Chemistry Reference
In-Depth Information
associated with the melt. Initial experiments can be performed with DSC, hot-stage
microscopy, and thermogravimetric analysis (TGA) to determine the melting point and
investigate weight loss and/or discoloration during melting. Samples can also be
analyzed with other methods, such as solution NMR or HPLC, to look for degradation.
The simplest thermal screening method is melt mixing, where a simple mixing
apparatus such as a stir bar or impeller is used with a heating source [57]. For these
experiments, an excipient, usually a low molecular weight polymer, is lique
ed at
elevated temperature and combined with the drug and, possibly, other components, such
as a surfactant. Viscosity limitations restrict this method to low molecular weight
polymers, and this can severely limit the number of polymers used in the screen.
Cooling conditions also need to favor producing a miscible dispersion containing
amorphous API rather than crystallization of the drug.
DSC has been used to evaluate API and polymer systems in a screen [58]. Pure API
and API:polymer blends are melted in a DSC pan using an appropriate ramp rate, such as
10 K/min, cooled rapidly (a liquid nitrogen cooling assembly is helpful), and then
rescanned to look for thermal events. Positive DSC results would show one glass
transition event and no melting endotherms for the components. Temperature informa-
tion obtained from this method can be applied to other methods at larger scale.
Melt compression can be used to produce about 100mg of dispersion [15]. Selected
formulation blends of API, polymer, and surfactant can be geometrically mixed in a
mortar and pestle and then melt compressed using a heated press to produce
films. A
typical force of 1500 lb and a dwell time of 30 s can be used while the appropriate
temperature is maintained (approximately 20
C above softening temperature of the
°
polymer). Speci
c conditions need to be determined using a placebo excipient mixture.
Gram quantities of dispersions have been made using a melt mixer [15]. The
components can be processed for 5
10min at a temperature previously determined from
DSC or other melt experiments. Ternary mixtures containing API, polymer, and
surfactant can also be produced using this method.
Small-scale melt extruders are also available and can be employed for screening
experiments if larger amounts of API are available at the screening stage. Often
laboratory melt extruders will be used to produce gram quantities of lead dispersions
for additional studies [15,58]. Temperatures and processing conditions will be based on
previous small-scale experiments. Conditions can also be determined at a larger scale on
the melt extruder if previous data are not available.
A combination of these methods is commonly used to produce different amounts of
material throughout the screening and selection process. For example, a combination of
DSC (5
-
-
10mg), stainless steel beakers and a hot plate (10 g), and small-scale extruder
(
find amorphous solid dispersions of indomethacin, lacidipine,
nifedipine, piroxicam, and tolbutamide with PVP [58]. Initial melting temperatures were
obtained from the DSC results and applied to the beaker and extrusion methods. A
second example involves initial evaluation using solvent casting with subsequent melt
compression, melt mixer, and melt extrusion methods used for screening and scale-up of
ternary amorphous solid dispersions using six polymers and eight surfactants [15].
Melt techniques offer a distinct advantage for poorly soluble compounds that do not
readily dissolve in organic solvents and because this is a
10 g) was used to
>
“
green
”
production method that
