Development of Solvent-Free Co-Ground Method to Produce Terbinafine Hydrochloride Cyclodextrin Binary Systems; Structural and In Vitro Characterizations

Molecular complexation with cyclodextrins (CDs) has long been a known process for modifying the physicochemical properties of problematic active pharmaceutical ingredients with poor water solubility. In current times, the focus has been on the solvent-free co-grinding process, which is an industrially feasible process qualifying as a green technology. In this study, terbinafine hydrochloride (TER), a low solubility antifungal drug was used as a model drug. This study aimed to prepare co-ground products and follow through the preparation process of the co-grinding method in the case of TER and two amorphous CD derivatives: (2-hydroxypropyl)-beta-cyclodextrin (HPBCD); heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB). For this evaluation, the following analytical tools and methods were used: phase solubility studies, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), hot-stage X-ray powder diffractometry (HOT-XRPD), Fourier-transform infrared (FT-IR), Raman spectroscopy, and Scanning Electron Microscopy (SEM). Furthermore, in vitro characterization (dissolution and diffusion studies) was performed in two kinds of dissolution medium without enzymes. In the XRPD and SEM studies, it was found that the co-grinding of the components resulted in amorphous products. FT-IR and Raman spectroscopies confirmed the formation of an inclusion complex through the unsaturated aliphatic chain of TER and CDs. In vitro characterization suggested better dissolution properties for both CDs and decreased diffusion at higher pH levels in the case of HPBCD.

Automated summary

Molecular complexation with cyclodextrins (CDs) can modify the physicochemical properties of active pharmaceutical ingredients. In this study, co-ground products of terbinafine hydrochloride (TER) and two amorphous CD derivatives were prepared using the co-grinding method. Various analytical tools were used to analyze the samples, and in vitro characterization was performed. The results showed the formation of amorphous products through co-grinding, and the inclusion complex between TER and CDs was confirmed by FT-IR and Raman spectroscopy. In vitro characterization suggested improved dissolution properties for CDs and decreased diffusion at higher pH levels for HPBCD.