The high-shear wet granulation process is one of

the more traditional and commonly used granulation

processes in design and development of a solid
oral drug product. It is used to achieve the desired
bulk density, flow, and compaction properties of the
formulation.1 It also helps minimize segregation and
offers better content uniformity.2 In certain instances it
can also be used to improve the bioavailability of a
formulation by providing intimate contact between
a poorly water-soluble drug and a surfactant, and
was shown to mitigate food effect.3,4 Another known
benefit of the wet granulation process is the robustness
of the process to handle changes in active
pharmaceutical ingredient (API) powder properties. This
can be
important during the early stages of drug product
development where the API manufacturing process
undergoes optimization and scale-up, thus producing
materials with some variations in powder properties.
Other manufacturing processes, such as direct
compression and dry granulation, usually experience a
more significant impact of any changes to API powder
properties.5,6 Direct compression has the advantage of
short manufacturing time, but requires formulation
with adequate density, flow, and compaction properties.
These criteria are not commonly met for high drug
loading formulations. On the other hand, low drug
loading formulations may present a high risk of blend
segregation and poor content uniformity when using
a direct compression process. There are also some
significant challenges with dry granulation (using roller
compaction), such as flow into the roller compactor
(especially at high drug loading), sticking to the rolls,
and loss of compaction after passing through the
rolls,7,8 all of which are not present for the high-shear
wet granulation process. Wet granulation is the
preferred manufacturing method for formulations with
high drug loading. However, the use of water and/or
high degree of shear during wet granulation offer a
different set of challenges for APIs that are sensitive
to water and shear and can undergo transformation
(eg, form conversion) that may lead to a worse drug
product stability profile.914 The wet granulation
process also requires an additional unit operation of
drying. There are other variants of wet granulation
process that may be used as alternatives to the high-
shear
process, such as low-shear, fluid bed, and twin-screw
granulation based on the specific formulation and process
challenges of the drug product. For APIs sensitive
to shear, a low-shear process may be preferrable.15
Fluid bed granulation has the advantage of providing
short exposure of the granulation to the water compared
with high-shear granulation. It imparts less shear
and densification of the granulation and results in
more porous granules that can have a higher dissolution
rate and better compaction properties. A choice
between these manufacturing processes can be made
by manufacturing process risk assessments based
on prior drug product formulation knowledge, such as
sensitivity to moisture, shear, and/or temperature.
A typical high-shear wet granulation formulation
consists of API, filler (eg, microcrystalline cellulose
and/or lactose), disintegrant (eg, superdisintegrants
such as croscarmellose sodium), binder (eg,
polyvinylpyrrolidone (PVP), hydroxypropyl cellulose
(HPC)),
and lubricant (eg, magnesium stearate). In some
cases it may also contain a surfactant (eg, sodium