Chemistry Reference
In-Depth Information
investigations, early GMP manufacture, and
first-in-human (FIH) clinical studies.
These efforts focus, in part, on assessing the potential for future solid dosage forms.
The balance of the work assesses stability both
in vivo
and on storage (in the course of
manufacture and on the shelf). We conclude the chapter with a brief summary.
7.2 TRANSLATIONAL DEVELOPMENT AT THE DISCOVERY STAGE
For our organization, laboratory studies of a new candidate drug begin during late
pharmacology, before dose range-
nding (DRF) studies are conducted. By the time a
compound moves forward into development
—
a shift marked by GLP toxicology studies
and, subsequently, a FIH trial
development scientists are responsible for delivering one
physical product: a suspension formulation that will be serviceable for initial animal and
human dosing. This is fairly typical for preformulation groups, and their equivalents,
across a number of pharmaceutical companies. Under a TDD or Development 3.0
paradigm, however,
—
the same group is responsible for a number of scienti
cor
intellectual deliverables as well
results aimed at elucidating mission-critical informa-
tion about a new compound as early as possible and guiding discovery stage decision
making. In addition, when the drug substance in question takes the form of an amorphous
dispersion, this group has the further task of developing the process to produce the
dispersion at laboratory scale, characterizing the resulting dispersion, and ensuring that it
remains amorphous during preparation and suspension dosing. Our procedures for all of
these tasks are described in this section in roughly chronological order.
—
7.2.1 Absorption Modeling
The
first studies undertaken by development scientists concern the absorption of an
API across the intestinal wall, through the hepatic portal vein to the liver, and
ultimately into the systemic circulation. As the Biopharmaceutical Classi
cation
System re
ects, absorption is driven by both permeability (of the intestinal wall to
a given API) and solubility (of the API in the aqueous media of the stomach and
intestine). Relatively higher permeability may make up for relatively lower solubility;
the reverse is also true. However, these properties differ in one crucial respect.
Solubility can be increased in the laboratory by rendering a compound in a thermo-
dynamically higher energy state
either a higher energy crystalline polymorph or, as
here, an amorphous dispersion. Permeability, however, is dif
—
cult to change for a
given compound: it is dependent on structure and is only an issue once the molecule is
already in solution. This is not to say that permeability is static: a compound
'
s
“
a parameter that takes into account the effect of cellular
transporters as well as passive uptake mechanisms, may vary along the length of the
gastrointestinal
effective permeability,
”
is solubility is within the
capacities of development scientists to change, permeability is not. For this reason,
it is important to understand, as early in discovery as possible, both what a compound
tract. Nonetheless, while a compound
'
s
absorption is likely to be and how much of that absorption depends on solubility, as
opposed to permeability.
'
