Study of complex formation between daclatasvir and some cyclodextrins using capillary electrophoresis and microcalorimetry

Summary Study of complex formation between daclatasvir and some cyclodextrins using capillary electrophoresis and microcalorimetry The goal of the present master thesis was to study the formation of Daklatasvir comlplex with cyclodextrins (CD) using capillary electrophoresis and microcalorimetric methods. Almost half of the drugs currently used in therapy have a chiral center in their molecule. Part of the chiral drugs are used in the form of racemates, which consist of an equimolar mixture of enantiomers. The enantiomers have the same physical and chemical properties in achiral environment and only way to distinguish between them in such environment is the sign of rotation angle of polarized light. Enantiomers act differently on biological organisms because they differ from each other in pharmacokinetics, toxicological and pharmacological action, as well as their action on proteins and receptors. These differences in interactions lead to differences in the biological activites. The living body with its numerous homochiral compounds being amazingly chiral selector, will interact each racemic drug differently and metabolize each enantiomer by a separate pathway to generate different pharmacological activity. This is why it is important to separate enantiomers and study their action. One of the methods of separation enantiomers is Capillary electrophoresis (CE). Separation of enantiomers in CE is achieved by using chiral selectors. CDs are important and frequently used class chiral selectors because they are non-toxic and multimodal selectors, since multiple chiral interactions are possible through very different stereoselective mechanisms. CDs are very convenient to use because of their solubility in aqueous solutions. In order to determine the mechanism of complex formation, it is important to study the thermodynamic parameters and the conditions required for the formation of a stable complex. Using the isothermal titration calorimetry (ITC) one can directly determine the stoichiometry of complexes and thermodynamic parameters of complex formation, such as enthalpy, entropy, Gibbs free energy... Daclatasvir (DCV) is a direct-acting antiviral agent against Hepatit C Virus (HCV) used for the treatment of chronic HCV genotype 1 and 4 infection. It is marketed under the name DAKLINZA and is contained in daily oral tablets as the hydrochloride salt. It exerts its antiviral action by preventing RNA replication via binding to NS5A, a nonstructural phosphoprotein encoded by HCV. In the present work we studied formation of DCV complex with various CDs by the ITC method.

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