Chemistry Reference
In-Depth Information
10.5.3 Maximizing Performance in the Finished Dosage Form
Converting a solid dispersion intermediate material into a
final dosage form is required
with the goal of maximizing the solubility enhancement potential of the dispersion from
the dosage form. In the case of a granular solid dispersion blended with other excipients,
the extragranular phase may perform critical dissolution functions similar to that of a
conventional immediate-release tablet or capsule. Considerations such as the ratio of
extragranular to granule components,
the selection and quantity of extragranular
disintegrant, lubricant, or other
flow aid are all part of identifying a tablet or capsule
finished dosage formulation.
Lakshman et al. investigated the oral bioavailability of a poorly soluble drug
dispersed in a PVP-based extrudate [29]. Extrudate was milled and screened to generate
a size-controlled granular form and then blended with poloxamer 188 surfactant with
microcrystalline cellulose (Avicel PH102) before
filling into hard gelatin capsules. The
amount of extragranular phase ranged from 38 to 48% w/w. Capsule formulations
containing solid dispersion blends produced a sevenfold increase in oral bioavailability
relative to a reference capsule of crystalline API with poloxamer 188. It was hypothe-
sized that the solubility advantage of the amorphous dispersion bene
ted from the
wetting properties of extragranular surfactant to produce enhanced oral bioavailability.
The dissolution bene
ts produced by the extragranular excipients may be speci
c to the
chemistry of the polymer used in the solid dispersion. For example, use of speci
c salts in
tablets containing carbamazepine
Soluplus solid dispersions were found to have dis-
integration and dissolution properties via rapid hydration and possibly effervescent
actions [30]. This approach was identi
-
ed to negate the gelling tendency of a hydrophilic
polymer used at high loading in a dosage form.
HME processing methods are emerging for pharmaceutical solid dispersions that
generate porous dispersions. Introduction of supercritical liquid into an extrudate is viable,
an approach that can modify the rheological properties of materials inside the extruder as
well as adjust the behavior of extrudate exiting the die as the supercritical phase converts
from liquid back to gas. Two groups report the supercritical CO
2
plasticizes model drug
-
polymer dispersions allowing lower processing temperatures and forming more porous
extrudate product [31,32]. Enhanced dissolution was reported in both systems.
10.6 SUMMARY
Hot melt extrusion is a frontline manufacturing solution for pharmaceutical amorphous
solid dispersions. The status of HME technology is validated by the presence of successful
commercial solid dispersion products, and is seeing widespread use in early-stage R&D
laboratories that are formulating poorly soluble compounds.
This chapter has described a number of important factors that justify HME
suitability for solid dispersion applications, ranging from materials performance and
quality, equipment performance and versatility, and the proven ability to generate robust
finished dosage forms that provide enhanced and controlled solubility behavior leading
to improved bioavailability.
