Crystal purity
Thermal analysis has been widely used as a method
of purity determination and the USP includes an
appendix describing the methods. This is particularly
pertinent at the preformulation stage, because early
samples of a new drug are inevitably 'dirty' while
improvements in synthetic route are made. Thermal
analysis is rapid and will discriminate 0.002 mole%
of impurity.
Solubility
The most important reason to determine melting
point during preformulation is crystalline solubility.
Such studies are particularly important because the
scarcity of available drug powder often precludes
accurate solubility determinations.
Melting point and solubility are related via the
latent heat of fusion, which is the amount of heat
generated during melting or fusion. A crystal with
weak bonds has a low melting point and low heat of
fusion. Conversely, a strong crystal lattice leads to a
high melting point and a high heat effusion. Because
solubility also requires the disruption of crystal
structure to allow molecular dispersion in the
solvent, it is also influenced by intermolecular forces.
Polymorphs differ in melting point and solubility.
The existence of different crystal arrangements for
the same compound inevitably leads to differences in
crystal lattice energy, as intermolecular distances will
be different in the alternative forms. This effect is
shown in Figure 8.5 for riboflavine.