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.

Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition

“…They suggested that it could happen if the total energy of the interactions between the molecules of different species was lower than that between molecules of the same species. This hypothesis has been confirmed via DFT calculations in our previous investigations of amorphous binary mixtures containing CEL or IBU with the addition of acMAL [ 16 , 22 ].…”

“…For many decades, it has been believed that the physical stability of drugs in both the supercooled and glass states is better if they are stronger materials, i.e., characterized by smaller values of the fragility parameter [ 13 , 36 , 37 , 38 , 39 , 40 ]. In the literature, there are known exceptions in the suggested correlation for both pure drugs and pharmaceutical compositions [ 2 , 5 , 10 , 22 , 41 , 42 , 43 ]. To verify the hypothesis in the case of the binary mixtures of ETB with acMAL, we calculated the values of m p by using Equations (4) and (5) and plotted the obtained results in Figure 8 c compared to those reported earlier for the CEL–acMAL mixtures.…”

“…Nevertheless, the increase in the values of m p observed after reaching a minimum of about 30 wt% acMAL in the binary compositions for both kinds cannot be correlated with the better physical stability of amorphous mixtures with a higher content of acMAL. The non-monotonic behavior of the fragility parameter dependence on the weight concentration of acMAL in the mixture with ETB constitutes an additional rationale [ 16 , 22 , 41 , 43 , 44 ] for the important role of specific interactions, as discussed herein hydrogen bonding, in the improvement of the physical stability of the ETB–acMAL compositions.…”

Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics

“…Predominantly, large molecular weight, massive conformational flexibility, uniform distribution of electronegative atoms, and hydrogen bonding are the factors favoring the existence of the glassy state, while molecular symmetry or aromaticity usually promote crystallinity [ 14 ]. Calorimetric and spectroscopic studies [ 15 ] as well as molecular-dynamics investigations [ 16 ] suggest that distinct trends of the vitrification tendency among similar chemicals can be traced to the strength of intermolecular interactions in bulk materials.…”

Crystallization Risk Assessment of Amorphous Solid Dispersions by Physical Shelf-Life Modeling: A Practical Approach

“…A first attempt to extrapolate the crystal growth kinetics using the augmentation of the approach by Genton and Kesselring introduced by Zhang et al, which links the natural logarithm of the rate constant for crystal growth to the water content in the ASD, has been presented in our previous study . Linking the crystal growth with the molecular mobility in glasses as published by Suryanarayanan et al, − Greco et al, Paluch et al, − and others, in this work, an approach is presented that correlates the crystal growth rate with the ratio of T g of the humid ASD and the storage temperature above T g . Although drug products are usually stored below T g and the glass physics is changed compared to the behavior above T g , this correlation allows us to give a worst-case estimation of crystal growth below T g , a sufficient approximation to determine ASD shelf life to ensure patient safety.…”