Chie-Shaan Su

Cooling sonocrystallization was investigated as a control strategy for cocrystallization, using the 2:1 cocrystal of the anticancer agent p-toluenesulfonamide with 4,4′-bipyridine as a structurally well-characterized model system. The influence of the sonication intensity and the probe diameter on the nucleation behavior, cocrystal recovery, particle size, and crystal habit was then examined. Ethanol was identified as the most suitable crystallization medium according to a preliminary solubility study. Each cooling run was then carried out by lowering the temperature linearly from 50 to 10 °C over 2 h. Compared with spontaneous nucleation at 22.8 °C, sonication raised the nucleation temperature to as high as 40.4 °C, indicating the efficient narrowing of the metastable zone width. In addition, applying sonication reduced the mean size of the recrystallized cocrystal from 168.2 μm under spontaneous nucleation to values as small as 68.6 μm. The nucleation temperature could therefore be raised by up to 17.6 °C, and the mean particle size could be tuned across the 68.6–87.7 μm range by adjusting the sonication intensity and the probe diameter alone. Powder X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry identified all sonocrystallized products as the 2:1 cocrystal. Ultrasound also changed the product from irregular rods to small rectangular prisms with a narrow size distribution. In dissolution tests, the sonocrystallized cocrystal released PTS considerably faster than a physical mixture of the two components.

Using CO ₂ hydrate formation and dissociation, CO ₂ -hydrate-based techniques have been developed for carbon capture, CO ₂ sequestration, gas separation, energy storage, desalination, and gas exchange for methane hydrate exploitation. Understanding the effect of additives is crucial for designing, developing, and simulating CO ₂ -hydrate-based processes. This study aims to investigate the effect of the additive cyclohexanone on the effective thermal conductivity (ETC) of the CO ₂ hydrate sample. A high-pressure apparatus and a needle probe were designed to generate CO ₂ hydrate in situ and simultaneously determine the ETC. The performance of the designed needle probe was first validated by measuring the thermal conductivity of an ASTM-recommended reference material, glycerol. Subsequently, the ETC of the CO ₂ hydrate sample was measured at different temperatures, pressures, and agitation speeds in the pure water system and compared accordingly. The measured ETC values for the pure water system ranged from 0.603 to 0.649 W m ⁻¹ K ⁻¹ . In contrast, adding cyclohexanone significantly decreased the measured ETC values, ranging from 0.419 to 0.338 W m ⁻¹ K ⁻¹ at additive concentrations of 1–10 mass%. By determining and comparing the induction times for systems with and without the additive, cyclohexanone was confirmed as an effective kinetic hydrate promoter for CO ₂ hydrate nucleation. The shorter induction time and faster nucleation rate accelerated the formation of hydrate nuclei. The random packing of CO ₂ hydrate crystals formed in a short period led to a loosely packed hydrate structure, resulting in a lower ETC in the system containing cyclohexanone.

This study developed a sonoseeding strategy for controlling the crystal size of acetaminophen during cooling crystallization by introducing sonication into a supersaturated solution, thereby inducing nucleation. Based on the synthetic route of acetaminophen, crystallization behavior in both water and acetic acid aqueous solutions was investigated, along with the influence of a structurally related additive, p-aminophenol, on nucleation. To establish the sonoseeding approach, the solubility of acetaminophen in water and an aqueous solution of acetic acid, with and without the additive, was measured over a temperature range of 10–70 °C using a titration method. In parallel, the nucleation temperatures and metastable zone widths of acetaminophen were systematically determined during cooling crystallization under varying operating conditions. Results demonstrate that sonication effectively induces nucleation and significantly narrows the metastable zone width, particularly in aqueous solutions of acetic acid. Guided by the determined solubility and nucleation behavior, sonoseeding crystallization experiments were conducted at various supersaturation levels, allowing for the efficient control of acetaminophen crystal size, which ranged from 27 μm to 95 μm, with narrower particle size distributions compared to spontaneous nucleation. Furthermore, the recrystallized acetaminophen was confirmed as Form I using PXRD, DSC, and FTIR analysis. This study demonstrates that the sonoseeding approach is an efficient method for controlling crystal size during the crystallization of active pharmaceutical ingredients.

Continuous crystallizations have promising potential for effectively controlling and modifying the crystal properties of active pharmaceutical ingredients (APIs). In this study, a continuous antisolvent sonocrystallization process was developed to recrystallize a poorly water-soluble API, mefenamic acid, for microparticle production. This method offers advantages such as efficient sonication, enhanced heat removal, and potential for scalability. The effects of operating parameters, such as sonication intensity, crystallization temperature, antisolvent flow rate, and solution flow rate, were investigated and compared. Using continuous antisolvent sonocrystallization, the particle size of mefenamic acid was controlled within the range of 2.6–3.5 μm, achieving a narrower particle size distribution compared to the unprocessed sample. In addition, scanning electron microscopy (SEM) analysis confirmed that the sonocrystallized mefenamic acid exhibited an improved crystal shape. Analytical results from powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) showed that the crystal structure, spectroscopic characteristics, and thermal behavior of mefenamic acid remained unchanged after the sonocrystallization process.