Solving the puzzle of 2-hydroxypropyl β-cyclodextrin: Detailed assignment of the substituent distribution by NMR spectroscopy.

2-Hydroxypropyl-β-cyclodextrin (HPBCD) is one of the most important cyclodextrin derivatives, finding extensive applications in the pharmaceutical sector. Beyond its role as an excipient, HPBCD achieved orphan drug status in 2015 for Niemann-Pick type C disease treatment, prompting research into its therapeutic potential for various disorders. However, the acceptance of HPBCD as an active pharmaceutical ingredient may be impeded by its complex nature. Indeed, HPBCD is not a single entity with a well-defined structure, instead, it is a complex mixture of isomers varying in substituent positions and the degree of hydroxypropylation, posing several challenges for unambiguous characterization. Pharmacopoeias' methods only address the average hydroxypropylation extent, lacking a rapid approach to characterize the substituent positions on the CD scaffold. Recognizing that the distribution of substituents significantly influences the complexation ability and overall activity of the derivative, primarily by altering cavity dimensions, we present a straightforward and non-destructive method based on liquid state NMR spectroscopy to analyze the positions of the hydroxypropyl sidechains. This method relies on a single set of routine experiments to establish quantitative assignment and it provides a simple yet effective tool to disclose the substitution pattern of this complex material, utilizing easily accessible (400 MHz NMR) instrumentation.

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Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Szabolcs Beni reports financial support was provided by European Commission. Thorbjorn Terndrup Nielsen reports financial support was provided by Carlsberg Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.