Chemistry Reference
In-Depth Information
amorphous phase should be dispersed in the glassy carrier as a function of domain size. A
critical success factor in the operation of a solid dispersion is its ability to induce and
maintain supersaturation [52]. In this respect, the glassy carrier should preferably serve
the dual role as a dispersant as well as a precipitation inhibitor [53]. High-throughput
assays can be incorporated into the early dispersion
finding protocols to aid in such
assessments. Glassy elements that may serve as precipitation inhibitors are considered by
assessing the effect of these materials on the tendency to generate and maintain
supersaturation. Thus, supersaturation can be induced by various methods as reviewed
by Bevernage et al. [54], including the use of the solvent-shift or cosolvent quench
method wherein the drug of interest is solubilized in a water-miscible organic solvent
such as DMSO, DMF, DMA, PEG, or propylene glycol [53,55]. This solution is then
added to a solution containing the excipient to be tested or to blank media and the ability
of the excipient to maintain supersaturation is assessed using UPLC/HPLC or nephe-
lometry. These systems are simple and can be automated using robotics and 96-well plate
technology and have the advantage of reducing the API budget as well as increasing the
accessible excipient space [56]. Other supersaturation approaches include the pH shift
approach where a base-solubilized acid or acid-solubilized base is pH adjusted such that
supersaturation ensues subsequent to the loss of solubilizing capacity of the solu-
tion [52,54]. This is often done for weak bases through the use of a two-phase or transfer
dissolution model where the test article is
first assessed at pH values associated with the
stomach and then at pH values associated with the proximal intestine. Finally, a
potentiometric method is available as incorporated in Sirius CheqSol
system [57
59].
In this system, compounds are characterized as either chasers (i.e., they form super-
saturated systems upon neutralization) or nonchasers (i.e., they do not supersaturate
under these conditions). The effect of excipients on precipitation kinetics can also be
assessed. Once ef
-
cient precipitation inhibitors are selected, their ability to act as a
carrier is judged by assessing cast
films [44]. In this screen, the drug and selected carrier
(s) are dissolved in a common solvent, dispensed to specially designed 96-well plate, and
the solvent is then removed. The resulting
films are assessed for homogeneity (via white
light and birefringence microscopy), crystallinity (through
p
XRD), and phase separation
(via RAMAN and IR imaging). The ability of these systems to generate a rapidly
dissolving, supersaturating system can then be assessed by adding dissolution media to
the 96-well plates (either in a traditional or two-phase protocol) and determining
concentration by the UPLC or by a UV plate reader. Importantly, cast
films may or
may not faithfully re
ect the properties of the ultimate dispersion depending on which
processing technique is eventually selected. To this point, downscaled processing
approaches are often applied to the excipient(s) selected to con
rm whether they are
likely to be useful. Downscaled equipment available for this purpose include those for
assessing spray drying (e.g., microspray drying and ProCepT), melt extrusion (minimelt
extrusion, Haake, and melt compression), milling/cryomilling, and supercritical
fluid-
based processing. These techniques also allow a better assessment of stability to be
garnered as well as downstream processability in addition to items such as allowing the
assessment of Gordon
62]. These downscaled assessments
can then be translated to prototype formulations that can be evaluated in appropriate test
animals and eventually in man.
-
Taylor/Fox behavior [60
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