Predicting self-diffusion coefficients in semi-crystalline and amorphous solid dispersions using free volume theory.

The self-diffusion coefficient of active ingredients (AI) in polymeric solid dispersions is one of the essential parameters for the rational formulation design in life sciences. Measuring this parameter for products in their application temperature range can, however, be difficult to realise and time-consuming (due to the slow kinetics of diffusion). The aim of this study is to present a simple and time-saving platform for predicting the AI self-diffusivity in amorphous and semi-crystalline polymers on the basis of a modified version of Vrentas' and Duda's free volume theory (FVT) [A. Mansuri, M. Völkel, T. Feuerbach, J. Winck, A.W.P. Vermeer, W. Hoheisel, M. Thommes, Modified free volume theory for self-diffusion of small molecules in amorphous polymers, Macromolecules. (2023)]. The predictive model discussed in this work requires pure-component properties as its input and covers the approximate temperature range of T < 1.2 Tg, the whole compositional range of the binary mixtures (as long as a molecular mixture is present), and the whole crystallinity range of the polymer. In this context, the self-diffusion coefficients of the AIs imidacloprid, indomethacin, and deltamethrin were predicted in polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate, polystyrene, polyethylene, and polypropylene. The results highlight the profound importance of the kinetic fragility of the solid dispersion on the molecular migration; a property which in some cases might entail higher self-diffusion coefficients despite an increase in the molecular weight of the polymer. We interpret this observation within the context of the theory of heterogeneous dynamics in glass-formers [M.D. Ediger, Spatially heterogeneous dynamics in supercooled liquids, Annu. Rev. Phys. Chem. 51 (2000) 99-128] by attributing it to the stronger presence of "fluid-like" mobile regions in fragile polymers offering facilitated routes for the AI diffusion within the dispersion. The modified FVT further allows for identifying the influence of some structural and thermophysical material properties on the translational mobility of AIs in binary dispersions with polymers. In addition, estimates of self-diffusivity in semi-crystalline polymers are provided by further accounting for the tortuosity of the diffusion paths and the chain immobilisation at the interface of the amorphous and crystalline phases.

Water Sorption in Rubbery and Glassy Polymers, Nifedipine, and Their ASDs.

Polymers like poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) are commonly used as a matrix for amorphous solid dispersions (ASDs) to enhance the bioavailability of the active pharmaceutical ingredients (APIs). The stability of ASDs is strongly influenced by the water sorption in the ASD from the surrounding air. In this work, the water sorption in the neat polymers PVPVA and HPMCAS, in the neat API nifedipine (NIF), and in their ASDs of different drug loads was measured above and below the glass-transition temperature. The equilibrium water sorption was predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) combined with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP).The water-sorption kinetics were modeled using the Maxwell-Stefan approach whereas the thermodynamic driving force was calculated using PC-SAFT and NET-GP. The water diffusion coefficients in the polymers, NIF, or ASDs were determined using the Free-Volume Theory. Using the water-sorption kinetics of the pure polymers and of NIF, the water-sorption kinetics of the ASDs were successfully predicted, thus providing the water diffusion coefficients in the ASD as a function of relative humidity and of the water concentration in polymers or ASDs.

Fundamental advances in hydrogels for the development of the next generation of smart delivery systems as biopharmaceuticals.

Recent advances in developing and applying therapeutic peptides for anticancer, antimicrobial and immunomodulatory remedies have opened a new era in therapeutics. This development has resulted in the engineering of new biologics as part of a concerted effort by the pharmaceutical industry. Many alternative routes of administration and delivery vehicles, targeting better patient compliance and optimal therapeutic bioavailability, have emerged. However, the design of drug delivery systems to protect a range of unstable macromolecules, including peptides and proteins, from high temperatures, acidic environments, and enzymatic degradation remains a priority. Herein, we give chronological insights in the development of controlled-release drug delivery systems that occurred in the last 70 years or so. Subsequently, we summarise the key physicochemical characteristics of hydrogels contributing to the development of protective delivery systems concerning drug-targeted delivery in the chronospatial domain for biopharmaceuticals. Furthermore, we shed some light on promising hydrogels that can be utilised for systemic bioactive administration.

Solute Diffusivity and Local Free Volume in Cross-Linked Polymer Network: Implication of Optimizing the Conductivity of Polymer Electrolyte.

