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)-β-cyclodextrin (HPBCD); heptakis-(2,6-di-O-methyl)-β-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.

Solvent-free preparation types for cyclodextrin complexation, such as co-grinding, are technologies desired by the industry. However, in-depth analytical evaluation of the process and detailed characterization of intermediate states of the complexes are still lacking in areas. In our work, we aimed to apply the co-grinding technology and characterize the process. Fenofibrate was used as a model drug and dimethyl-β-cyclodextrin as a complexation excipient. The physical mixture of the two substances was ground for 60 min; meanwhile, samples were taken. A solvent product of the same composition was also prepared. The intermediate samples and the final products were characterized with instrumental analytical tools. The XRPD measurements showed a decrease in the crystallinity of the drug and the DSC results showed the appearance of a new crystal form. Correlation analysis of FTIR spectra suggests a three-step complexation process. In vitro dissolution studies were performed to compare the dissolution properties of the pure drug to the products. Using a solvent-free production method, we succeeded in producing a two-component system with superior solubility properties compared to both the active ingredient and the product prepared by the solvent method. The intermolecular description of complexation was achieved with a detailed analysis of FTIR spectra.

Cyclodextrins (CD) are used extensively in the pharmaceutical industry to improve the water solubility and bioavailability of drugs. Preparing ternary systems by applying a third component can enhance these beneficial effects. The complexation methods of these ternary systems are the same as those of two-component complexes. These methods are solvent (co-evaporation, co-precipitation, etc.) or solventless “green” techniques (co-grinding, microwave irradiation, etc.). Using solvent-free methods is considered to be an economically and environmentally desirable technology.

Recent scientific publications have already demonstrated that co-grinding appears to be an efficient, solvent-free technique for preparing cyclodextrin (CD) complexes and improving physicochemical properties (solubility, stability, etc.) of active ingredients. The improvement of solubility and dissolution rate could enhance the biopharmaceutical properties of the active ingredients in pharmaceutical products. 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 two amorphous cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin (HPBCD); heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB)) were used for the preparation of products. Products were analyzed by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), hot-humidity stage X-ray powder diffractometry (HOT-XRPD), Raman spectroscopy, and Fourier-transform infrared spectroscopy (FT-IR). Dissolution studies of TER and products were also performed out. DSC and XRPD studies suggested that the crystallinity of products gradually decreased by the increasing grinding time, and after 75 min of co-grinding the products were completely amorphous. HOT-XRPD studies revealed that the amorphous product containing HPBCD did not change with increasing temperature. However, in the same process, the DIMEB-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 in both simulated gastric and intestinal fluid, depending on the pH of the dissolution medium.