Molecular Dynamics and Physical Stability of Ibuprofen in Binary Mixtures with an Acetylated Derivative of Maltose

Abstract

In this paper, we explore the strategy increasingly used to improve the bioavailability of poorly water-soluble crystalline drugs by formulating their amorphous solid dispersions. We focus on the potential application of a low molecular weight excipient octaacetyl-maltose (acMAL) to prepare physically stable amorphous solid dispersions with ibuprofen (IBU) aimed at enhancing water solubility of the drug compared to that of its crystalline counterpart. We thoroughly investigate global and local molecular dynamics, thermal properties, and physical stability of the IBU+acMAL binary systems by using broadband dielectric spectroscopy and differential scanning calorimetry as well as test their water solubility and dissolution rate. The obtained results are extensively discussed by analyzing several factors considered to affect the physical stability of amorphous systems, including those related to the global mobility, such as plasticization/antiplasticization effects, the activation energy, fragility parameter, and the number of dynamically correlated molecules as well as specific intermolecular interactions like hydrogen bonds, supporting the latter by density functional theory calculations. The observations made for the IBU+acMAL binary systems and drawn recommendations give a better insight into our understanding of molecular mechanisms governing the physical stability of amorphous solid dispersions.

Keywords: amorphous drug; amorphous solid dispersion; crystallization; devitrification; glass transition; ibuprofen; molecular dynamics; physical stability.

Chart 1. Chemical Structures of Investigated Compounds

Figure 1

DSC thermograms of the pure IBU and acMAL obtained during heating (10 K/min), their crystalline and amorphous forms. The first run was performed for crystalline samples (dashed lines), whereas the second one for amorphous samples (solid lines) was obtained by cooling the fully melted crystals below the glass transition temperatures T_g (vitrification).

Figure 2

Dielectric loss spectra for pure IBU (a) and for its binary mixtures with 5 wt % (b), 10 wt % (c), 20 wt % (d), and 30 wt % (e) of acMAL at several temperatures.

Figure 3

Dielectric loss spectra for pure IBU and for its binary mixtures with 5, 10, and 20 wt % of acMAL obtained at the same temperature, T = 259 K. The inset shows the dependence of the dielectric strength of the α- and s-processes vs content of acMAL in the binary mixtures (IBU+acMAL) at T = 259 K.

Figure 4

Dielectric loss spectra for a mixture of IBU+10 wt % acMAL obtained immediately after sample preparation at T = 247 K (black points) and after 9 h of its storage at the same temperature (red points).

Figure 5

Molecular structure of the ibuprofen homodimer (a) and ibuprofen-acMal complex (b). Geometry of structures optimized at the DFT/B3LYP/Def2-TZVP level of theory.

Figure 6

Reduced crystallization temperature T_red as a function of acMAL concentration in binary mixtures with different drugs: ibuprofen (black stars), celecoxib (red points), and nifedipine (blue points are calculated on the basis of data from ref (21)).

Figure 7

(a) Dielectric loss spectra for pure IBU and IBU+10 wt % acMAL obtained at temperatures 263 and 269 K, respectively, at which structural relaxation times for both systems are the same τ_α = 2 μs. Dielectric spectra of the real part of the complex dielectric permittivity collected during an isothermal crystallization of (b) pure IBU and (c) IBU+10 wt % acMAL at the same α-relaxation times τ_α ≈ 2 μs. (d) Time dependence of normalized real permittivity ε_N^′ for pure IBU and its binary mixture IBU+10 wt % acMAL, obtained during the isothermal storage of these systems at different temperatures T = 263 K and T = 269 K, but at the same α-relaxation times τ_α ≈ 2 μs for both of the systems.

Figure 8

Relaxation map obtained at T > T_g for pure IBU and pure acMAL and for their binary mixtures (IBU+acMAL) with different concentrations of acMAL. Circle and triangle points indicate the dielectric α- and s-relaxation times, respectively, whereas stars denote calorimetric α-relaxation times evaluated from TMDSC data.

Figure 9

Plot of T_g values of the binary mixtures (IBU+acMAL) from dielectric and calorimetric measurements as a function of acMAL concentration. The red line indicates the fit curve of experimental data to eq 5 with the fixed-parameter K = 0.90 evaluated from DSC data, whereas the blue line shows the free fit curve of the experimental data to eq 5 for which the parameter K = 0.35 deviates significantly from that determined from DSC.

Figure 10

Dependences of acMAL mole fraction on different molecular factors for binary mixtures (drug+acMAL): (a) isobaric fragilities (data for binary mixtures indomethacin (IND), nifedipine (NIF), and celecoxib (CEL) with acMAL were taken from refs (22), (21), and (10), respectively), (b) activation energy E_a of dielectric α-relaxation at T_g of the binary systems (the inset shows glass transition temperatures for IBU+acMAL and CEL+acMAL as a function of weight concentration of acMAL), (c) numbers of dynamically correlated molecules N_α at T_g evaluated from Donth model (eq 8) based on temperature dependences of the heat capacity C_p of investigated systems showed in the inset, (d) the change in the heat capacity ΔC_p at T_g of investigated systems of IBU+acMAL derived from data showed in the inset of panel c.

Figure 11

(a) Comparison of dielectric spectra for pure IBU, acMAL, and binary mixtures of IBU with acMAL obtained in the glassy state of investigated systems at the same temperature (218 K) at which secondary relaxations are observed. (b) Temperature dependences of structural (α) and secondary (β, (βμ), μ, and γ) relaxations times for pure IBU, acMAL, and binary mixtures of IBU with acMAL.

Figure 12

(a) Molecular structure of ibuprofen monomer. Geometry of structures optimized at the DFT/B3LYP/Def2-TZVP level of theory. Rotation coordinates are depicted: Φ₁, Φ₂, Φ₃, and Φ₄. (b–e) Energy (black line) and dipole moment changes (red line) of ibuprofen molecule as a function of rotation angle Φ₁, Φ₂, Φ₃, and Φ₄, respectively.

Figure 13

Equilibrium water solubilities of the pure crystalline IBU and amorphous IBU in ASDs with large contents of acMAL (i.e., for IBU+83 wt % acMAL, IBU+86 wt % acMAL, and IBU+87.5 wt % acMAL) at room temperature.

Figure 14

Dissolution profiles in water for the pure crystalline IBU and amorphous IBU from ASDs with various amounts of acMAL at 37 °C.