For poorly soluble compounds, drug product performance in patients with Ulcerative Colitis (UC) compared to healthy subjects can be affected due to differences in drug solubility in GI fluids. A risk assessment tool was developed to identify compounds with a high risk of altered solubility in the GI fluids of UC patients. Pathophysiological changes impacting on the composition of GI fluids in UC patients were considered and UC biorelevant media representative of the stomach, intestine and colon were developed based on biorelevant media based on healthy subjects and literature data using a Design of Experiment approach. The UC media were characterised and revealed differences in surface tension, osmolality and buffer capacity compared to media based on healthy subjects. The solubility of six drugs was investigated in UC biorelevant media and results were related to media- and drug-dependent factors. A lower drug solubility in UC intestinal media was observed for compounds with a high lipophilicity. In UC simulated colonic fluids, drug solubility was altered for ionisable compounds. Additionally, a higher solubility of neutral lipophilic drugs was observed in UC fasted state colonic media with increased concentrations of soluble proteins. The developed UC biorelevant media offer the possibility to identify the risk of altered drug solubilisation in UC patients without conducting expensive clinical trials. A high risk was related to drug ionization properties and lipophilicity in the current study with all investigated drugs showing differences in solubility in biorelevant media based on UC patients compared to healthy subjects.