The diffusion of small molecules or ions within polymeric materials is critical for their applications, such as polymer electrolytes. Cross-linking has been one of the common strategies to modulate solute diffusivity and a polymer's mechanical properties. However, various studies have shown different effects of cross-linking on altering the solute transports. Here, we utilized coarse-grained molecular dynamics simulation to systematically analyze the effects of cross-linking and polymer rigidity of solute diffusive behaviors. Above the glass transition temperature Tg, the solute diffusion followed the Vogel-Tammann-Fulcher (VTF) equation, D = D0 e-Ea/R(T-T0). Other than the conventional compensation relation between the activation energy Ea and the pre-exponential factor D0, we also identified a correlation between Ea and Vogel temperature T0. We further characterized an empirical relation between T0 and cross-linking density. Integrating the newly identified correlations among the VTF parameters, we formulated a relation between solute diffusion and the cross-linking density. The combined results proposed the criteria for the optimal solute diffusivity in cross-linked polymers, providing generic guidance for novel polymer electrolyte design.

Measuring and Modeling Water Sorption in Amorphous Indomethacin and Ritonavir.

The amorphous state of an active pharmaceutical ingredient (API) enhances its water solubility compared to its crystalline state. However, it is well known that amorphous substances can absorb significant amounts of water therewith inducing API recrystallization. This work explores methods to obtain reliable information about water sorption in amorphous APIs and its modeling. Experimental water-sorption curves over a broad humidity range were obtained by measuring the mass increase of well-defined films of amorphous APIs. Water-sorption isotherms modeled using perturbed-chain statistical associating fluid theory (PC-SAFT) showed better accordance with the experimental data than those obtained using the Flory-Huggins model. Crank's diffusion equation was used to describe the water-sorption kinetics providing Fickian diffusion coefficients of water in indomethacin and in ritonavir. Stefan-Maxwell diffusion coefficients were obtained by converting Fickian diffusion coefficients using water activity coefficients obtained from PC-SAFT. Finally, the free-volume theory was applied to explain the persistent water concentration dependency of the Stefan-Maxwell diffusion coefficients.

Numerical Study on the Fatigue Limit of Metallic Glasses under Cyclic Tension-Compression Loading.

Numerical study was performed to determine the fatigue limit of metallic glass under tension-compression cyclic loading. A revised free-volume theory which considers the hydrostatic stress was utilized to make the predictions. Systematical simulations showed that a higher strain amplitude is prone to making the sample completely damaged earlier. However, lower strain fluctuations could result in a longer fatigue life. Shear banding evolution history described by free-volume localization could reasonably explain the mechanical responses of different samples. In addition, compressive loading could give rise to a higher stress than that under tensile loading because of hydrostatic stress contribution. In the end, a correlation between fatigue life and applied strain amplitude was plotted which could supply a guidance for designing the engineering application of metallic glass under periodic loading.

Understanding Free Volume Characteristics of Ethylene-Propylene-Diene Monomer (EPDM) through Molecular Dynamics Simulations.

Understanding the underlying processes associated with the viscoelasticity performance of ethylene-propylene-diene monomer (EPDM) during its service life is essential for assessing and predicting its waterproofing performance in underground infrastructure. The viscoelasticity of the polymer is closely related to its free volume, and both of these properties depend on multiple factors, such as temperature, stress magnitude, and strain level. To explore the fundamental viscoelastic behavior of EPDM using free volume as a proxy for viscoelasticity, this article investigates the influence of temperature, stress magnitude, and strain level, as well as their combined effect, on the free volume through molecular dynamics (MD) simulations. An EPDM cross-linked molecular model was built and verified by comparing the simulation values of glass transition temperature, mechanical properties, and gas diffusivity with the experimental results reported in the literature. Then, the dependence of EPDM's fractional free volume on temperature, strain, and their combined effect was investigated via MD simulations, on the basis of which the applicability of various superposition principles was also evaluated.

Crowding in polymer-nanoparticle mixtures.

The cell nucleus is a highly crowded environment, filled with a multicomponent, polydisperse mixture of biopolymers and nuclear bodies dispersed in a viscous solvent. With volume fractions approaching 20%, excluded-volume interactions play a key role in determining the structure, dynamics, and function of macromolecules in vivo. Under such constraints, the ensembles of macromolecular conformations can differ substantially from those prevailing in dilute solutions. Crowding thus can affect protein and RNA folding, conformational stability, and reaction kinetics, as well as phase stability of macromolecular mixtures. From the perspective of soft matter physics, this chapter reviews recent studies on crowding in polymer-nanoparticle mixtures, seeking to demonstrate the utility of simple physical models for addressing challenging issues in cell biology. The focus is on applications of free-volume theory and Monte Carlo simulation, based on geometrical models of polymers as fluctuating spheres or ellipsoids. Ideal polymer coils respond to hard-sphere crowding agents by compactifying, reducing their radius of gyration, and becoming more spherical. At sufficiently high concentrations, polymers and crowders phase-separate. The goal of this review is to identify universal principles governing macromolecular crowding and to establish a general framework for future explorations of more realistic models that may include nonsteric (e.g., electrostatic) interactions.