Kinetics Of Phase Separation Research Articles

Novel multiscale simulations on the membrane formation via hybrid induced phase separation process based on dissipative particle dynamics

A novel simulation methodology, that was based on dissipative particle dynamics (DPD) combined with information from molecular dynamics (MD) and calculations of an extended Maxwell-Stefan (MS) equations, was established to obtain multiscale analysis on the dynamics of hybrid induced phase separation (HIPS), taking polyvinylidene fluoride-diphenyl carbonate/water–ethanol (PVDF-DPC/water–ethanol) system as an example. Firstly, MS equations were derived to describe the heat transfer across the interface between the casting solution and coagulation to get the temperature profiles of the casting solution. Secondly, MD simulations for the PVDF-DPC solution were conducted to acquire bond and angle distributions of the PVDF chains. And compared to the DPD particle distributions, a novel DPD force field to describe the real flexibility of PVDF chains and a coarse-graining mapping between the MD and DPD were developed. Thirdly, based on the quenching time calculated by the MS equations and the DPD time scale, DPD simulations were carried out to demonstrate the dynamics of phase separation and membrane formation for different parts of the polymer solution via HIPS and compared to that via thermally induced phase separation (TIPS). The simulation results indicated that the mass transfer had a decisive effect on the phase separation of polymer solution near the interface and resulted in a highly asymmetric structure with a denser polymer top layer and porous sublayer, and this effect was together decided by the quenching rate and polymer solidification. For the inner parts of the polymer solution, a mainly isotropic structure was formed due to heat transfer. Based on experimental verification and simulation results, it can be known that the multiscale simulation was much closer to reality and can provide deep insights into the membrane formation prepared via the HIPS process.

Determining Phase Separation Dynamics with an Automated Image Processing Algorithm.

The problems of extracting products efficiently from reaction workups are often overlooked. Issues such as emulsions and rag layer formation can cause long separation times and slow production, thus resulting in manufacturing inefficiencies. To better understand science within this area and to support process development, an image processing methodology has been developed that can automatically track the interface between liquid-liquid phases and provide a quantitative measure of the separation rate of two immiscible liquids. The algorithm is automated and has been successfully applied to 29 cases. Its robustness has been demonstrated with a variety of different liquid mixtures that exhibit a wide range of separation behavior-making such an algorithm suited to high-throughput experimentation. The information gathered from applying the algorithm shows how issues resulting from poor separations can be detected early in process development.

Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid.

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 α-relaxation 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.

Features of L-Menthol Crystallization in Optically Active Medium Based on L- and D-Asparaginate Chitosan

The phase separation kinetics of an ethanolic L-menthol solution in an aqueous solution of optically and biologically active chitosan L- and D-aspartate was studied. It has been established that this process proceeds according to the extraction crystallization mechanism and combines two types of phase separation, namely: liquid–liquid and liquid–crystal. The effect of aspartic acid stereoisomer, chitosan molecular weight, and polymer: acid ratio on the optical, structural-morphological, and dimensional characteristics of dispersed phase droplets at the initial stage of phase separation and crystal aggregates of the L-menthol condensed phase at the final stage was assessed. In the chitosan D-aspartate medium, as well as with an increase in the concentration of components in the optically active medium and the molecular weight of the polymer, the rate of phase separation, the size of droplets and particles increase. It has been suggested that the system under study is promising for encapsulating hydrophobic drugs, creating chirooptic waveguides, and sensors for biomedical purposes, as well as developing new methods for studying the fundamental principles of phase separation in intracellular regulation of membraneless organelles and subcellular organization of biosystems, including under stress conditions of a living organism underlying the development of new pharmaceuticals to treat rare and currently incurable diseases.

Pressure-jump kinetics of liquid-liquid phase separation of fused in sarcoma.

