Figure 7: Solubility curves of Form A phenylbutazone in 17 solvents.
The solubility curves of Form III carbamazepine in 13 single good solvents, Form A cimetidine in five single good solvents,
and Form A phenylbutazone in 17 single good solvents are shown in Figures 5, 6, and 7, respectively. The solubility of all
three APIs in different solvents increased with temperature. The enthalpy of dissolution (ΔHd) and the entropy of dissolution (ΔSd) of an API in a particular good solvent could be approximated from the slope and the y-intercept of a straight line, respectively, when the solubility curve of the API in that particular good solvent was replotted
in the form of the van 't Hoff equation (16).
Solids characterizations. All API solids generated from the saturated solutions of their corresponding good solvents by temperature cooling were isolated
and analyzed with optical microscopy, DSC, thermogravimetric analysis (TGA), and FTIR. Optical micrographs of carbamazepine,
cimetidine, and phenylbutazone solids are illustrated in Figures 8, 9, and 10, respectively. The crystal habits, the aspect
ratios, the polymorphism, and the crystallinity of carbamazepine, cimetidine, and phenylbutazone solids grown from the 13
good solvents are summarized in Table IV.
Most of the carbamazepine solids exhibited the typical DSC thermograms for Form III and Form I crystals, respectively. Unlike
Form III carbamazepine crystals, Form I crystals showed no transformation and only one sharp melting endotherm at 190 °C (17).
A carbamazepine acetone solvate produced in acetone agreed with this observation (18). The TGA scan (see Figure 11) further
showed that the carbamazepine acetone solvate had a 1:1 stoichiometric ratio and the DSC curve (see Figure 11) demonstrated
the removal of acetone from the solvate at 50–88 °C and a phase change of the material to Form I with a melting endotherm
at 190 °C (17, 19).
Table IV: Crystal habits, aspect ratios, polymorphism, and crystallinity of solids of carbamazepine, cimetidine, and phenylbutazone
generated from their corresponding good solvents.
In contrast with the previous observations that solvents with low dielectric constants yielded Form I crystals and those with
high dielectric constants yielded Form III crystals, the authors obtained Form I needles not only from solvents such as chloroform
and 1,4-dioxane with low dielectric constants, but also from acetonitrile with a high dielectric constant (see Figures 8c,
8g, and 8j) (1, 18, 20, 21). Form III prisms were also harvested from a solvent such as isopropyl alcohol with a low dielectric
constant when enough aging time was given for the transformation of Form I to Form III according to Ostwald's Rule of Stages
(see Figure 8i). The rest of the good solvents generated the thermodynamically stable Form III prisms (see Figures 8a, 8b,
8d, 8e, 8f, 8h, 8k, 8l, and 8m) (1, 20, 21). Isopropyl alcohol tended to give a mixture of needled and prismatic carbamazepine
solids (see Figure 8i). The interplay between thermodynamics and kinetics made concomitant crystallization possible (22).
The DSC curves of the physically isolated needles and prisms by a pair of tweezers were resolved to Form I (see Figure 1)
and Form III crystals, respectively.
Apparently, the needle or prism crystal habit of carbamazepine was affected only by polymorphism and not by microscopic properties
such as the Hansen parameters and the dielectric constants of the solvents. The dominant factor that influenced the crystallization
outcomes could have been the degree of supersaturation imposed by temperature cooling, which placed the crystallization under
either kinetic or thermodynamic control (22). This inference was supported by the feasibility of a one-solvent polymorph screen
of carbamazepine and the appearance of the metastable Form I carbamazepine from a high degree of supersaturation, either by
a sudden drop of the solubility through the introduction of an antisolvent or by cooling the system with a relatively steep
solubility curve such as chloroform and acetonitrile (see Figure 5) (11). The drive for structures that could be formed more
quickly than others might override the drive for settling with structures of the maximum decrease in energy. However, this
speed seldom affected the crystallinity, as was seen by the relatively high percent crystallinity of Form I carbamazepine
Figure 11: Differential scanning calorimetry and thermogravimetric analysis scans of 1:1 carbamazepine acetone solvate made