Chemistry Reference
In-Depth Information
Freeze drying or lyophilization is another method that may be available in
laboratories [4,63]. Water is commonly used for this method, which poses problems
when dealing with poorly soluble compounds. Organic solvents for this method are
limited, so adequate solubility in appropriate solvents (such as dioxane,
t
-butanol,
pyridine, DMSO, or aqueous mixtures of these when applicable) is necessary and
modi
cations to the equipment to accommodate organic solvents are needed. Small
(milligram) and large (gram) quantities can be produced using this method. Using
manifold equipment, the number of samples is limited by the ports available on the
equipment. Using a tray dryer allows for a larger number of vials to be processed at the
same time. Determining the optimal conditions for the various stages of prefreezing,
primary drying, and secondary drying may be needed to produce amorphous material
during the screen.
Producing
films is commonly reported in the literature for small-scale dispersion
preparation. Different methods have been reported including
film casting [64] and spin
coating [24,65,66]. In
film casting, a solution containing the API and polymer is poured
onto a glass plate covered with a Te
film and the solution is left to dry at room
temperature. For spin coating, a similar procedure is used with the solution (1
on
-
3 drops or
l) being added to cover slip or chip and the sample being spun at high speeds
(such as 2000
200
μ
∼
20 s) to disperse the solution and
evaporate the solvent. Samples can be analyzed immediately after preparation.
Spray drying has also been used for screening studies [37,61,62]. A variety of
organic solvents (such as methanol, ethanol, toluene, hexane, acetone, ethyl acetate, and
dichloromethane) can be used, but the spray dryer has to be equipped with certain
features to make it compatible for use with these solvents. Mini spray dryers have been
reported to produce samples ranging from 1mg to 1 g [67], which would help to extend
the number of experiments in a screen. For typical laboratory-scale spray dryers, sample
sizes of 0.5 g to hundreds of grams can be produced. These spray dryers require larger
amounts of material than previous methods and the number of experiments may be limited
based on the amount of sample available. In addition to being used for larger scale
screening, spray dryingwith laboratory spray dryers is commonly used to scale-up a limited
number of dispersions for additional investigation, such as animal bioavailability studies.
Solvent-based screening methods cover a wide range of processing variables and
sample sizes. The choice of solvent is critical for many of these processes and quick
removal of solvent is usually a key parameter to produce amorphous instead of
crystalline material. A combination of techniques can be useful during a screen, for
example, using a 96-well plate for initial screening and then spray drying [61,62] or melt
extrusion [15] to produce larger amounts of lead dispersions.
-
8000 rpm) for short periods of time (3
-
Initial testing of the amorphous solid disper-
sion samples can cover physical testing (X-ray powder diffraction (XRPD), DSC,
miscibility, hygroscopicity, and solvent content) and/or properties (solubility, dissolu-
tion, physical/chemical stability, and bioavailability). The amount of testing will depend
on the amount of material available as well as the purpose of the screen and the desired
properties. This will vary from project to project, but an overview of approaches will be
presented here.
3.2.3.3 Initial Characterization