The RNA-binding protein fused in sarcoma, FUS, is intrinsically disordered protein consisting of 526 amino acids. Interactions between tyrosine residues in the low-complexity region and arginine resides in Arg-Gly-Gly regions drive a formation of liquid condensates via liquid-liquid phase separation (LLPS). The liquid condensates transform to solid aggregates, which causes onset of familial amyotrophic lateral sclerosis (ALS). To understand the mechanism underlying the liquid-to-solid transition in FUS condensates, we conducted UV-Vis measurements and microscope observation at variety of pressure and temperature. We found two types of FUS-LLPS states, LP-LLPS (<2 kbar) and HP-LLPS (2 kbar <) (Li et al., J. Phys. Chem. B 125, 6821-6829, 2021). We also analyzed formation and vanishing rates of the two LLPS states by pressure-jump UV-Vis experiments (Kitahara et al., J. Am. Chem. Soc. 143, 19697-19702, 2021). The formation and vanishing rates of HP-LLPS are 2-fold and 20-fold slower than those of LP-LLPS, respectively. Interestingly, the liquid-to-solid phase transition was accelerated with HP-LLPS. Arginine suppressed aging of droplets and HP-LLPS formation more strongly than LP-LLPS formation (Li et al., Phys. Chem. Chem. Phys 24, 19346-19353, 2022). Our data highlight the potential of HP-LLPS to be used as a therapeutic target and arginine as a plausible drug candidate for ALS-causing FUS.

Regulation of actin and microtubules by TDP-43 and profilin.

TDP-43 is a classic DNA/RNA binding protein important for the normal function of numerous cellular activities that directly and indirectly impinge on the actin and microtubule cytoskeletons. When TDP-43 levels are reduced, neurons display phenotypes consistent with the loss of actin-microtubule crosstalk functions including aberrant morphology, fewer dendritic branches, and diminished area of growth cones. TDP-43 is direct binding partner of profilin (kD = 115.2 nM), which also regulates actin and microtubule dynamics, and variants of either protein are considered causative agents in several neurodegenerative diseases. First, we explored whether TDP-43 directly interacts with the actin or microtubules cytoskeletons and whether TDP-43 could mediate cytoskeletal crosstalk by forming phase-separated biomolecular condensates. We used TIRF microscopy assays to measure the impact of purified TDP-43 on actin and microtubule assembly. TDP-43 bound and sequestered both actin and tubulin (kD = 22.7 nM). inhibiting the assembly of either polymer. We also explored how interactions between profilin and TDP-43 modulated the dynamics of either cytoskeleton or phase separation. The addition of profilin increased TDP-43 condensate formation (number and size), further inhibited actin assembly, but stabilized microtubule assembly. To investigate this in a more physiological context, we imaged the cytoskeleton and TDP-43 in Neuroblastoma-2a cells. Cells lacking profilin displayed less robust actin and microtubule arrays compared to endogenous or rescue controls. In addition, TDP-43 is mislocalized to the cytoplasm, mirroring the disease state of amyotrophic lateral sclerosis (ALS). Rescue experiments expressing wild type profilin on plasmids restored actin and microtubule arrays and the nuclear localization of TDP-43, whereas profilin plasmids harboring ALS-related mutations did not. Thus, profilin and TDP-43 are important regulators of actin and microtubule dynamics in cells and in the context of ALS.

Irradiation Effects on Stability of δ-UZr2 phase in U-50 wt% Zr Alloy

U-50wt%Zr is a candidate metallic nuclear fuel with potential application in light water reactors due to its excellent thermal properties and high radiation tolerance. The Zr-rich UZr fuels possess greater swelling resistance and fission gas release characteristics compared with U-rich UZr fuels. In this current study, the δ-phase U-50wt%Zr is proton irradiated at room temperature to 1 displacement per atom (dpa) to provide insights on phase stability under irradiation conditions. High resolution characterization of Transmission Electron Microscopy (TEM) and Atom Probe Tomography (APT) characterization techniques are used to elucidate microstructural changes due to irradiation. TEM and APT results show highly oriented bcc β-Zr-rich platelet precipitates nucleating adjacent to α-U phases inside the UZr2 matrix. Formation of this platelet morphology is characteristic of Widmänstatten structure which can be attributed to a variety of factors such as differences in thermal expansion coefficient between the phases, grain size, alloy composition, and cooling rate. The phases present are distinctly different than those observed through in situ annealing, but irradiation accelerates diffusion and phase separation kinetics. These microstructural changes in U-50wt%Zr are different from those achieved by pure thermodynamic or high temperature heavy ion irradiation experiments. Our work, together with previous ones, highlight the necessity to study the U-Zr phase diagram under non-equilibrium thermodynamics conditions to support this material's deployment as a viable nuclear fuel form.

