Particle Size and Crystal Habit Modification of Active Pharmaceutical Ingredient Using Cooling Sonocrystallization: A Case Study of Probenecid

Abstract

This study uses a cooling sonocrystallization process to recrystallize an active pharmaceutical ingredient, probenecid, and to improve the crystal qualities such as crystal habit and particle size characteristics. To screen the appropriate solvent system, solubility data of probenecid in organic solvent are measured, reported, and correlated by van't Hoff equation. According to the measured solubilities and data acquired from literature, sonocrystallization experiments using solvents with acceptable theoretical recovery are performed. Owing to the satisfactory throughput, yield, and crystal qualities, ethanol is finally decided as the appropriate solvent system. The effect of operating parameters in sonocrystallization including the solution concentration, sonication intensity, sonication duration, and cooling rate using ethanol as the solvent is further studied. With applying power ultrasound, probenecid crystals with narrow size distribution, regular crystal habit, and mean size around 15 µm are successfully produced. Finally, crystal form and spectroscopic property of sonocrystallized sample and probenecid as received from the supplier are compared and confirmed consistent from the analytical results of powder X‐ray diffractometer and Fourier transform infrared spectroscopy.

Recent progress on strategies for the enhancement of crystal growth process

“…In addition, compared with the ultrasonic bath, the ultrasonic horn has a stronger cavitation effect, and thus the crystal prepared using the ultrasonic horn has better properties. Chang et al 58 found that probenecid crystals prepared by conventional cooling crystallization were in a disordered needle-like state, while after ultrasonic treatment, regular rod-like probenecid crystals with a small crystal size and narrow particle size distribution were obtained. Under the same cooling rate and ultrasonic conditions, the particle size of probenecid crystals could be increased from 9.4 μm to 15.3 μm, as the solution concentration increased from 45 mg mL −1 to 90 mg mL −1 .…”