Characterization and Interconversion of Two Crystal Forms of NEt-3IB, a Retinoid X Receptor Agonist

Retinoid X receptor (RXR) agonist NEt-3IB (1) is a candidate for the treatment of inflammatory bowel disease (IBD), and we have established a process synthesis of 1 in which the final product is obtained by recrystallization from 70% EtOH. However, we found that there are two crystal forms of 1. Here, to characterize and clarify the relationship between them, we conducted thermogravimetry, powder X-ray diffraction, and single crystal X-ray diffraction. The crystal forms were identified as the monohydrate form I and anhydrate form II. The crystal form I, obtained as a stable form by our established synthesis, was easily dehydrated simply by drying to afford the form II', which was similar to the crystal form II obtained by recrystallization from anhydrous EtOH. Storage of the form II' in air regenerated the form I. The molecular conformations of 1 in the crystals of the two forms are similar, and they can be reversibly interconverted. The solubility of the monohydrate form I and anhydrate form II was examined and the former was found to be less soluble than the latter. Thus, form I may be superior to form II for targeting IBD, because of higher delivery to the lower gastrointestinal tract and reduction of systemic side effects associated with lower absorption due to lower water solubility.

Automated summary

In this study, two crystal forms of the RXR agonist NEt-3IB were characterized and investigated through thermogravimetry, powder X-ray diffraction, and single crystal X-ray diffraction. The crystal forms were identified as monohydrate form I and anhydrate form II, which could be reversibly interconverted. The solubility of form I was found to be lower than form II. Thus, form I may be more suitable for targeting IBD due to higher delivery to the lower gastrointestinal tract and reduced systemic side effects associated with lower water solubility.