Chemistry Reference
In-Depth Information
The theoretical solubility advantage that can be attained for amorphous materials has
already been discussed in Section 6.2 and has recently been the subject of a literature
report [54]. Importantly, one major issue entailed in determining amorphous solubility is
the inherent tendency of these materials to crystallize and hence the actual measured
solubility may not reach the maximum attainable amorphous solubility [85]. One
additional caveat for amorphous dispersions is the impact of the carrier or polymer.
As reviewed in Sections 6.2 and 6.3, polymers are frequently added to amorphous
materials to create amorphous solid dispersions. The polymer, if selected appropriately,
can stabilize the amorphous material, delay the conversion to crystalline drug form in the
solid state, and prolong the supersaturated state in an aqueous environment. The polymer
can and will however impact the solubility experiment, and as discussed in detail in
Section 6.4, it will in
uence the particle engineering and therefore the interaction of the
medium with the amorphous material [85]. Given this complexity, what is then the best
and recommended way to measure solubility of amorphous material and dispersions? In
the context of this chapter, which takes a late-discovery/early-development view, the
main objective of solubility experiments is to attain IVIVR (as discussed in Sections 6.1
and 6.4) and therefore the biorelevance of the measurement. The recommendation is
therefore to consider the maximum value of a biorelevant dissolution curve (solubility
value and time) in the context of the transit time through the small intestine of the species
targeted for bioperformance. This recommendation is in line with recent publications and
reviews [38,85,87].
This leaves the question: How to conduct a dissolution experiment for an amorphous
dispersion? The steps involved have been discussed in Sections 6.1 and 6.4 and recently
reviewed [38,85,87]. A
flowchart for the suggested steps is presented in Figure 6.6. The
authors recommend starting with the end in mind; in other words, the desired outcome.
Figure 6.6 outlines three main outcomes for dissolution studies: (i) early characterization
of discovery batches for dispersion optimization, (ii) early development studies feeding
into IVIVR or maybe even IVIVC considerations, and (iii) studies aimed at quality
control aspects of formulations, such as batch-to-batch variability. The latter dissolution
studies have not been the focus of this chapter and the reader is encouraged to read
FDA and ICH guidelines for more details on this important area of dissolution study
design [21
24].
In terms of determining the study objective (the next step in Figure 6.6), which is the
desired outcome best served by a (i) solubility study, (ii) biorelevant dissolution study, or
(iii) QC dissolution study? Focusing on the former two and since solubility of an
amorphous dispersion is best determined by the maximum concentration on the
dissolution curve, these studies may be conducted in an identical fashion and information
collected to conclude on both aspects. However, the experimental design could be
different according to the stage of discovery or development. The discovery or
development stage usually dictates the availability of resources and material. As recently
reviewed, biorelevant dissolution and solubility experiments may be conducted at small
scale in plates, tubes, and beakers rather than large-scale traditional dissolution equip-
ment to save time and material [85,87].
The next step is selection of the appropriate testing equipment. As already
mentioned, a variety of plates, tubs, and vessels may be used for early-development
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