Particle Size Control of Mefenamic Acid Using the Circulation-Type Sonocrystallization Process

The design and development of crystallization processes are crucial, particularly in the pharmaceutical industry, for efficiently controlling and modifying the solid-state properties of active pharmaceutical ingredients (APIs). In this study, circulation-type cooling and antisolvent sonocrystallization processes were developed to recrystallize a poorly water-soluble API, mefenamic acid, for particle size control. The circulation-type sonocrystallization method offers advantages such as an efficient sonication application, improved heat removal performance, and potential scalability. To identify suitable solvent candidates for crystallization, the solid solubility of mefenamic acid was determined in four organic solvents, methyl ethyl ketone, methanol, acetonitrile, and tetrahydrofuran, over a temperature range of 278–328 K. The effect of operating parameters in the circulation-type cooling and antisolvent sonocrystallization processes was investigated, compared, and discussed. By applying circulation-type sonocrystallization, the particle size of mefenamic acid was controlled within the range of 2–22 μm, achieving a narrower particle size distribution compared to the unprocessed sample. Furthermore, scanning electron microscopy analysis confirmed that sonocrystallized mefenamic acid exhibited improved crystal morphology. Analytical results from powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry demonstrated that the crystal structure, spectroscopic properties, and thermal behavior of mefenamic acid remained consistent before and after sonocrystallization.