Amorphous−Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The αrelaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.
The main goal of this study is to develop an experimental toolbox to estimate the self-diffusion coefficient of active ingredients (AI) in single-phase amorphous solid dispersions (ASD) close to the glass transition of the mixture using dielectric spectroscopy (DS) and oscillatory rheology. The proposed methodology is tested for a model system containing the insecticide imidacloprid (IMI) and the copolymer copovidone (PVP/VA) prepared via hot-melt extrusion. For this purpose, reorientational and the viscoelastic structural (α-)relaxation time constants of hot-melt-extruded ASDs were obtained via DS and shear rheology, respectively. These were then utilized to extract the viscosity as well as the fragility index of the dispersions as input parameters to the fractional Stokes−Einstein (F-SE) relation. Furthermore, a modified version of Almond−West (AW) formalism, originally developed to describe charge diffusion in ionic conductors, was exercised on the present model system for the estimation of the AI diffusion coefficients based on shear modulus relaxation times. Our results revealed that, at the calorimetric glass-transition temperature (T g ), the self-diffusion coefficients of the AI in the compositional range from infinite dilution up to 60 wt % IMI content lied in the narrow range of 10 −18 − 10 −20 m 2 s −1 , while the viscosity values of the dispersions at T g varied between 10 8 Pa s and 10 10 Pa s. In addition, the phase diagram of the IMI-PVP/VA system was determined using the melting point depression method via differential scanning calorimetry (DSC), while mid-infrared (IR) spectroscopy was employed to investigate the intermolecular interactions within the solid dispersions. In this respect, the findings of a modest variation in melting point at different compositions stayed in agreement with the observations of weak hydrogen bonding interactions between the AI and the polymer. Moreover, IR spectroscopy showed the intermolecular IMI-IMI hydrogen bonding to have been considerably suppressed, as a result of the spatial separation of the AI molecules within the ASDs. In summary, this study provides experimental approaches to study diffusivity in ASDs using DS and oscillatory rheology, in addition to contributing to an enhanced understanding of the interactions and phase behavior in these systems.
Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.
Diffusion of small molecules in amorphous polymers near the glass transition is a topic of interest for a variety of technological applications. Within this study, the free volume theory (FVT) of Vrentas and Duda as a predictive tool for estimating self-diffusion coefficients is extended by suggesting modifications to certain aspects of this model. These modifications encompass the description of the free volume of the mixture, the viscosity−diffusivity interplay, and the energetics of the diffusion. To support the derived modifications, they are exercised on the diffusion of three active ingredients in polyvinylpyrrolidone. The results are partly compared with experimental data based on dielectric spectroscopy as well as secondary ion mass spectrometry (adopted from the literature). Concerning the specific hole free volume, an approach for describing nonideal mixtures achieved by means of estimating the mixtures' Vogel temperature at each composition is proposed. Moreover, a new fragility-dependent parameter, ξ 1 , is introduced into the main equation of the FVT model, which brings the model in harmony with the fractional Stokes−Einstein (F-SE) relation at the pure diffusant limit, hence improving its predictions at higher diffusant mass fractions. Furthermore, the F-SE equation is employed to describe the preexponential factor as well as the effective molar jump energy at the pure diffusant extreme. The resulting molar energy is subsequently combined with an empirically obtained effective energy at the pure polymer limit and weighted according to a quadratic expression analogous to the cohesive energy of a solution. In conclusion, the modified FVT model discussed in this study presents a fully predictive platform for describing diffusion in polymers and offers an extended temperature and compositional applicability range compared to the original version of FVT. This model is expected to be applicable to the diffusion of small molecules, which are commensurate in size with typical segments of the polymer.
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