In Part 1 of this article, which appeared in the May 2009 issue of Pharmaceutical Technology, the authors described characterization methods for the functional properties and the process-dependent polymorphic flow charts
of the three soft pharmaceutical materials: carbamazepine, cimetidine, and phenylbutazone. This part presents several indispensable
processing properties (i.e., solubility, polymorphism, crystallinity, and crystal habit) of those three active pharmaceutical
ingredients. The underlying principles can be easily extended to other nonconventional sytems such as metal–organic framework
materials, infinite coordination polymer particles, and cocrystals.
Results and discussion
Figure 1: Differential scanning calorimetry scan of the carbamazepine. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Use tests. The differential scanning calorimetry (DSC) use-test scan of carbamazepine in Figure 1 exhibited the first endothermic peak
at 170–174 °C, which corresponded to the melting of Form III, followed immediately by an exothermic peak at 175 °C, which
corresponded to the crystallization of Form I, and a second endothermic peak at 193 °C, which corresponded to the melting
of Form I (1). The DSC use-test thermogram of phenylbutazone in Figure 2 displayed a single endothermic peak around 105 °C,
which corresponded to the melting of Form A (2). Thus, the polymorphisms of carbamazepine and phenylbutazone were Form III
and Form A, respectively, at room temperature. The use test for cimetidine was performed by Fourier transform infrared spectroscopy
(FTIR) because the melting points of the different forms of cimetidine are close to each other (3).
Figure 2: Differential scanning calorimetry scan of the phenylbutazone.
The FTIR spectrum in Figure 3 showed four significant infrared peaks for Form A cimetidine at 1204, 1156, 1077, and 954 cm-1 and two well-resolved characteristic peaks at 1243 and 1228 cm-1 (4–5). Therefore, the polymorphism of cimetidine at room temperature was Form A. The cimetidine molecule has three hydrogen-donor
centers (i.e., N1H, N10H, and N13H) and three hydrogen acceptor centers (i.e., N3, N12, and N17) (see Figure 4) (6). Two cimetidine
molecules formed a dimer unit in Form A with an eight-member ring through the hydrogen bonds between N10H of one molecule
and N12 of the other. The cimetidine molecule absorbed water at the N1H group (6). Cimetidine was weakly basic, and its reported
pKa values were 6.80 and 6.93. The imidazolium peaks were 1204 and 954 cm-1 (6). The peak at 1077 cm-1 was attributed to a CH deformation and a ring deformation (6, 7). The peak at 1156 cm-1 could either be a coupled ring and a CH bending mode or the deprotonation of the N1H group on the complexation with a water
molecule (6, 7). Two imidazole tautomers coexisted in the cimetidine structure: one with a hydrogen atom bound to the N1 atom
and the other with the hydrogen atom bound to the N3 atom (see Figure 4). However, only the N1-H form was present in the crystal
states of cimetidine and its monohydrates. In the solution, cimetidine also assumed two staggered (E, Z) configurations of the cyanoguanidine group (8).
Figure 3: Fourier transform infrared spectrum of the cimetidine.
Form spaces. To construct the form space for an active pharmaceutical ingredient (API), which contains the possible solvent combinations
for discovering a new polymorph, 19 common solvents for scale-up were first arranged vertically and horizontally in ascending
order of the solvent's Hildebrand value. This arrangement resulted in a 19 x 19 matrix of 361 boxes (see Tables I–III). Each
box represented a specific binary-solvent combination, except for the 19 boxes descending diagonally from the upper left corner
to the lower right corner. These 19 boxes represented the 19 pure solvent systems. The yellow boxes were the good solvents,
and the red boxes the bad solvents, with respect to a particular API. The yellow and red boxes were the material properties
of an API. Besides the red and yellow boxes, the gray boxes were also determined experimentally. They represented the immiscible
solvent pairs that were independent from the nature of an API. Once the locations of the red, yellow, and gray boxes were
fixed, the location of the green, blue, and white boxes representing the antisolvent system (i.e., a good solvent and a bad
solvent), the good cosolvent system (i.e., a good solvent and a good solvent), and the bad cosolvent system (i.e., a bad solvent
and a bad solvent), respectively, could be deduced graphically. Since the 19 x 19 matrix was symmetrical along the diagonal
boxes, the actual possible solvent combinations were reduced from 361 boxes to a total of 19 + (361 – 19) ÷ = 190 boxes or
fewer because it is normally impractical to perform experiments in the white-boxed areas.
The form space of carbamazepine had 13 yellow, 6 red, 69 green, 78 blue, 14 gray, and 10 white boxes (see Table I); the form
space of cimetidine had 5 yellow, 14 red, 66 green, 10 blue, 14 gray, and 81 white boxes (see Table II); and the form space
of phenylbutazone had 17 yellow, 2 red, 22 green, 135 blue, 14 gray, and 0 white boxes (see Table III). The actual form spaces
would have been significantly bigger if various solvent compositions of binary mixtures,temperatures, and ternary solvent
systems had been considered (9–11).