is possible to cover
a similar range of molecular properties while also yielding potential improvements in solid-dispersion attributes by reducing
the number of manufacturing phases.