Tiagabine (TGB) is an antiepileptic agent enhancing the activity of GABA at neuronal and glial region. It has recently been shown that enhancement of TGB chemical stability was improved by complexation with 2-hydroxypropyl-beta-cyclodextrin (2-HPβCD). The aim of this project is to explain the improvement of the chemical stability of complexed TGB by studying the inclusion properties and factors affecting the complexation selectivity between 2-HPβCD and TGB. Analysis of the interaction between 2-HPβCD and TGB and the effect of 2-HPβCD on TGB solubility was performed by phase solubility method described by Higuchi and Connors; the complexation was followed by characterization using DSC, FTIR and NMR spectroscopy. In aqueous media, the analysis of NMR proton shift change continuous variation method (Job’s plot) and the NMR diffusion-ordered spectroscopy (DOSY) measurements clearly show that TGB form 1:1 inclusion complex with 2-HPβCD with an association constant (K a) of 3396 M⁻¹. More detailed information about the inclusion mode and the geometry of the complex was obtained by the analysis of 2D NMR NOESY experiment and molecular modelling calculations. The inclusion process indicates that A-ring, C10–C11 double bond and the half of the B-ring of TGB molecule were located inside the cavity while the nipecotic acid part of TGB (Ring C) was exposed towards the outside of the 2-HPβCD cavity. These results suggest that the inclusion of the C10–C11 double bond in the 2-HPβCD cavity may possibly the reason of improvement of TGB chemical stability.

The aim of this paper was to describe the use of a 2-hydroxypropyl beta-cyclodextrin (2-HPβCD) as a tool to improve the chemical stability of tiagabine hydrochloride (TGB). HPLC method was used to quantify TGB. The correlation coefficient of the linearity (r2) of HPLC method was more than 0.999 whilst the limit of detection and the limit of quantification of TGB were 0.6494 μg ml-1 and 1.765μg ml-1 respectively. The effect of 2-HPβCD on the chemical stability of TGB was compared with α-tocopherol and ascorbic acid, the most recognized antioxidants used to enhance the stability of TGB. The stability was expressed by (% w/w) of the total related substances (TRS) of TGB. When TGB was exposed for 24 h to 50°C, the TRS were 3.264% (SD ±0.077) and 3.125% (SD ±0.053) in the presence of α-tocopherol and ascorbic acid, respectively. The TRS of TGB complexed with 2-HPβCD was 2.142% (SD ±0.045). This study demonstrates that 2-HPβCD exhibits an obvious enhancement of TGB chemical stability with a different mechanism compared with the usual antioxidants.