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Stability and Structure of Inclusion Complex of Zaleplon with Natural and Modified Cyclodextrins

Zaleplon (ZAL), N-[3-(3-cyanopyrazolo[1, 5- a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, is a nonbenzodiazepine hypnotic drug of the pyrazolopyrimidine class. In the dose of 5 to 10 mg, the drug is indicated for the short term management of insomnia.1-2 ZAL also shows potent anticonvulsant activity against electroshock- induced convulsions.3 The drug is a lipophilic compound which is practically insoluble in water.4 It has been recognised that a certain level of aqueous solubility is required of the drug substance to be readily delivered to the cellular membrane, but at the same time it has to be lipophilic enough to cross the membrane itself. In the case of lipophilic compounds such as ZAL, the dissolution in gastrointestinal media is often a rate-limiting step for the absorption, thus limiting the oral bioavailability of the drug.5 In the liver, ZAL is extensively metabolized into pharmacologically inactive metabolites.3 Low aqueous solubility of ZAL and its significant presystemic metabolism lead to a rather low oral bioavailability of about 30%.6 Various formulation techniques can be applied to overcome the low aqueous solubility of drugs without affecting their optimised pharmacological action. Among different approaches for enhancing the aqueous solubility of lipophilic drugs, cyclodextrin (CD) complexation proved to be one of the most effective.7 The interaction between zaleplon (ZAL) and different cyclodextrins in aqueous solutions was investigated by spectrofluorimetric and phase solubility studies. Stability constants determined by both methods showed that among natural cyclodextrins, β-cyclodextrin (βCD) formed the most stabile complex but its solubilizing efficiency was limited. Among βCD derivatives, the complex stability and solubilisation efficiency decreased in order: randomly methylated-βCD (RAMEB) > sulphobutylether-βCD (SBEβCD) > hydroxypropyl-βCD (HPβCD). The inclusion complexes of ZAL with βCD and RAMEB were further characterised by 1H-NMR spectroscopy and the inclusion complex formation was confirmed in both cases. ROESY spectra showed two binding modes between ZAL and βCD which exist simultaneously in the solution. The first binding mode occurs by the inclusion of the phenyl ring of ZAL into the βCD central cavity via the wider rim of the cyclodextrin cone and is dominant. The second one is formed by the inclusion of pyrazolo[1, 5- a]pyrimidine ring of ZAL.

Cyclodextrins; Zaleplon; Thermodynamics of Complexation; Fluorescence; 1H NMR

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