Chemistry Reference
In-Depth Information
not be thorough because many samples are being screened and the characterization tools
used are not yet optimized.
Another example of a well-integrated HME feasibility study reports polymer
screening experiments for two active ingredients: indomethacin and lacidipine [20].
The authors successfully used solubility parameters to predict miscible mixtures in
different molecular weight PEG and PVP polymers, plus copovidone. The detection of a
single
T
g
measured by DSC was described as an important criterion for selecting miscible
mixtures, and these mixtures were successfully prepared as amorphous dispersions by
HME. While Forster et al. [20] show a single
T
g
may be a good predictor of amorphous
state miscibility, some drug and polymer systems are harder to characterize by DSC due
to complex phase behavior and complex thermal properties. Screening for a single
T
g
should not be a prerequisite for investigating the feasibility of an amorphous dispersion
by HME.
The screening experiments and feasibility criteria must be designed around the
nature of the dispersion formers under investigation. An example is a study investigating
dispersion formation of drug in cyclodextrin using HME [21]. Solution-phase solubility
experiments were
rm that the drug, ketoprofen, was capable of
molecular interaction with the cyclodextrins. These experiments were followed by
extrusion of 1:1 (w:w) blends of drug:cyclodextrin that yielded solid phase with reduced
drug crystallinity. The process conditions were in the region of drug melting temperature
to enable excipient dispersion in the molten drug phase. The degree of molecular
interaction between drug and cyclodextrin was greater for HME-prepared dispersions
relative to freeze-drying or cogrinding methods.
Formulation screening will typically include
in vivo
assessment, partly because the
poor solubility of the API means that
in vitro
dissolution data have limited value. The
in vivo
assessment is also important because changes in absorption have been reported
for amorphous dispersions. For example, the polymer Soluplus was shown to increase
permeability of poorly soluble drugs in a Caco-2 model, an effect thought to contribute to
the increased bioavailability seen in a dog model [22]. Understanding how different
carrier molecules may interact with drugs in dispersed form and how the carrier
molecules may affect factors other than solubility
in vivo
is essential when comparing
and selecting prototypes at the feasibility stage of development.
first performed to con
10.5.2 HME Formulation Optimization
It is common for initial HME formulation feasibility work to focus on binary mixtures
of drug/polymer. One bene
t of this approach is that a direct assessment of the
supersaturation provided by an amorphous dispersion can be measured. It is recom-
mended that formulation optimization experiments be performed with the goal of
enhancing the dissolution properties of the dispersion so that the solubility and
dissolution advantage of the system is maximized. Examples of the mechanism for
such enhancement include improving the wetting and disintegration of the dispersion,
as well as prolonging the length of time a supersaturated solution of active is
maintained.
