Chemistry Reference
In-Depth Information
considered include melting point of the crystalline solid, glass transition temperature (
T
g
)
of the amorphous solid, solubility in organic solvents, stability and solubility over a
range of pH values, solubility parameters, and hydrogen bond acceptors and donors. In
the case of the polymer or surfactant utilized as the carrier for the ASD, physical
properties to be considered include molecular weight,
T
g
, solubility in organic solvents,
thermal stability, melt viscosity, and the ability to process the polymer by various
methods. The ability to utilize these important API and polymer properties combined
with the critical parameters for the process used for creating the amorphous solid
dispersion can guide a formulator to create a stable ASD.
2.4.1 Important Attributes
cant attribute of any physically stable
ASD is the miscibility of the drug in the carrier matrix [66]. The cohesive energy and the
solubility parameters are the key components to determine the extent to which a drug will
be miscible with the carrier matrix. The cohesive energy represents the total energy of all
intermolecular interactions including those arising from electrostatic and van der Waals
interactions and hydrogen bonding [67]. Typically, cohesive energy is referred to in
terms of the cohesive energy density, or the amount of energy required to vaporize a mole
of liquid per unit volume, and detailed discussions of the calculation of the cohesive
energy density have been previously published [67,68]. The solubility parameter is
de
2.4.1.1 Solubility Parameters
A signi
ned as the square root of the cohesive energy density [69]. More practically, the
solubility parameter is made up of three main factors: dispersion, polar, and hydrogen
bonding. Experimental methods for determining solubility factors include direct methods
such as measuring the solubility in solvents with known parameters using the heat of
vaporization through calorimetry [68] or indirect methods such as inverse gas chroma-
tography [70]. Despite a variety of methods to determine the solubility parameters of a
compound, the most common approach is to use group contribution theory. In this
method, each compound is broken into fragments with known parameters and the sum
of the parts gives the estimate of solubility parameters. Group contribution methods fail
to account for long-range interactions and compounds that have highly directional
interactions [71].
Despite limitations in solubility parameters, they are frequently utilized to predict
the miscibility of a drug in a carrier matrix [71,72a]. Although commonly used, there is
no clear-cut rule for how similar the solubility parameter for a drug and carrier matrix
needs to be to ensure full miscibility. Nevertheless, Greenhalgh et al. demonstrated for
ibuprofen with various polymers that full miscibility of the drug and carrier was observed
when the difference in solubility parameters between the two was less than
7MPa
0.5
[72b]. However, larger variations in the difference of carrier polymers should
not serve as an exclusion for assessing a speci
drug combination due to other
factors such as intermolecular forces that could stabilize the ASD.
c polymer
-
Amorphous solids and ASDs are
frequently characterized by their glass transition temperature (
T
g
), the temperature at
2.4.1.2 Glass Transition Temperature