Phase-separation physics underlies new theory for the resilience of patchy ecosystems.

Spatial self-organization of ecosystems into large-scale (from micron to meters) patterns is an important phenomenon in ecology, enabling organisms to cope with harsh environmental conditions and buffering ecosystem degradation. Scale-dependent feedbacks provide the predominant conceptual framework for self-organized spatial patterns, explaining regular patterns observed in, e.g., arid ecosystems or mussel beds. Here, we highlight an alternative mechanism for self-organized patterns, based on the aggregation of a biotic or abiotic species, such as herbivores, sediment, or nutrients. Using a generalized mathematical model, we demonstrate that ecosystems with aggregation-driven patterns have fundamentally different dynamics and resilience properties than ecosystems with patterns that formed through scale-dependent feedbacks. Building on the physics theory for phase-separation dynamics, we show that patchy ecosystems with aggregation patterns are more vulnerable than systems with patterns formed through scale-dependent feedbacks, especially at small spatial scales. This is because local disturbances can trigger large-scale redistribution of resources, amplifying local degradation. Finally, we show that insights from physics, by providing mechanistic understanding of the initiation of aggregation patterns and their tendency to coarsen, provide a new indicator framework to signal proximity to ecological tipping points and subsequent ecosystem degradation for this class of patchy ecosystems.

Control of the Crystallization and Phase Separation Kinetics in Sequential Blade‐Coated Organic Solar Cells by Optimizing the Upper Layer Processing Solvent

AbstractSequential deposition of the active layer in organic solar cells (OSCs) is favorable to circumvent the existing drawbacks associated with controlling the microstructure in bulk‐heterojunction (BHJ) device fabrication. However, how the processing solvents impact on the morphology during sequential deposition processes is still poorly understood. Herein, high‐efficiency OSCs are fabricated by a sequential blade coating (SBC) through optimization of the morphology evolution process induced by processing solvents. It is demonstrated that the device performance is highly dependent on the processing solvent of the upper layer. In situ morphology characterizations reveal that an obvious liquid–solid phase separation can be identified during the chlorobenzene processing of the D18 layer, corresponding to larger phase separation. During chloroform (CF) processing of the D18 layer, a proper aggregation rate of Y6 and favorable intermixing of lower and upper layers results in the enhanced crystallinity of the acceptor. This facilitates efficient exciton dissociation and charge transport with an inhibited charge recombination in the D18/CF‐based devices, contributing to a superior performance of 17.23%. These results highlight the importance of the processing solvent for the upper layer in the SBC strategy and suggest the great potential of achieving optimized morphology and high‐efficiency OSCs using the SBC strategy.

The pH-dependent phase separation kinetics of type-A gelatin and dextran with different initial microstructures

The phase separation kinetics of type A gelatin and dextran (GE/DE) with different microstructures were investigated to get information on the relation between technofunctional properties and structures using static multiple light scattering (S-MLS), fluorescence microscopy, and macroscopic observations. GE/DE mixtures of 5.0 wt%/2.0 wt% and 5.0 wt%/3.0 wt% at pH = 5.50–9.00 were selected as the typical samples with the DE-in-GE and bicontinuous microstructures, respectively. Macrophase separation was found to occur in both the two mixtures at pH = 5.50–9.00 with the upper phase rich in GE and the lower phase rich in DE. However, the effect of pH on the phase separation rates of the two mixtures was different: pH-independent in DE-in-GE mixtures, while pH-dependent in bicontinuous mixtures. Specifically, the order of phase separation rates for the bicontinuous mixtures at pH = 5.50–9.00 was pH5.50 > pH6.00 > pH9.00 > pH7.00 ≈ pH8.00. Changes in the electrostatic interaction or steric exclusion effect among GE (DE) droplets at pH = 5.50–9.00 were used to explain the different phase separation kinetics of GE/DE mixtures with GE-in-DE, DE-in-GE, and bicontinuous microstructures. This work characterized the phase separation processes of GE/DE mixtures with three kinds of microstructure and provided the parameters for the phase separation kinetics at the macro-level.

Long term phase separation dynamics in liquid crystal-enriched microdroplets obtained from binary fluid mixtures.

