Chemistry Reference
In-Depth Information
Chill rolls can be used to deliver cooling to particulates or intact ribbon quickly after
exiting the die. Examples of vendors providing this equipment are Thermo Electron,
Germany, and the CCR units from BBA Innova, Switzerland. The roller has active
cooling, which ensures that low surface temperature is maintained through repeated
surface contact with extrudate. This technology is standard for collection of ribbon
extrudate as the material can pass through subsequent rollers controlling torque and
thickness, and ultimately wound onto a collecting roll. A rapid cooling cycle delivered by
a chill roll may be advantageous for amorphous solid dispersions, delivering consistency
of the glassy state formed. Chill rolls can be perfectly combined with online connected
mills to grind the cooled extrudate immediately into a powder [13]. Calendering
equipment feeds heated extrudate ribbon through counterrotating rollers, each with
aligned cavities that produce molded tablets in-line [14]. This technology has been
commercialized for solid dispersion products Kaletra
and Norvir
[15].
When milling of cooled extrudate intermediate is needed, conventional granule
milling equipment can be used. Due to the physical properties of many extrudates,
excessive temperature increase during the milling operation must be avoided. This
precaution may be achieved by careful selection of equipment variables and feed rate,
otherwise milling equipment with chilling functionality may be required. Homogenous,
free-
owing granules are often generated from extruded drug
-
polymer dispersions that
are suited to
final blending and compression in a conventional tableting process.
10.4 PROCESS DESIGN AND CONTROL
Solid dispersion development using hot melt extrusion typically includes
in vitro
and/or
in vivo
assessment of early formulation prototypes before any process development has
occurred. Screening of early prototypes is common because demonstration of a solubility
or bioavailability increase will be a critical selection criterion for a solid dispersion. Once
a lead prototype is identi
ed, process development experiments are commonly initiated
in parallel to formulation optimization.
There are two main reasons why HME process development activities begin early in
a project life cycle. First, HME must generate multicomponent dispersions for which
both the physical and chemical phase homogeneities are extremely critical. The
“
phase
uniformity
quality attribute for HME may represent a tighter control requirement than,
for example, the
”
requirement for a dry powder blend used for direct
compression of a tablet. Second, the HME process has a large number of process
variables with a strong interrelationship with formulation variables. An example is a
thixotropic polymer for which dynamic viscosity at a certain process temperature will
vary depending on shear rate, which is in turn a function of screw design and rotation
speed. Adjustment of critical process variables may have a signi
“
blend uniformity
”
cant effect on the drug
delivery or stability properties of a solid dispersion prototype, possibly affecting the
decision to select an HME prototype or not.
The most important equipment settings are powder feed rate, temperature, and screw
speed (screw con
guration is not listed but can be considered as another equipment
variable). These equipment parameters are dependent variables, which together affect the
