The effect of ultrasound on the reactive crystallization process of cloxacillin benzathine crystals was investigated to develop a better understanding of the characteristics of this poorly water-soluble active pharmaceutical ingredient. Characteristics of the products generated under different experimental conditions were compared by offline Malvern Mastersizer measurements and microscopy. The ultrasonic waves applied to reactive crystallization of cloxacillin benzathine were found to be suitable in generating highly regular surface areas for crystal growth. The increased surface areas resulted in decreased average particle sizes and more uniform particles.