Solubility problems in stability trial
A solution formulation of a drug, intended as clinical trial material, was put on stability to document allowable storage conditions and time periods. It was however noted that in some vials, a precipitate was formed during storage. There was no rationale why these individual samples behaved differently and the stability had to be stopped. Since the project had a very tight timeline, these findings were very troublesome to our client.
Within one day we could identify the problem. Using a combination of chromatography and XRPD it could be established that the precipitated form was the free base of the drug. Solubility experiments in a narrow range around the intended clinical pH showed that the intended drug concentration was very close to the solubility limit. Further investigations revealed that the drug itself had a profound influence on the pH of the weakly buffered solution, thereby increasing the precipitation risk.
Using this knowledge it was possible to design a more robust clinical formulation by increasing the buffer strength and adjusting pH slightly to a higher solubility range. A new stability trial is ongoing, without any unwanted surprises.