Inclusion of anesthetics in cyclodextrins: Structural investigation of solid inclusion complexes of butamben

Single crystal and powder X-ray diffraction techniques were used to characterize inclusion complexes formed between the local anesthetic butamben (4-aminobenzoic acid butyl ester) and various cyclodextrins (CDs). Kneading butamben with the native hosts beta- and gamma-CD yielded microcrystalline products, unequivocally identified as inclusion complexes by powder X-ray diffraction. Single crystals of a 1:1 inclusion complex between butamben and permethylated beta-CD (TRIMEB) were isolated. X-ray analysis revealed that the guest is included with the ester moiety fully encapsulated in the TRIMEB cavity. However, a major part of the phenylamine residue protrudes from the host primary side, entering the secondary side of a translated TRIMEB molecule to which it hydrogen bonds, both directly [-(NHAO)-O-...(host)] and indirectly [-(NHBO)-O-...(water)(...) O(host)]. This unusual mode of guest inclusion is associated with a novel channel-like complex packing arrangement in the monoclinic space group P2(1). The included drug molecule adopts a more extended conformation than that found in the crystal of butamben, whose X-ray structure was also determined in this study.