Effect of Cyclodextrin Complexation on the Aqueous Solubility of Diazepam and Nitrazepam: Phase-Solubility Analysis, Thermodynamic Properties

Jasmina Hadžiabdić, Alisa Elezović, Ognjenka Rahić, Indira Mujezin

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.

DOI: 10.4236/ajac.2012.312107                

Abstract

The solubility enhancement of diazepam and nitrazepam in water was analyzed depending on temperature and amount of α-cyclodextrin ( α-CD), β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The interactions of drug-cyclodextrin in solution were investigated by the phase-solubility analysis. Diazepam (nitrazepam) content in aqueous complexation medium was analyzed UV spectrophotometrically. Classical solubility data were used to derive apparent stability constants (K_1:1) which were used to derive thermodynamic parameters for the diazepam (nitrazepam)-cyclodextrin complexes. Since all phase solubility plots were of A_L–types, and calculated Slopes after linear regression analysis were found to be less than 1, it could be assumed that stoichiometry of the formed binary systems was 1:1. According to the calculated K_1:1 values, the stability of the complexes of diazepam and nitrazepam with a-CD, β-CD and 2-HP-β-CD varies as follows: 2-HP-β-CD > β-CD > β-CD. The a-CD has higher affinity for dissolving nitrazepam compared to diazepam. While all parameters lead to an improvement in solubility, the largest effect was obtained for guest-host complexation with 2-HP-β-CD. The solubility of diazepam and nitrazepam in water increased 93.02 times and 64.23 times, respectively, in the presence of 40% (w/w) 2-HP-β-CD, at 25°C. Solubility data for diazepam and nitrazepam in aqueous 2-HP-b-CD were used to derive thermodynamic parameters, ΔG° at 298 K = –14.43 kJ·mol^–1, ΔH° = 0.79 kJ·mol^–1, ΔS° at 298 K = 51.17 J·mol^–1·K^–1 and ΔG° at 298 K = –13.43 kJ·mol^–1, ΔH° = 2.38 kJ·mol^–1, ΔS° at 298 K = 53.01 J·mol^–1·K^–1, respectively. Formation of inclusion complexes substantially increases the water solubility of diazepam and nitrazepam. Diazepam and nitrazepam dissolution thermodynamics in aqueous 2-HP-β-CD were characterized by spontaneous and endothermic dissolution and hydrophobic interactions.

Keywords

Diazepam; Nitrazepam; Phase-Solubility Analysis; Thermodynamic; Parameters

Conflicts of Interest

The authors declare no conflicts of interest.

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