Inclusion complex of 2-chlorobenzophenone with cyclomaltoheptaose (b-cyclodextrin): temperature, solvent effects and molecular modeling Matias I. Sancho a,b , Estela Gasull a , Sonia E. Blanco a,b,⇑ , Eduardo A. Castro c a Área de Química Física, Facultad de Química Bioquímica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis, Argentina b Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-SL) CONICET, 5700 San Luis, Argentina c INIFTA, Dpto. de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 Buenos Aires, Argentina article info Article history: Received 24 March 2011 Received in revised form 2 May 2011 Accepted 4 May 2011 Available online 10 May 2011 Keywords: b-Cyclodextrin 2-Chlorobenzophenone Solubility Reversed-phase liquid chromatography Apparent formation constants Molecular modeling abstract A thermodynamic study of the inclusion process between 2-chlorobenzophenone (2ClBP) and cyclomal- toheptaose (b-cyclodextrin, b-CD) was performed using UV–vis spectroscopy, reversed-phase liquid chro- matography (RP-HPLC), and molecular modeling (PM6). Spectrophotometric measurements in aqueous solutions were performed at different temperatures. The stoichiometry of the complex is 1:1 and its apparent formation constant (K c ) is 3846 M 1 at 30 °C. Temperature dependence of K c values revealed that both enthalpy (DH° = 10.58 kJ/mol) and entropy changes (DS° = 33.76 J/K mol) are favorable for the inclusion process in an aqueous medium. Encapsulation was also investigated using RP-HPLC (C18 column) with different mobile-phase compositions, to which b-CD was added. The apparent formation constants in MeOH–H 2 O(K F ) were dependent of the proportion of the mobile phase employed (50:50, 55:45, 60:40 and 65:35, v/v). The K F values were 419 M 1 (50% MeOH) and 166 M 1 (65% MeOH) at 30 °C. The thermodynamic parameters of the complex in an aqueous MeOH medium indicated that this process is largely driven by enthalpy change (DH° = 27.25 kJ/mol and DS° = 45.12 J/K mol). The results of the study carried out with the PM6 semiempirical method showed that the energetically most favor- able structure for the formation of the complex is the ‘head up’ orientation. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Benzophenones (BPs) are compounds present in a large number of natural products, 1–3 and they can also be obtained through syn- thetic methods. 4 They exhibit interesting physicochemical and bio- logical properties. For example, due to their capacity to absorb and dissipate UVA and UVB radiation (200–350 nm), a group of 12 BPs is used in the cosmetics industry to produce sunscreens, 5 and numerous analytical methods have been used to perform quality control on these products. 6 BPs are also used in pharmacological applications, such as the synthesis of tamoxifen 7 and clomiphene citrate. 8 Benzodiazepines that are generally used as sedative, anx- yolitic, anticonvulsant and muscle relaxant agents are derived from chlorinated benzophenones. Some common examples are diaze- pam and alprazolam (both derived from 5-chlorobenzophenone), or clonazepam (derived from 2-chlorobenzophenone). Specifically, 2-chlorobenzophenone is also a reagent in the synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3- [ 11 C]carboxamide, which is used as a benzodiazepine receptor ligand. 9 However, the poor aqueous solubility of BPs limits their phar- macological uses due to their low dissolution rate and bioavailabil- ity. Different methods can be used to increase drug solubility, such as the use of organic solvents, 10 emulsions, 11 liposomes, 12 mi- celles 13 and the interaction of drugs with complexing agents. Among these, a very frequently used method is the formation of inclusion complexes with cyclomaltooligosaccharides (cyclodex- trins, CDs). 14–18 CDs are cyclic oligomers with a truncated cone shape which are made up of six, seven or eight units of a-(1?4)- D-glucose per molecule (a-, b- and c- CD, respectively). The outer layer of the molecule is hydrophilic, and organic molecules (drugs) with an appropriate size and shape, and low solubility in water can enter into its hydrophobic cavity, forming non-covalent inclusion complexes as a result. 19 This inclusion phenomenon may increase the apparent solubility of the drug, and it can also modify its phys- icochemical stability and its bioavailability. As a pharmaceutical agent cyclomaltoheptaose (b-CD) appears particularly useful be- cause of its complexing ability, cavity dimensions, low cost and higher productive rate. Because of these applications new experi- mental and theoretical techniques devoted to the determination of the solution structure and the binding constants of the CD–drug complexes are constantly under development. 20 To the best of our knowledge, there is no information in the existing literature reporting the effect of b-CD on the solubility of 0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.05.002 ⇑ Corresponding author. Tel.: +54 2652 424689; fax: +54 2652 430224. E-mail addresses: sblanco@unsl.edu.ar, sonia.e.blanco@gmail.com (S.E. Blanco). Carbohydrate Research 346 (2011) 1978–1984 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres