Chemistry Reference
In-Depth Information
A number of physical tests can be performed on small amounts of material, as shown
in Table 3.1. XRPD can be used to determine if an amorphous material has been
produced and to help identify minor amounts of crystalline material that may be present.
This information will be important in assessing conditions to produce the amorphous
dispersion and changing parameters as needed to generate the desired amorphous
material. DSC and modulated DSC (mDSC) will identify the glass transition tempera-
ture. A higher glass transition temperature (such as greater than about 50
C above room
temperature) could result in improved physical stability. DSC will also help determine
miscibility; one
T
g
usually indicates a miscible dispersion, whereas two
T
g
events
indicate a nonmiscible system [20]. Small amounts of crystalline material can be detected
with DSC and crystallization exotherms will help determine thermal stability of the
various dispersions. The amount of water/solvent in the materials is important and can be
initially assessed with TGA to get a total volatile content. Other techniques such as Karl
Fisher, solution NMR, or gas chromatography will be needed to identify other solvents
present in the dispersion. Solvents will act as plasticizers to lower the
T
g
and cause
instability even at low levels; therefore, it is important to understand how solvent
contents will affect dispersion properties. Spectroscopy can be used to investigate
interactions between components and determine miscibility. It can also be used to
detect small amounts of crystalline material that may exist. Moisture sorption with an
automated system will establish water uptake at various RH conditions, which
can provide information on handling and storage. Crystallization is sometimes evident
in these curves, which can help rule out certain dispersions. Other characterization
techniques that can be used for screening and scale-up are given in Chapter 4.
Other properties of dispersions related to performance are also important to evaluate
during the screen and should be related to the properties required in the development plan
for the compound. Dispersions are commonly used to improve solubility and this
parameter is commonly measured as part of the screen. Miniaturized solubility mea-
surements are available that can be integrated into well plate screens [15,68,69]. Solution
stability, or the ability of the dispersion to be dispersed or dissolved in simulated GI
°
fluids
without crystallization, provides information on whether the material will stay solubi-
lized
in vivo
. For most systems, this will be attributed to the polymer used in the
dispersion and this type of information has been used to perform early screens in order to
select polymers [24] or can be performed after the preliminary screen as part of the
dispersion selection. These studies can be performed with relatively small amounts of
material, but amounts will depend on the analysis needed for the solid or solution.
Dissolution rate and physical/chemical stability can be compared for different disper-
sions, but additional material may be needed for these studies.
For many companies, the ultimate test in performance is bioavailability and
dispersions/formulations will be dosed to animals to assess blood levels and other
pharmacokinetic parameters. In early development, the dispersion is commonly com-
pared with the crystalline material to determine the advantage gained with the dispersion.
For late development compounds, the dispersion may be compared with marketed
products or other high-level formulations [21].
A combination of physical testing and property determination will be needed for
comparison and assessment of various amorphous solid dispersions. Not all properties