The dynamics of long term phase separation in binary liquid mixtures remains a subject of fundamental interest. Here, we study a binary liquid mixture, where the minority phase is confined to a liquid crystal (LC)-rich droplet, by investigating the evolution of size, defect and mesogen alignment over time. We track the binary liquid mixture evolving towards equilibrium by visualising the configuration of the liquid crystal droplet through polarisation microscopy. We compare our experimental findings with computational simulations and elucidate differences between bulk phases and confined droplets based on the respective thermodynamics of phase separation. Our work provides insights on how phase transitions on the microscale can deviate from bulk phase diagrams with relevance to other material systems, such as the liquid-liquid phase separation of polymer and protein solutions.

Segregation of fluids with polymer additives at domain interfaces: a dissipative particle dynamics study.

This paper investigates the phase separation kinetics of ternary fluid mixtures composed of a polymeric component (C) and two simple fluids (A and B) using dissipative particle dynamics simulations with a system dimensionality of d = 3. We model the affinities between the components to enable the settling of the polymeric component at the interface of fluids A and B. Thus, the system evolves to form polymer coated morphologies, enabling alteration of the fluids' interfacial properties. This manipulation can be utilized across various disciplines, such as the stabilization of emulsions and foams, rheological control, biomimetic design, and surface modification. We probe the effects of various parameters, such as the polymeric concentration, chain stiffness, and length, on the phase separation kinetics of the system. The simulation results show that changes in the concentration of flexible polymers exhibit perfect dynamic scaling for coated morphologies. The growth rate decreases as the polymeric composition is increased due to reduced surface tension and restricted connectivity between A- and B-rich clusters. Variations in the polymer chain rigidity at fixed composition ratios and degrees of polymerization slow the evolution kinetics of AB fluids marginally, although the effect is more pronounced for perfectly rigid chains. Whereas flexible polymer chain lengths at fixed composition ratios slow down the segregation kinetics of AB fluids slightly, varying the chain lengths of perfectly rigid polymers leads to a significant deviation in the length scale and dynamic scaling for the evolved coated morphologies. The characteristic length scale follows a power-law growth with a growth exponent ϕ that shows a crossover from the viscous to the inertial hydrodynamic regime, where the values of ϕ depend on the constraints imposed on the system.

Experimental study of phase separation in dynamically asymmetric unentangled polymer blend.

We examined a phase separation process of a dynamically asymmetric blend of unentangled polyisoprene (PI) and poly(4-ethylstyrene) (PC2St) exhibiting the upper critical solution temperature. PI having the type-A dipole was the dielectrically active fast component, whereas PC2St was the dielectrically inert slow component whose dynamics can be detected by rheological measurements. To precisely model the phase separation process, it is important to estimate the composition dependence of the mobility, which is needed to describe the phase separation dynamics. For that purpose, we conducted dielectric and rheological measurements to determine the friction coefficient of each component in a homogeneous state sufficiently above the phase separation temperature. The temperature dependence of the friction coefficient of each component was reasonably expressed by the Williams-Landel-Ferry equation. Extrapolating this dependence obtained for blends of various compositions to the test temperature T* below the phase separation temperature, we were able to estimate the friction coefficient of the chain at T* as a function of the composition. This friction coefficient was then used to determine the mobility Λ defined for the material fluxes at T*. The time-dependent Ginzburg-Landau (TDGL) equation incorporating this Λ well described the experimentally observed phase separation dynamics. In particular, the 2D TDGL simulation with this Λ qualitatively captured the phase-separated structure observed with the optical microscope as well as broad dielectric mode distribution of the blend at T*.

Phase-Separation Kinetics in the Two-Dimensional Long-Range Ising Model

Using MonteCarlo computer simulations, we investigate the kinetics of phase separation in the two-dimensional conserved Ising model with power-law decaying long-range interactions, the prototypical model for many long-range interacting systems. A long-standing analytical prediction for the characteristic length is shown to be applicable. In the simulation, we relied on our novel algorithm which provides a massive speedup for long-range interacting systems.

