Physical–chemical characterization of binary systems of metformin hydrochloride with triacetyl-β-cyclodextrin

Interaction products of metformin hydrochloride (MF·HCl), an oral anti-hyperglycaemic agent highly soluble in water, with triacetyl-β-cyclodextrin (TAβCyD), a hydrophobic CyD derivative practically insoluble in water, were prepared to evaluate their suitability for the development of a sustained-release dosage form of the drug. Equimolar MF·HCl–TAβCyD solid compounds were obtained by different techniques, i.e., physical mixing, kneading, co-grinding, sealed-heating, and spray-drying, in order to investigate and compare their effectiveness and influence on the physical–chemical properties of the final products. Differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy were used for the solid-state characterization of the different MF·HCl–TAβCyD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. According to the results of solid-state studies, the ability of the different preparation methods to promote effective interactions between drug and CyD varied in the order: spray-drying > co-grinding > kneading > sealed-heating ≈ physical mixing. The same effectiveness rank order was observed also in dissolution studies. In fact the time to dissolve 100% drug varied increased from 1 min, for pure drug, to 3, 7, 40, 120 up to 420 min for physically mixed, sealed-heated, kneaded, co-ground and spray-dried products, respectively. Thus the drug–TA(CyD products obtained by spray drying and co-grinding were selected as the best candidates for the future development of a suitable prolonged-release oral dosage form of MF·HCl.