Table Ia: Characterization methods for four polymorphs and two dihydrates of carbamazepine.
Although carbamazepine has numerous polymorphs and solvates, it has four main polymorphs and two hydrates: Forms I–IV, and
Dihydrates I and II (36, 43, 44). Forms I–III are enantiotropic with respect to each other (34, 36). The stability of carbamazepine
is in the order of Form III, Form I, Form IV, Form II, based on the density rule, and the initial dissolution rate of carbamazepine
is in the order of Form III, Form I, Dihydrate III (38, 43). Cimetidine has four polymorphs and three monohydrates: Forms
A–D, and Monohydrates 1–3 (53). Forms A–D are monotropic (57). Although Forms A and D are virtually isoenergetic crystals,
the stability of Form D is slightly higher than that of Form A (58). The solubility of Form A is greater than that of Form
B, and Form C (54). Phenylbutazone has six polymorphs and six solvates: Forms α, β, γ, δ, ε, and ζ, and phenylbutazone 2:1
solvates with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, tetrachloromethane, and chloroform (62, 63, 65, 69). Forms
β and δ are monotropic. Forms α and β, and Forms α and δ are enantiotropic (66).
Materials and methods
Table Ib: Characterization methods for four polymorphs and three monohydrates of cimetidine.
APIs. Carbamazepine, white crystalline prismatic powders (C15H12N2O, MW: 236.67 g/mol, melting point (mp) = 191–192 °C, reagent grade, Lot: 036k1219) and cimetidine, white crystalline rodlike
powders (C10H16N6S, MW: 252.34 g/mol, mp = 141–143 °C, reagent grade, Lot: 088H1317) were purchased from Sigma-Aldrich (St. Louis, MO) and
used as received. Phenylbutazone, white crystalline needle-shaped powders (C19H20N2O2, MW: 308.38 g/mol, mp = 106–108 °C, 99+% purity, Lot: A0230775), was purchased from Acros Organics (Morris Plains, NJ) and
used as received. Use tests for carbamazepine and phenylbutazone were carried out by differential scanning calorimetry (DSC).
However, the use test for cimetidine was performed by Fourier transform infrared spectroscopy (FTIR) instead because DSC was
unable to clearly distinguish the polymorphs of cimetidine (57).
Table Ic: Characterization methods for six polymorphs and six solvates of phenylbutazone.
Solvents. Out of the 23 common solvents useful for scale-up, only the following 19 environmentally benign solvents were employed: n-heptane, xylene, p-xylene, ethyl acetate, toluene, methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), chloroform, tetrahydrofuran (THF), N,N-dimethylaniline (DMA), acetone, 1,4-dioxane, n-butyl alcohol, isopropyl alcohol (IPA), acetonitrile, N,N-dimethylformamide (DMF), ethanol, methanol, and water (28–30). Two other solvents, n-propanol and cyclohexane, were used to verify the solubility sphere in the three-dimensional (3-D) Hansen plot.