The transformation of a monohydrate into an anhydrous form of risedronate monosodium (RS) in a methanol and water mixture was investigated. The phase transformation was detected by monitoring the number of particles, particle size, and shape. At the same time, polymorphic forms of crystals were identified by various offline techniques such as XRPD, TGA, and DSC. The kinetics of phase transformation was found to be controlled by three-dimensional nuclear growth. The reaction of water in the solvent mixture was a main factor determining the stability of anhydrate and monohydrate forms. The time required for phase transformation was strongly affected by temperature and agitation rate. The phase transformation could be successfully determined in real time by using an in situ particle measurement system.