In the Laboratory
Determination of Thermodynamic Parameters of the Cyclodextrin Inclusion Process
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An Undergraduate Physical Chemistry Laboratory Experiment M. Valero, L. J. Rodríguez, and M. M. Velázquez* Departamento de Química Física, Facultad de Farmacia, Universidad de Salamanca, Apdo. 449, E-37080 Salamanca, Spain
Students often learn the concept of intermolecular forces in the physical chemistry course. However, it is difficult to incorporate inexpensive experiments into the physical chemistry curriculum to demonstrate the role of these forces on the behavior and properties of substances. We describe an investigation of the thermodynamics of the formation of cyclodextrin inclusion complexes by using fluorescence spectroscopy. A naphthalene derivative, 4-(6methoxy-2-naphthyl)-2 butanone (nabumetone), was used as guest and two different cyclodextrins, β-cyclodextrin ( β-CD) and hydroxypropyl β-cyclodextrin (HP β-CD), were used as hosts or molecular receptors. Cyclodextrins, cyclic nonreducing oligosaccharides, form inclusion complexes with various compounds. The inclusion complex involves the spatial entrapment of a simple guest molecule in the cyclodextrin cavity without the formation of any covalent bonds (1). The nature of the binding forces is still controversial (2). In this laboratory experiment, students can investigate the thermodynamics of the inclusion process itself by providing a direct measure of the enthalpy and entropy effects that occur when the naphthalene derivative is included in the two guests. By examining thermodynamic parameters, students also explore the nature of the driving forces for the inclusion process. Finally, they can observe the role of the solute microenvironment on the nabumetone fluorescence spectrum. It is important to consider that nabumetone is a nonsteroidal antiinflammatory drug that is very slightly soluble in water and causes ulceration of the stomach. Cyclodextrin complexation of antiinflammatory drugs reduces their ulcerogenic potencies (3); therefore, by choosing a guest of pharmaceutical importance, we try to facilitate integration of this physical chemistry experiment with other subdisciplines. The experiment is designed for physical chemistry laboratory students. In addition, molecular encapsulation by means of monomolecular inclusion complex formation offers a new form of dosage whose importance in pharmaceutical formulation has been fully realized (1). Therefore this lab experiment can be used in either physical chemistry or physical pharmacy courses. (Our experiment was developed by graduate students in pharmacy.) In general, students should be able to carry out this experiment individually in five 4-hour laboratory W
Supplementary materials for this article are available on JCE Online at http://JChemEd.chem.wisc.edu/Journal/issues/1999/ Mar/abs418.html.
periods if the detailed experiment procedure is provided in advance. However, it can also be carried out in a shorter time (e.g., in two 4-hour labs) if students work in groups of four and each member of the group determines the association constant at only one temperature. The thermodynamic parameters of the inclusion process were determined from the temperature dependence of the association constant by using the van’t Hoff relation. Fluorescence spectroscopy is used to determine the association constants by measuring changes in the nabumetone spectrum caused by the formation of the inclusion complexes. The thermodynamic parameters obtained in this work show two different behaviors as a function of the nature of the host molecule. Complexation with β-CD proceeds with negative enthalpy and entropy changes; complexation with HP β-CD is carried out with negative enthalpy and positive entropy changes. We think that these different behaviors are very interesting for students, to help them understand the nature of the driving forces involved in the formation of cyclodextrin inclusion complexes. Thus, this lab experiment illustrates two typical examples of inclusion complex formation. In the nabumetone- β-CD complex, hydrogen bonds between drug and cyclodextrin are the main source of the interaction. Students can confirm this assumption from the position of the maximum of the complexed nabumetone fluorescence spectrum. In the case of HP β-CD, the entropy increases as a consequence of the increase of water disorder after drug complexation. In the design of this experiment we had several educational goals in mind. First, we wanted to introduce quantitative fluorescence spectroscopy into the physical chemistry laboratory curriculum and to relate this instrumentation to classical concepts such as thermodynamic properties or intermolecular forces. Second, we wanted to show the role of intermolecular forces in the formation of cyclodextrin inclusion complexes. Finally, we wished to facilitate integration of the apparently abstract physical chemistry concepts with other subdisciplines. For this reason a guest of pharmaceutical importance, nabumetone, was chosen. Safety Considerations No hazards are associated with the chemicals used in this lab experiment.
*Corresponding author. Email:
[email protected].
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Journal of Chemical Education • Vol. 76 No. 3 March 1999 • JChemEd.chem.wisc.edu
In the Laboratory
Acknowledgment We would like to acknowledge the Junta de Castilla y León for financial support of this work (Project SA 05-95). Literature Cited 1. Szejtli, J. Cyclodextrins and Their Inclusion Complexes; Akademiai Kiado: Budapest, 1982. 2. Örstan, A.; Ross, J. B. A. J. Phys. Chem. 1987, 91, 2739. 3. Szejtli, J.; Szente, L. Pharmazie 1985, 36, 694.
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