**12. Low bioavailability and stability: an obstacle to the clinical translation of RES**

The poor water solubility of RES is well established. However, RES is highly stable in aqueous solutions of acidic pH. Moreover, researchers must consider that RES

degrades rapidly in buffers of 7.4 pH or higher [115]. For example, RES incorporated into buffered cell medium was found to degrade to 50% of its original concentration within 24 h of incubation at 37°C [115]. Hence, many of the *in vitro* studies, which assume that the pre-determined RES concentration is consistent for the study duration, are likely to produce misleading results regarding therapeutic dose.

Research has emerged employing novel RES formulations to overcome the pharmacological limitations and optimise therapeutic potential, ultimately improving its clinical translation [116–119].
