Chemistry Reference
In-Depth Information
where
F
absorption
is the mass transport of free dissolved active pharmaceutical ingredient
(API) molecules across the intestinal membrane proportional to
P
, the permeability,
C
b,
the free concentration of drug in the unstirred water layer, and
SA, the surface area available for absorption [14].
In addition to drug concentration in solution and permeability, it can be seen that
gastrointestinal (GI) surface area is also important. Surface area in the humanGI is highest in
the small intestine (jejunum
duodenum) and permeability generally decreases as
a function of distance down the GI tract [14,15]. As a result, there is a need to keep as much
drug in solution in the upper GI tract as possible. Therefore, the transit time of the upper
GI tract (jejunum
>
ileum
>
1.5 h) in terms of desired time in solution before
precipitation and the pH-dependent solubility pro
2 h and ileum
∼
∼
le of the drug (jejunumpH
6.2
-
6.4 and
∼
ileum pH
7.4) become important considerations when designing formulations to
achieve optimal bioperformance. This is especially important for formulations designed to
drive absorption via supersaturation such as amorphous solid dispersions.
How does suboptimal solubility or dissolutionmanifest itself
in vivo
? Dissolution, in a
very general sense, becomes rate limiting when the amount of time required for dissolution
is longer than the window of time that the compound is available for absorption across the
relevant GI membranes. In this case, the drug either remains undissolved as it is transported
further down the GI tract or ultimately dissolves but in a region of the GI in which
absorption is poor. For many drugs (but not all) the absorption window will mainly be the
small intestine, and the small intestinal transit time is
6.6
-
∼
4 h in humans as mentioned
previously. Solubility-limited absorption, on the other hand, mainly occurs when the dose
is so high that the gut
3
-
∼
fluids are saturated with the drug(s) and therefore demonstrate a
less than proportional increase in AUC with dose [16]. Stated differently, the excess
compound in the GI that cannot be dissolved for lack of solubility remains undissolved and
is excreted with the feces, not entering systemic circulation.
Moreover, a number of additional processes such as chemical degradation in the GI
tract, active transport, substrate-speci
first pass metabolism can either
facilitate and/or limit systemic exposure. These important processes are beyond the scope
of this brief introduction, but the reader is encouraged to consult recent reviews on these
topics [16
cef
ux, and
18].
With these principles in mind, how do we make our solubility and dissolution studies
relevant for oral absorption? There are generally two types of experiments described in the
literature: dissolution testing as a quality control (QC) measure and/or as a bioperformance
test (QC dissolution experiments exist, but is not a focus of this chapter) [19]. Comprehen-
sive topics [20] and of
-
24] describe important dissolution studies that
are to be performed as quality control on dosage form batches to ensure consistency, limit
batch-to-batch variability, and ensure drug release on stability. These methods are typically
developed using USP (United States Pharmacopeia) apparatus 1 (basket) or 2 (paddle) and
are robust, well accepted, and therefore suited for routine quality control testing [11].
However, surfactants are often added to the buffer systems in nonphysiological amounts to
ensure dissolution of insoluble and/or poorly wetting drugs. The addition of surfactant in
cial guidelines [21
-
