Complexation of Fluvastatin Sodium with b-Cyclodextrin: NMR Spectroscopic Study in Solution SYED MASHHOOD ALI 1, *, SANTOSH KUMAR UPADHYAY 1 , ARTI MAHESHWARI 1 and MAMORU KOKETSU 2 1 Department of Chemistry, Aligarh Muslim University, Aligarh-202 002, UP, India; 2 Division of Instrumental Analysis, Life Science Research Center, Gifu University, 501-1193, Gifu, Japan (Received: 16 November 2005; in final form: 30 January 2006) Key words: b-cyclodextrin, fluvastatin sodium, inclusion complex, NMR spectroscopy Abstracts 1 H NMR spectroscopic study of fluvastatin sodium (FLU), b-Cyclodextrin (b-CD) and their mixtures confirmed the formation of FLU/b-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (K s ) was calculated to be 340 M )1 . Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the b-CD cavity and there is chiral differentiation by the b-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the b-CD cavity was also established and structure of the complex has been proposed. Introduction Fluvastatin sodium (FLU) helps in preventing heart disease, angina, stroke and heart attacks by reducing the cholesterol and certain other fatty substances in the blood [1, 2]. It is a competitive inhibitor of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase and lowers the overall blood cholesterol as well as blood LDL (bad) cholesterol levels, which is responsible for coronary artery diseases. FLU is light sensitive and its solubility in water is 1.91 mg/ml. Complexation of pharmaceutical compounds with cyclodextrins (CDs) leads to altered physicochemical properties of the guest. Inclusion complexes of phar- maceutical compounds with CDs, therefore, have been extensively studied and utilized to improve the solubility [3], dissolution rate [4] and bioavailability of poorly water-soluble drugs [5] and other desirable properties [6]. CDs are cyclic oligomers of a-D-glucose linked through glycosidic a-1,4-bonds resulting in the forma- tion of doughnut shaped molecules having one rim (narrow) lined with n primary hydroxyl groups while the other rim (wider) lined with 2n secondary hydr- oxyl groups. The H-3¢, H-5¢ and glycosidic oxygen are located inside the cavity which is relatively hydrophobic. The CDs, therefore, act as hosts for a variety of non- polar molecules [7–9]. NMR spectroscopy is an important tool to study CD inclusion complexes [10]. 1 H NMR spectra of mixtures of CD and guest molecule are recorded and changes in the chemical shifts (Dd) of both the host as well as guest are studied. The formation of the inclusion complex is indicated by highfield shift changes in the CD protons situated inside the cavity, namely H-3¢ and H-5¢ and downfield shift changes in the guest protons. The chemical shift change data can be used for the deter- mination of stoichiometry, binding constant and mode of penetration of the guest into the CD cavity. ROESY [11] spectroscopy is particularly useful in the study of inclusion complexes. NOE correlation peaks observed between the protons of the included part of the guest and b-CD cavity protons give direct evidence for the formation of inclusion complex and provide very useful information regarding the structure of the complex. We are interested in the study of the inclusion com- plexes of pharmaceutical compounds with b-CD in solution [12, 13] and report herein our results on the detailed NMR spectroscopic study of b-CD–fluvastatin sodium complexation. Results and discussion All the 1 H NMR spectra were recorded on a Varian Mercury Plus-300 instrument while COSY, DEPTO and ROESY experiments were performed on a JEOL * Author for correspondence. E-mail: smashhoodali@yahoo.com Journal of Inclusion Phenomena and Macrocyclic Chemistry (2006) 55:325–328 Ó Springer 2006 DOI 10.1007/s10847-006-9099-9