Chemistry Reference
In-Depth Information
frequently apolar and hydrophobic. Identifying and validating an alternative target,
meanwhile, can be both an uncertain and a resource- and time-intensive process. Hence,
when a discovery group identi
es an effective inhibitor of a valuable target, it is useful to try
to get that molecule into a state that will give it the desired exposure
in vivo
. For certain
compounds, amorphous dispersions are a possible option.
To date, only a handful of amorphous pharmaceutical dispersions have been brought
to market (Table 11.1 [5]). The pace of new releases has increased in recent years.
However, amorphous dispersions pose certain risks and demand certain considerations
that crystalline drugs do not. They are not broadly used in commercial products, mainly
because there is the possibility that during processing (mechanical stress) or storage
(temperature and humidity stress) the amorphous state may undergo crystallization [6-9].
The effect of moisture on the storage stability of amorphous pharmaceuticals is also a
signi
cant concern, because it may increase drug mobility and promote crystalliza-
tion [8,10]. Moreover, most of the polymers used in solid dispersions can absorb
moisture, which may result in phase separation, crystal growth, or conversion from the
amorphous to the crystalline state or from a metastable crystalline form to a more stable
form during storage. This may result in decreased dissolution rate and solubility [6,11].
Therefore, exploitation of the full potential of solid dispersions requires their stabiliza-
tion in solid state as well as during
in vivo
performance and a sound scienti
c under-
standing of scale-up for de
ning a robust manufacturing process. As these materials
become more common in pharmaceutical development organizations
—
and pharmacy
shelves
it is important that our collective knowledge keeps pace with our activity.
Being thoroughly informed, while adopting a rigorous technical approach allowed by the
state of the art, will solidify this knowledge and may mitigate these risks.
This chapter examines the development of clinical and commercial formulations of
amorphous dispersions. We consider
—
rst, in this introduction, the various means available to
render a crystalline drug amorphous in the
first place. Next we consider the downstream
rami
cations of each technique, such as on the dosage forms available, and special processing
and handling. In Section 11.2, we give the high-level strategic picture of amorphous
formulation development, a process that best
fits the framework of quality by design
(QbD) advocated for by the FDA. Finally, in Section 11.3, we turn to a detailed case study
of the
rst (of two) amorphous dispersion-based drugs we developed and commercialized in-
the hepatitis C protease inhibitor VX-950 or telaprevir (Incivek
). In this case study,
we focus,
house
—
ning
parameters, developing the design space, modeling, and applying the QbD framework to
manufacture. Next we turn to the analytical methods used to discriminate dispersion
attributes and tablet properties that could affect performance of the product in the clinic.
Finally, we turn to a scienti
first, on developing a drug product manufacturing process, including de
c understanding of product stability, as it is used to de
ne
speci
cations for the raw materials, the
finished product, and the product
'
s packaging.
Throughout, we remain continually mindful
that we are describing a QbD
approach
—
one that uses statistical models and process controls to in
uence technical
decision making, always mindful of upstream in
final products. While
moving forward with an amorphous dispersion with a limited scienti
uences on
c or technical
understanding
is
risky, we emphasize (and, we hope, demonstrate) that with a rigorous
