Next, 0.02-mL portions of a bridging liquid were added in the remaining slurry every once in a while by a micropipette until all suspended crystals were transformed into agglomerates by sight. The amount of the bridging liquid used should be kept at minimum without causing any dissolution of the primary crystals or exceeding 80% volume (i.e., 16 mL in total solution volume) of the scintillation vial. All trials were performed at room temperature, and all agglomerates were filtered, oven-dried under mild conditions of 40 °C overnight, and characterized. For carbamazepine spherical agglomerates, oven-drying at 100 °C for 4 h was performed before any further characterization. For the solution systems that gave rise to spherical agglomerates, experiments were repeated again without the addition of any bridging liquid to produce primary crystals that were filtered, oven-dried at 40 °C overnight, and characterized for their polymorphism by either DSC or FTIR.

DSC. Thermal analytical data of 3 to 5 mg of solids placed in perforated-aluminum-sealed 60-µL pans were collected on a calorimeter (Perkin Elmer DSC-7, Perkin Elmer, Waltham, MA), with the following temperature scanning rates: 10 °C/min from 50 to 200 °C for carbamazepine; 5 °C /min from 50 to 170 °C for cimetidine (mainly for the crystallinity measurements); and 8 °C/min from 50 to 130 °C for phenylbutazone using nitrogen with purity of 99.990 % as a blanket gas (32, 33, 35, 39, 41). The temperature axis was calibrated with indium with purity of 99.999% (Perkin Elmer) with a melting onset at 156.6 °C.

TGA. Sample-weight loss as a function of temperature was monitored by a thermogravimetric analyzer (TGA 7, Perkin Elmer). The heating rate was 10 °C/min from 50 to 200 °C, 5 °C/min from 50 to 170 °C and 8 °C/min from 50 to 130 °C for carbamazepine, cimetidine, and phenylbutazone, respectively (32, 33, 39, 41). Weight loss was usually associated with either solvent evaporation close to the boiling point of a solvent, as in the case of solvates, or sample decomposition. The open platinum pan and stirrup were rinsed by ethanol and burned by a spirit lamp to remove all impurities. All samples were heated under nitrogen atmosphere to avoid oxidization. About 3 mg of sample were placed on the open platinum pan suspending in a heating furnace.

Digital camera. A digital still camera (DSC-T7 Cyber-shot, Sony, Tokyo) was used to take photographs of millimeter-sized spherical agglomerates before and after the friability test. The number of spherical agglomerates and their individual diameters were measured based on the image analysis.

Angle of repose. Because of the small amount of spherical agglomerates produced, the angle of repose was measured with the oven-dried spherical agglomerates inside the 20-mL scintillation vial. The vial was mounted on a lever that had one end pivoted to the benchtop and was originally laid flat on the benchtop surface. The vial was tilted by raising the other end of the lever gradually. The angle made between the lever and the benchtop surface at which the spherical agglomerates inside the vial began to flow was the angle of repose. Each angle measurement was repeated at least 10 times with a protractor.

Friability. Spherical agglomerates harvested from each trial were placed in a 20-mL scintillation vial that was subjected to a rotating speed of 50 rpm on a ball-milling machine (MUBM-236-RTD, Shin Kwan Machinery, Taipei) for 30 min. Photographs of spherical agglomerates before and after this friability test were taken. Image analysis was performed to calculate the friability index.

SEM. An SEM (Hitachi S-3500N, Hitachi Ltd., Tokyo) was used to observe the internal morphology of spherical agglomerates that were cross-sectioned by a razor blade. Because the cutting was done by hand, it might have crushed the agglomerates. To avoid imaging the artifacts, the cross-sectioned area was blown with compressed air to remove surface debris. Both secondary electron imaging and backscattered electron imaging were used for the SEM detector, and the magnification was 15- to 300,000-fold. The operating pressure was 10^-5 Pa vacuum, and the voltage was 15.0 kV. All samples were mounted on a carbon conductive tape (Prod. No. 16073, TED Pella, Redding, CA) and sputter-coated with gold (Hitachi E-1010 Ion Spotter) with a thickness of about 6 nm. The discharge current used was about 0 to 30 mA, and the vacuum was around 10 Pa.

Tu Lee* is an associate professor, and Yan Chan Su and Hung Ju Hou were graduate students in the Department of Chemical and Materials Engineering, and Hsiang Yu Hsieh was 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, tulee@cc.ncu.edu.tw
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*To whom all correspondence should be addressed.

Submitted: Feb. 2, 2009; Accepted May 20, 2009.