Complexation and Chiral Drug Recognition of an Amphiphilic Phenothiazine Derivative with β‐Cyclodextrin

Promethazine hydrochloride (PTZ) is an amphiphilic drug derived from the phenothiazine structure that possesses a charged aliphatic chain with a chiral carbon. In the presence of β‐cyclodextrin (β‐CD), this drug undergoes significant changes of its photophysical properties in aqueous solution. Fluorescence spectroscopy measurements show the formation of a 1:1 stoichiometry complex with quantum yield lower than that of the pure PTZ, and two fluorescence lifetimes, which can be assigned to the free and complexed forms of the drug. In addition, 1H NMR spectra, and 2D rotating‐frame Overhauser enhancement spectroscopy (ROESY) were used to characterize the drug and the complex, and to determine the effects of the complexation on the aggregation. For the drug binary system, a noncooperative association process is observed, and in the presence of macrocycle, the chemical shifts reveal a chiral resolution of the drug enantiomers, with different stability constants of the complexes. β‐CD modifies the aggregation of PTZ in an extension that confirms the formation of a 1:1 complex. ROE enhancements and molecular modeling strategies show the most likely structure of the complex in solution, in which one of the phenyl rings is buried into the CD cavity, with a slight inclusion of the aliphatic part. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1484-1498, 2008