Proparacaine complexation with β‐cyclodextrin and p‐sulfonic acid calix[6]arene, as evaluated by varied ¹H‐NMR approaches

Abstract

This study focused on the use of NMR techniques as a tool for the investigation of complex formation between proparacaine and cyclodextrins (CDs) or p-sulfonic acid calix[6]arene. The pH dependence of the complexation of proparacaine with beta-CD and p-sulfonic acid calix[6]arene was studied and binding constants were determined by (1)H NMR spectroscopy [diffusion-ordered spectroscopy (DOSY)] for the charged and uncharged forms of the local anesthetic in beta-CD and p-sulfonic acid calix[6]arene. The stoichiometries of the complexes was determined and rotating frame Overhauser enhancement spectroscopy (ROESY) 1D experiments revealed details of the molecular insertion of proparacaine into the beta-CD and p-sulfonic acid calix[6]arene cavities. The results unambiguously demonstrate that pH is an important factor for the development of supramolecular architectures based on beta-CD and p-sulfonic acid calix[6]arene as the host molecules. Such host-guest complexes were investigated in view of their potential use as new therapeutic formulations, designed to increase the bioavailability and/or to decrease the systemic toxicity of proparacaine in anesthesia procedures.

Encapsulation of Drug Molecules into Calix[n]arene Nanobaskets. Role of Aminocalix[n]arenes in Biopharmaceutical Field

“…The pH of the complexation media was shown to be an important factor for enhancing solubility of the local anesthetics, tetracaine and proparacaine, with 125 and β‐cyclodextrin. For both guest molecules, interaction at acidic pH is driven by ion pairing of the ammonium group of drug and sulfonate group of CA.…”

Investigation into Drug Solubilisation Potential of Sulfonated Calix[4]Resorcinarenes

“…In particular, there is an established evidence base confirming that water-soluble calix[n]arenes which possess sulfonate groups in the 4-position on the upper rim are capable of solubilising drug molecules which otherwise possess poor solubility in aqueous media [9][10][11][12][13][14][15][16][17][18][19][20][21]. However, few investigations into the properties and utility of simple calix[4]resorcinarenes which bear sulfonate groups in the 2-position on the upper rim have been reported.…”

Simple Calix[n]arenes and Calix[4]resorcinarenes as Drug Solubilizing Agents

“…Para-Sulfonatocalix [6]arene was shown to form complexes with the local anaesthetics tetracaine and proparacaine in their protonated forms, which would be present in vivo at physiological pH [55,56]. para-Sulfonatocalix [6]arene formed a strong, stoichiometric host-guest complex with each molecule which was confirmed by NMR and other spectroscopic studies.…”

“…The association between para-sulfonatocalix [6]arene and the nonprotonated proparacaine was demonstrated to be considerably weaker. Indeed, studies revealed that the ionized amino groups are held closely to the calixarene cavity, highlighting the importance of ionic interactions in complex formation with calix[n]arenes in addition to any considerations of the hydrophobic effect [55,56]. [4]arene and para-sulfonatocalix [6]arene were employed in investigations into the solubilization of the hydrophobic anticonvulsant drug carbamazepine [57].…”