Materials and methods

APIs. Carbamazepine (C₁₅H₁₂N₂O), white, crystalline, and prismatic powders, molecular weight (mw) of 236.67 g/mol, melting point (mp) of 191–192 °C, reagent grade, Lot 036k1219, and cimetidine (C₁₀H₁₆N₆S), white crystalline rod-like powders, mw of 252.34 g/mol, mp of 141–143 °C, reagent grade, Lot 088H1317 were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Phenylbutazone (C₁₉H₂₀N₂O₂), white, crystalline, and needle-shaped powders, mw of 308.38 g/mol, mp of 106–108 °C, purity of 99+ %, Lot A0230775 was purchased from Acros Organics (Morris Plains, NJ) and used as received. Identification tests for carbamazepine and phenylbutazone were carried out by DSC. The use test for cimetidine was performed by FTIR instead of DSC because DSC was unable to distinguish the polymorphs of cimetidine clearly (39).

Solvents. The following sovlents were obtained from Tedia (Fairfield, OH): acetone (CH₃COCH₃), high-performance liquid chromatographical/spectrometrical (HPLC/spectro) grade with purity of 99.5%, boiling point (bp) of 56 °C, mw of 58.08 g/mole, Lot 411050; n-butyl alcohol (CH₃ (CH₂)₃OH), American Chemical Society (ACS) grade with purity of 99.4%, bp of 117.7 °C, mw of 74.12 g/mole, Lot 205027; N,N-dimethylformamide (HCON(CH₃)₂), ACS grade with purity of 99.8%, bp of 153 °C, mw of 73.10 g/mole, Lot 020505; n-heptane (CH₃ (CH₂)₅CH₃), HPLC/spectro grade with purity of 99.4%, bp of 98 °C, mw of 100.21 g/mole, Lot HS-1712 ; isopropyl alcohol ((CH₃)₂CHOH), HPLC/spectro grade with purity of 99.8%, bp of 82.4 °C, mw of 60.1 g/mole, Lot 503027; methanol (CH₃OH), HPLC/spectro grade with purity of 99.9%, bp of 64.7 °C, mw of 32.04 g/mole, Lot 411070; methyl ethyl ketone (C₂H₅COCH₃), ACS grade with purity of 99.6%, bp of 81.6 °C, mw of 72.11 g/mole, Lot 201021; methyl tert-butyl ether ((CH₃)₃COCH₃), certified grade with purity of 99.9%, bp of 55.2 °C, mw of 88.15 g/mole, Lot 712032; tetrahydrofuran (C₄H₈O), HPLC/spectro grade with purity of 99%, bp of 65–67 °C, mw of 72.11 g/mole, Lot 411013; and xylene (C₆H₄ (CH₃)₂), ACS grade with purity of 98.5%, bp of 137–144 °C, mw of 106.17 g/mole, Lot 305065.

Initial solvent screening. Under the initial solvent screening, the 19 solvents specified in the solvents section were chosen. The working procedures followed closely the details described in References 27–30. As previously defined, a good solvent was a solvent that gave solubility of ≥ 5 mg/mL at 25 °C. A bad solvent, or antisolvent, was a solvent that gave solubility of < 5 mg/mL at 25 °C). The form space was constructed in a framework of 19 X 19 solvent matrix (27–30).

Solvent-miscibility studies. The working logics followed the procedures laid out in References 27–30.

Spherical agglomeration . Good solvents, antisolvents, and bridging liquids were chosen according to the form space of each API. For carbamazepine and phenylbutazone, approximately 30 mg of API were dissolved in 2 mL of a good solvent in a 20-mL scintillation vial. For cimetidine, 2 mL of saturated solution were prepared using a good solvent. Then, 10 mL of an antisolvent were added to all API solutions under a standardized agitation of 200 rpm by an orbital shaker (Model OS-701, TDK , Taipei). The 5:1 volume ratio of the antisolvent to the good solvent was based on a specified cystallization method (11). Crystallization only took place in some of the solution systems.

Two hours after the first appearance of solids, the solids were filtered, oven-dried under a mild condition at 40 °C overnight, and characterized for their purity, polymorphism, solvates, and crystallinity by DSC, thermal gravimetric analysis (TGA), and FTIR.