A modelling study of interfacial polyamidation

Interfacial polymerization (IP) is a fast polymerization technique that does not have stringent requirements on operating conditions or extreme monomer purity. The fast reaction kinetics, and the involvement of a complex array of several transport, reaction, and equilibrium processes, make its mathematical modelling challenging, and very few attempts have been made to model IP reaction, especially to predict the film properties. In particular, no detailed models exist for the commercially important polyamide system, in which the liberation of HCl brings in some unique complications and features.This work extends the earlier work on polyurea (Dhumal and Suresh, 2009) to the interfacial reaction of a diamine with a diacid chloride and accounts for different physicochemical processes associated with the reaction, such as ionic equilibria in the aqueous phase, external mass transfer, monomer diffusion through the film, solution thermodynamics, phase separation kinetics, and film formation. Flory–Huggins theory has been used to calculate the solubility limits of the oligomers in different solvents. A competition between nucleation and spinodal decomposition-based phase separation has been postulated to predict the film’s crystallinity.Since only the unprotonated fraction of the amine monomer takes part in the reaction, HCl evolved in of the reaction, and restricts monomer availability in the reaction zone. The present model explains the experimental observation that the reaction ceases in spite of both monomers being still available, as being due to the amine monomer being almost entirely protonated by about 33% conversion. The consequences of this on the reaction kinetics and film properties are explored.

Phase separation and aging dynamics of binary liquids in porous media

We employ the state-of-the-art molecular dynamics simulations to study the kinetics of phase separation and aging phenomena of segregating binary fluid mixtures imbibed in porous materials. Different random porous structures are considered to understand the effect of pore morphology on coarsening dynamics. We find the effect of complex geometrical confinement resulting in the dramatic slowing down in the phase separation dynamics. The domain growth follows the power law with an exponent dependent on the porous host structure. After the transient period, a crossover to a slower domain growth is observed when the domain size becomes comparable to the pore size. Due to the geometric confinement, the correlation function and structure factor modify to a non-Porod behavior and violate the superuniversality hypothesis. The role of porous host structure on the nonequilibrium aging dynamics is studied qualitatively by computing the two-time order-parameter autocorrelation function. This quantity exhibits scaling laws with respect to the ratio of the domain length at the observation time and the age of the system. We find the scaling laws hold well for such confined segregating fluid mixtures.

Phase separation control of PDMS/PNIPAAm IPNs and the effect on drug release

Poly (dimethyl siloxane) (PDMS) possesses good mechanical properties, oxygen permeability and optical transparency, making it an excellent candidate biomaterial, including for ophthalmic purposes. PDMS, however, is a hydrophobic polymer with poor water uptake and surface wettability, limiting its overall usefulness. Therefore, combination with one or more hydrophilic polymers, in which the immiscible materials form a stable interpenetrating polymer network (IPN), has the potential to improve the utility of PDMS in biomaterials applications. In the current work, IPNs consisting of PDMS and poly(N-isopropylacrylamide) (PNIPAAm) were synthesized. Three separate approaches were employed to generate IPNs possessing controllable and tunable phase separation, interfacial properties, and drug release kinetics. First, IPNs were synthesized with long chain PDMS prepolymers (LC-IPN), to create a looser host network capable of supporting the integration of a more interconnected PNIPAAm guest phase. In the second approach, NIPAAm was copolymerized with Tris(trimethylsiloxy) silyl-propyl methacrylate (TRIS) to compatibilize the silicone and hydrogel interface. Finally, a methacrylate-containing silicone-coupling agent, methacryloxypropyltriethoxysilane (MATO), was used to generate a PDMS host network that was more compatible with the guest PNIPAAm phase. LC-IPNs yielded materials with more pronounced temperature-induced phase transition properties compared with IPNs previously prepared. TRIS copolymerization and MATO crosslinking generated IPNs with decreased domain sizes and increased transparency. Release of the model drugs dexamethasone, timolol maleate, riboflavin and lysozyme were examined from the various IPNs. The results demonstrated that controlled release properties were possible, depending on the nature of the drug. Therefore, by varying the host and guest compositions to balance drug solubility and diffusion characteristics, it is possible to tune IPN release properties to meet the demands of the desired application. • IPNs consisting of PDMS and PNIPAAm were made 3 different ways. • Controllable and tunable phase separation, interfacial properties, and drug release. • Varying the compositions balances drug solubility and diffusion characteristics.

