Chemistry Reference
In-Depth Information
rapid prototyping needs of modern drug candidate assessment that complicate both early
formulate ability and robustness [10]. The drug target dilemma is especially vexing and
can further diverge drug candidate properties from those required for a useful bio-
pharmaceutical pro
le [8]. The trend toward receptor modulator development is a useful
example with negative and positive allosteric modulators (NAMs and PAMs) attracting
attention. For a variety of classes of these modulators, the SAR does not tolerate basic
nitrogen in their structure removing one molecular tool for impacting drug solubility and
permeability. Taken in aggregate, this evolution in dosage form development challenges
has forced formulators to innovate with a variety of novel approaches promulgated in the
last few years [11
14]. Generally, these approaches are associated with either increasing
the chemical potential (
μ
) of the drug substance in the solid state through a change in the
drug form or reducing the
-
of the drug in its dissolved state. Technologies in the latter
category include the use of complexation as in the case of cyclodextrin-based formula-
tions [15
μ
-
19],
the use of cosolvent systems [20,21], and certain lipid-associated
strategies [22
25]. Altering the drug form can be executed through the use of different
salts, cocrystals, and less stable polymorphic forms or through the use of amorphous,
smectic, or nematic mesophases of the drug or drug candidate [26
-
30]. The selection of
an appropriate candidate formulation is generally tied to assessment of the active
pharmaceutical ingredient (API) aspects of its formulation as well as biopharmaceutical
factors. This entails assessing design space elements and drug ability information
associated with preformulation, dosage form, and screening evaluations in animals.
Brachau et al. suggested a three-part strategy in this context with step 1 associated with
deciding whether a conventional or enabling formulation strategy is needed, if enable-
ment is needed, which is the best strategy (step 2), and
-
finally what process or excipient
design space features should be considered for the selected trajectory (step 3) [31]. A
biopharmaceutical dimension is also added usually by an indirect assessment of the
in vivo
dissolution rate in the rat or dog (Figure 8.1) [32,33].
Figure 8.1.
Solution
-
suspension comparison in the rat and dog to assess
in vivo
dissolution rate
or solubility limitations.
