Ternary Eutectic Ezetimibe-Simvastatin-Fenofibrate System and the Physical Stability of Its Amorphous Form

Abstract

In this study, the phase diagram of the ternary system of ezetimibe-simvastatin-fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.

Keywords: amorphous pharmaceuticals; eutectic system; ezetimibe; fenofibrate; physical stability; simvastatin; ternary eutectic.

Figure 1

Chemical structures of EZB, SVT, and FEN.

Figure 2

DSC thermograms of the crystalline physical mixtures of: (a) ezetimibe–simvastatin (EZB/SVT), (c) ezetimibe–fenofibrate (EZB/FEN), and (e) simvastatin–fenofibrate (SVT/FEN) together with their phase diagrams (b, d, f, respectively) which were constructed on the basis of both experimentally determined data (black squares) and theoretical data obtained based on the Schröder–Van Laar equation (black dashed lines).

Figure 3

(a) Ternary plot illustrating by points the investigated compositions of EZB/SVT/FEN; colors represent the concentration areas where during heating one, two, or three melting endotherms were registered (one—red area, two—green area, three—blue area); (b) the DSC thermograms of the representative systems from those three areas (c) the XRD patterns of the EZB/SVT/FEN sample for 60/30/10 concentration as a function of temperature from 295 to 415 K. Diffractograms for neat crystalline FEN, SVT, and EZB are also shown. Melting of FEN, SVT, and EZB is observed as the Bragg peaks disappear corresponding to their crystalline phases at 350, 383, and 415 K, respectively.

Figure 4

(a) 3D phase diagram of the EZB/SVT/FEN system constructed based on the experimental data; (b-d) 2D layers represents three melting areas presented in panel a; (e) 3D phase diagram of the EZB/SVT/FEN system constructed based on the theoretical data.

Figure 5

DSC thermograms of neat amorphous FEN (blue line), SVT (green lines), and EZB (red lines) measured with heating rates of 10, 5, and 2.5 K/min.

Figure 6

(a) DSC thermograms of eight representative ternary amorphous EZB/SVT/FEN systems, (b) the concentration dependence of the glass transition temperature of the EZB/SVT/FEN system.

Figure 7

(a) Dielectric loss spectra collected above the glass transition temperature of ternary amorphous EZB 5.3/SVT 10.5/FEN 84.2 systems. (b) Temperature dependence of the structural relaxation times determined by using the BDS technique for pure amorphous EZB (gray squares), pure amorphous SVT (gray triangles), pure amorphous FEN (gray circles), and their ternary mixtures that contain various mass ratios of: EZB 70/SVT 10/FEN 20 (orange circles), EZB 40/SVT 40/FEN 20 (yellow squares), EZB 10/SVT 70/FEN 20 (dark green triangles), EZB 30/SVT 30/FEN 40 (light green diamonds), EZB 40/SVT 10/FEN 50 (cyan hexagons), EZB 10/SVT 40/FEN 50 (light blue pentagons), EZB 10/SVT 20/FEN 70 (dark blue triangles), and EZB 5.3/SVT 10.5/FEN 84.2 (navy stars). Solid black lines are the VFT₁ fits, dashed red line marks the region, where τ_α = 0.63 μs, while red arrows represent the temperatures which corresponds to τ_α = 0.63 μs for each sample.

Figure 8

(a-c) Dielectric spectra of the real parts of the complex dielectric permittivity collected during the time-dependent isothermal experiment of: (a) EZB performed at 388 K, (b) FEN performed at 298 K, and (c) SVT performed at 353 K. (d) normalized dielectric constants ε′_N of EZB (squares), SVT (triangles), and FEN (circles) as a function of time from crystallization processes occurring at T = T(τ_α = 0.63 μs).

Figure 9

Normalized dielectric constants ε′_N of neat amorphous EZB (gray squares), SVT (gray triangles), and FEN (gray circles) as well as their ternary amorphous systems containing 5.3/10.5/84.2 (navy stars), 10/20/70 (dark blue triangles), 10/40/50 (light blue pentagons), 40/10/50 (cyan hexagons),and 30/30/40 (green diamonds) mass ratio of EZB/SVT/FEN as a function of crystallization time occurring at T = T(τ_α = 0.63 μs).

Figure 10

Comparison of the crystallization onset, half-life time, and endset of neat amorphous EZB, SVT, and FEN, as well as their ternary amorphous systems containing 5.3/10.5/84.2, 40/10/50, 10/40/50, 30/30/40, and 10/20/70 mass ratio of EZB/SVT/FEN.

Figure 11

Representative XRD patterns of the selected ternary amorphous systems of EZB/SVT/FEN measured: (a) just after amorphization and (b) after long-term storage of the samples at T = 298 K.