Miscibility of isotactic polypropylene with random and block ethylene-octene copolymers studied by atomic force microscopy-infrared

Ethylene-octene random copolymers (EOCs) and block copolymers (OBCs) have been used extensively in toughening isotactic polypropylene (iPP). In this work, the miscibility of iPP/EOC and iPP/OBC blends has been investigated quantitatively using an atomic force microscopy-infrared (AFM-IR) technique. A blend of a partially deuterated iPP and EOC at 80/20 mass ratio was found to phase separate, and in situ AFM-IR analysis revealed the presence of deuterated iPP in both phases, indicating partial miscibility between the two components. Quantitation methods for phase compositions of iPP/EOC and iPP/OBC blends using AFM-IR were established, and phase separation kinetics for a solution-mixed iPP/OBC 50/50 blend at 200 °C was investigated using AFM-IR. The phase compositions reach an equilibrium state in ∼4 h, and each component exhibits a solubility of ∼10 wt% in the other one in the molten state. Moreover, an interphase of ∼1 μm thickness and transitional composition is present in between the iPP-rich and the OBC-rich phases, indicative of good compatibility between iPP and OBC. In contrast, an iPP/EOC 50/50 blend under the same conditions contains two co-existing phases, with an EOC content of 4.9 and 93.2 wt% for the iPP-rich and EOC-rich phase, respectively, with a sharp interface between, implying poorer compatibility of EOC with iPP than for OBC. Composition analyses for iPP/EOC 80/20 and iPP/OBC 80/20 blends prepared by melt-blending support these observations.

Droplet Microfluidics for the Label-Free Extraction of Complete Phase Diagrams and Kinetics of Liquid-Liquid Phase Separation in Finite Volumes.

Liquid-liquid phase separation of polymer and protein solutions is central in many areas of biology and material sciences. Here, an experimental and theoretical framework is provided to investigate the thermodynamics and kinetics of liquid-liquid phase separation in volumes comparable to cells. The strategy leverages droplet microfluidics to accurately measure the volume ofthe dense phase generated by liquid-liquid phase separation of solutions confined in micro-sized compartments. It is shown that the measurement of the volume fraction of the dense phase at different temperatures allows the evaluation of the binodal lines that determine the coexistence region of the two phases in the temperature-concentration phase diagram. By applying a thermodynamic model of phase separation in finite volumes, it is further shown that the platform can predict and validate kinetic barriers associated with the formation of a dense droplet in a parent dilute phase, therefore connecting thermodynamics and kinetics of liquid-liquid phase separation.

High spatial resolution ToF-SIMS imaging and image analysis strategies to monitor and quantify early phase separation in amorphous solid dispersions

Amorphous solid dispersions (ASDs) are formulations with enhanced drug solubility and dissolution rate compared to their crystalline counterparts, however, they can be inherently thermodynamically unstable. This can lead to amorphous phase separation and drug re-crystallisation, phenomena that are typically faster and more dominant at the product’s surfaces. This study investigates the use of high-resolution time of flight-secondary ion mass spectrometry (ToF-SIMS) imaging as a surface analysis technique combined with image-analysis for the early detection, monitoring and quantification of surface amorphous phase separation in ASDs. Its capabilities are demonstrated for two pharmaceutically relevant ASD systems with distinct re-crystallisation behaviours, prepared using hot melt extrusion (HME) followed by pelletisation or grinding: (1) paracetamol-hydroxypropyl methylcellulose (PCM-HPMC) pellets with drug loadings of 10%–50% w/w and (2) indomethacin-polyvinylpyrrolidone (IND-PVP) ground material with drug loadings of 20%–85% w/w. PCM-HPMC pellets showed intense phase separation, reaching 100% PCM surface coverage within 1–5 months. In direct comparison, IND-PVP HME ground material was more stable with only a moderate formation of isolated IND-rich clusters. Image analysis allowed the reliable detection and quantification of local drug-rich clusters. An Avrami model was applied to determine and compare phase separation kinetics. The combination of chemical sensitivity and high spatial resolution afforded by SIMS was crucial to enable the study of early phase separation and re-crystallisation at the surface. Compared with traditional methods used to detect crystalline material, such as XRPD, we show that ToF-SIMS enabled detection of surface physical instability already at early stages of drug cluster formation in the first days of storage.