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Stoichiometry and Thermodynamic of Inclusion Complexation Between Zaleplon and Hydrophilic Cyclodextrin Derivatives

The objective of this paper was to determine the thermodynamic parameter of zaleplon (ZAL) complexation with a series of cyclodextrins (CDs) aimed to improve solubility and bioavailability of this poorly soluble hypnotic agent. This knowledge is important since it would allow the determination of critical parameters affecting the drug complexation affinity and to obtain more general understanding of the driving forces behind such inclusion phenomena. This is essential for further method development of inclusion complex preparation in the solid state and could help to develop novel CD derivatives with superior complexation properties for a specific class of drugs. The list of CDs used comprised natural ß-cyclodextrin (ßCD) and its hydrophilic derivatives (HPßCD, RAMEB and SBEßCD). To obtain thermodynamic parameters of the system studied, fluorescence and nuclear magnetic resonance (1H-NMR) was used. The stoichiometry of the complexes formed was obtained from the 1H-NMR data using continuous variation method (Job’s plot) and by the statistical analysis of spectrofluorimetric titration data. The obtained results confirmed the formation of equimolar complexes in all cases, excluding the possibility of higher order complex formation. Thermodynamic parameters obtained by both methods gave similar and negative values of ∆G^0 for all complexes, indicating spontaneous inclusion of ZAL into CDs. From a thermodynamic point of view, two types of inclusions were determined. One is enthalpy driven ZAL complexation with ßCD, HPßCD and RAMEB, while the other is entropy driven complexation observed in the case of SBEßCD. The mechanisms behind each type of inclusion were discussed in details.

zaleplon; cyclodextrin; thermodynamic; inclusion complexes

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