The hydration state of a compound depends on the activity of water (aH2O) in its crystallizing medium. This study utilized powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to investigate the crystalline states of ciprofloxacin precipitation. In these long equilibrated water-methanol systems, a series of water activities were obtained by adjusting the water-methanol volume ratios. We used high performance liquid chromatography (HPLC) to measure the solubility of ciprofloxacin hydrate, anhydrate, and their mixtures in these solutions with various water activities. The results showed that ciprofloxacin's solubility basicallychanged according to the crystallization state of the precipitated solid. A relationship was determined between the phase stability of the ciprofloxacin anhydrate/hydrate and the water activity of the solutions. By comparing the relationships we established above with the PXRD data of the ciprofloxacin samples that were stored for 12 weeks under constant relative humidity and room temperature, we found that the methodology employed in this experiment was able to accurately and efficiently predict the phase conversion between ciprofloxacin anhydrate and hydrate. We also demonstrated how the water activity could affect the relative stability of these crystalline solids in water-methanol solutions.