The cimetidine solids showed the two typical FTIR spectra in Figure 3 and Figure 13 as Form A and Form B crystals. The FTIR
spectrum in Figure 13 displayed the six characteristic infrared peaks for Form B cimetidine at 1375, 1230, 1192, 1184, 1176,
and 1066 cm-1 (4, 23). The thermodynamically Form A cimetidine was formed in Class 1 solvents such as n-butyl alcohol and in isopropyl alcohol as rods (see Figures 9a and 9b) (3). Isopropyl alcohol yielded Form A cimetidine (3).
However, the steep slope for the solubility curves of Form A cimetidine in solvents of Classes 1 and 2 such as N,N-dimethylformamide, methanol, and ethanol produced metastable Form B cimetidine needled crystals (see Figures 9c, 9d, and
9e) without the need of adding and seeding crystals because of the high degree of supersaturation created by temperature cooling
(see Figure 6) (3). Apparently, the crystal habits for Forms A and B cimetidine depended on the solvents and the polymorphs,
Figure 12: Differential scanning calorimetry thermogram of Form I carbamazepine crystals grown from chloroform.
Almost all of the phenylbutazone solids exhibited the typical DSC scan in Figure 2 for Form A long-needled crystals (see Figures
10a–k and 10m–q). However, the phenylbutazone solids grown from n-butyl alcohol could be a newly discovered Form F (see Figure 10l) because its DSC thermogram in Figure 14 showed two endothermic
peaks at 85 and 103 °C, and its TGA scan showed no weight loss at 85 °C. Therefore, the first and second endothermic peaks
corresponded to the heat of transformation from Form F to Form A and the melting of Form A, respectively. Despite the many
forms of phenylbutazone, phenylbutazone revealed only the ketoform in all polymorphs (24). Furthermore, two solvates were
produced. Rather than a phenylbutazone solvate to tetrahydrofuran ratio of 2:1, a ratio of 3:1 (see Figure 10h) was obtained
when the isolated solids crystallized from tetrahydrofuran were oven dried at 40 °C for 9 h instead of the crystal surface
being blotted with filter paper (15). DSC and TGA thermograms in Figure 15 showed the desolvation endotherm from 70 to 90
°C and the sharp melting of Form A phenylbutazone at 103 °C under a heating rate of 8 °C/min. However, the stoichiometric
ratio of 2:1 of phenylbutazone solvate with 1,4-dioxane (see Figure 10k) oven dried at 40 °C for 9 h remained the same as
that prepared by blotting the crystal surface with filter paper (15). DSC and TGA thermograms in Figure 16 illustrate the
desolvation endotherm from 80 to 84 °C and the sharp melting of Form A phenylbutazone at 103 °C under a heating rate of 8
Figure 13: Fourier transform infrared spectrum of Form B cimetidine produced from methanol.
Obviously, given the moderate slope of the solubility curve of phenylbutazone Form A in n-butyl alcohol, the degree of supersaturation could not explain the production of Form F in n-butyl alcohol. Since the b-axis of phenylbutazone is > 5.1 Å, it belongs to the a-type structure (24). The molecule is stabilized more uniformly by
a larger number of near neighbors (24). The molecular coordination is between 6 and 10. The C-H···O interaction, especially
in the n-butyl side chain of phenylbutazone, plays an important role in stabilizing the crystal packing in addition to the stacking
of the benzene rings (24). The authors hypothesized that the similar molecular structures of n-butyl alcohol and the n-butyl side chain of phenylbutazone and the interference of the hydroxyl group of n-butyl alcohol with the C-H···O interaction might have induced the formation of a thermodynamically metastable Form F nucleus
and perturbed the crystal lattice order, as reflected by the low crystallinity of 61%. Since needle-shaped crystals were obtained
from all good solvents, it seemed that solvents did not play a dominant role in the induction of the habits characteristic
of the crystals, but rather the processing conditions and the polymorphism did (24).
Figure 14: Differential scanning calorimetry thermogram of Form F phenylbutazone grown from n-butyl alcohol.
The form space constructed from the common organic solvents by initial solvent screening provided information not only about
materials properties such as solubility curves, solubility spheres, crystallinity, crystal habits, and a possible solvent
combination for discovering a new polymorph, but also about a systematic way of finding the ideal combination of a good solvent,
an antisolvent, and a bridging liquid for solvent-based processes in a miniaturized scale. Initial screening by common laboratory
tools could be easily integrated by automation and be applied to other compounds as well.
Figure 15: Differential scanning calorimetry and thermogravimetric-analysis scans of 3:1 phenylbutazone tetrahydrofuran solvate.
This work was supported by a grant from the National Science Council of Taiwan, R.O.C. (NSC 95-2113-M-008-012-MY2). Suggestions
about DSC from Jui-Mei Huang, assistant at National Central University's Precision Instrument Center, and about scanning electron
microscopy from Ching-Tien Lin, assistant at National Central University's Precision Instrument Center, are gratefully acknowledged.
Figure 16: Differential scanning calorimetry and thermogravimetric-analysis scans of 2:1 phenylbutazone 1,4-dioxane solvate.
Tu Lee* is an associate professor in the Department of Chemical and Materials Engineering and the Institute of Materials Science
and Engineering, Yan Chan Su and Hung Ju Hou are graduate students at the Department of Chemical and Materials Engineering, and Hsiang Yu Hsieh is a graduate student at the Institute of Materials Science and Engineering, all at National Central University, 300 Jhong-Da
Rd., Jhong-Li City 320, Taiwan, ROC, tel. +886 3 422 7151 ext. 34204, fax 886 3 425 2296, firstname.lastname@example.org
*To whom all correspondence should be addressed.
Submitted: July 8, 2008. Accepted: Sept. 15, 2008.
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