Recent scientific publications have already demonstrated that co-grinding appears as an efficient, solvent-free technique for preparing cyclodextrin complexes and improving physicochemical properties of active ingredients. The improvement of solubility and dissolution rate could enhance the biopharmaceutical properties of the active ingredients in solid pharmaceutical products. Furthermore stable, amorphous, organic solvent-free inclusion complexes could be formed efficiently in the industrial environment. In this study terbinafine hydrochloride (TER), an antifungal BCS II drug was chosen as a model drug.
The aim of this study was the follow-through of inclusion complex preparation by co-grinding using several analytical methods.
TER and amorphous cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin; heptakis(2,6-di-O-methyl)-β-cyclodextrin) were used for the preparation of products. The thermoanalytical behavior was analyzed by differential scanning calorimetry (DSC), the occurred changes in crystalline properties were investigated by X-ray powder diffractometry (XRPD) and hot-humidity stage X-ray powder diffractometry (HOT-XRPD). Chemical interactions between the components were analyzed by Raman spectroscopy and Fourier transform infrared spectroscopy (FT-IR). Dissolution studies of TER and products were also carried out.
Cyclodextrin-TER complexes were prepared in the 1:1 molar ratio. DSC and XRPD studies suggested that the crystallinity of products gradually decreased by the increasing grinding time, and after 75 minutes of co-grinding the products were completely amorphous. HOT-XRPD studies revealed that the amorphous product containing hydroxypropyl-β-cyclodextrin did not change with increasing temperature. However, in the same process, the heptakis(2,6-di-O-methyl)-β-cyclodextrin containing product recrystallized in a new crystalline phase. Raman and FT-IR spectroscopy confirmed the molecular interactions between the components. Dissolution studies showed that the dissolution rate of complexes improved, and the solubility of TER increased both in simulated gastric and intestinal fluid, depending on the pH of the dissolution medium.
