Amorphous Phase Separation Research Articles

Highlighting amorphous phase separation process on cooling borosilicate melts using impedance spectroscopy

Four samples of sodium borosilicate glasses of composition (100 - x)(SiO2 - B2O3) - xNa2O with x = 4, 7, 10 and 25 mol% were synthesized and studied in a wide temperature range (up to 1673 K) using impedance spectroscopy, from the molten to the solid states. During melt cooling of three compositions (x = 4, 7 and 10), a clear transition was observed on the conductivity behavior at a critical temperature (Tcrit ≈ 973 K), highlighting the onset of an amorphous phase separation, in agreement with both Differential Scanning Calorimetry thermograms and literature. The amorphous nature of the phase separated samples was verified by in situ X-Ray Diffraction measurements performed under the same thermal conditions. Furthermore, Scanning Electron Microscopy micrographs taken on these three samples at room temperature after the impedance measurement confirmed the presence of two different phases, whose size and morphology vary with composition. As expected, the x = 25 sample did not show phase separation and remained homogeneous down to room temperature.

Discovering Novel Glass with Robust Crystallization Resistance via Amorphous Phase Separation Engineering

Discovering Novel Glass with Robust Crystallization Resistance via Amorphous Phase Separation Engineering

Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) containing the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance. Thermodynamic predictions using the PC-SAFT model revealed for each combination of polymers the optimal polymer ratio, maximum API load that is thermodynamically stable as well as miscibility of the two polymers. The stability predictions were validated by three months enduring stability tests, followed by a characterization of the dissolution behavior. The thermodynamically most stable ASDs were found to be the ASDs with deteriorated dissolution performance. Within the investigated polymer combinations, physical stability and dissolution performance opposed each other.

Kinetics of Water-Induced Amorphous Phase Separation in Amorphous Solid Dispersions via Raman Mapping.

The poor bioavailability of an active pharmaceutical ingredient (API) can be enhanced by dissolving it in a polymeric matrix. This formulation strategy is commonly known as amorphous solid dispersion (ASD). API crystallization and/or amorphous phase separation can be detrimental to the bioavailability. Our previous work (Pharmaceutics 2022, 14(9), 1904) provided analysis of the thermodynamics underpinning the collapse of ritonavir (RIT) release from RIT/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) ASDs due to water-induced amorphous phase separation. This work aimed for the first time to quantify the kinetics of water-induced amorphous phase separation in ASDs and the compositions of the two evolving amorphous phases. Investigations were performed via confocal Raman spectroscopy, and spectra were evaluated using so-called Indirect Hard Modeling. The kinetics of amorphous phase separation were quantified for 20 wt% and 25 wt% drug load (DL) RIT/PVPVA ASDs at 25 °C and 94% relative humidity (RH). The in situ measured compositions of the evolving phases showed excellent agreement with the ternary phase diagram of the RIT/PVPVA/water system predicted by PC-SAFT in our previous study (Pharmaceutics 2022, 14(9), 1904).

Effect of Copolymer Properties on the Phase Behavior of Ibuprofen–PLA/PLGA Mixtures

Prediction of compatibility of the active pharmaceutical ingredient (API) with the polymeric carrier plays an essential role in designing drug delivery systems and estimating their long-term physical stability. A key element in deducing API-polymer compatibility is knowledge of a complete phase diagram, i.e., the solubility of crystalline API in polymer and mutual miscibility of API and polymer. In this work, the phase behavior of ibuprofen (IBU) with different grades of poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA), varying in composition of PLGA and molecular weight of PLGA and PLA, was investigated experimentally using calorimetry and computationally by the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS). The phase diagrams constructed based on a PC-SAFT EOS modeling optimized using the solubility data demonstrated low solubility at typical storage temperature (25 °C) and limited miscibility (i.e., presence of the amorphous-amorphous phase separation region) of IBU with all polymers studied. The ability of PC-SAFT EOS to capture the experimentally observed trends in the phase behavior of IBU-PLA/PLGA systems with respect to copolymer composition and molecular weight was thoroughly investigated and evaluated.

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.

Detecting different amorphous – Amorphous phase separation patterns in co-amorphous mixtures with high resolution imaging FTIR spectroscopy

Many active pharmaceutical ingredients (API) in development suffer from low aqueous solubilities. Instead of the crystal form, the amorphous state can be used to improve the API’s apparent solubility. However, the amorphous state has a higher Gibb’s free energy and is inherently unstable and tends to transform back to the more stable crystal form. In co-amorphous mixtures, phase separation needs to occur before there can be crystallization. The aim of this study was to devise a method to study amorphous-amorphous phase separation with high resolution imaging Fourier transform infrared (FTIR) spectroscopy with seven 1:1 M ratio API-API binary mixtures being examined. The binary mixtures were amorphized by melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermodynamic properties (crystallization tendency, melting point (Tm) and Tg) of these mixtures were measured with differential scanning calorimetry (DSC) to verify the amorphization method and to assess the optimal storage temperature. The phase separation was examined with FTIR imaging in the transmission mode. Furthermore, measurements with two pure APIs were performed to ensure that the alterations occurring in the spectra were caused by phase separation not storage stress. In addition, the reproducibility of the imaging FTIR spectrometer was verified. The spectra were analyzed with principal component analysis (PCA) and a characteristic peak comparison method. Scatter-plots were produced from the amount of phase separated pixels in the measurement area as a way of visualizing the progress of phase separation. The results indicated that imaging with FTIR spectroscopy can produce reproducible results and the progress of phase separation can be detected as either a sigmoidal or as a start-to-finish linear pattern depending on the substances.

Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions.

In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid–liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid–liquid phase separation, as predicted by PC-SAFT.

Phase separation in surfactant-containing amorphous solid dispersions: Orthogonal analytical methods to probe the effects of surfactants on morphology and phase composition

Amorphous–amorphous phase separation (AAPS) is an important phase transition process for amorphous solid dispersion (ASD) performance both in terms of drug release as well as physical and chemical stability during storage. Addition of surfactants to ASD systems can impact both of these processes. One possible mechanism through which surfactants affect ASD performance is via their impact on AAPS. Unfortunately, despite their increasing usage in ASD formulations, the effect of surfactant on AAPS is still poorly understood, and there are limited analytical techniques that provide microstructural and composition information about phase separated ASDs. In this study, the impact of four surfactants (sodium dodecyl sulfate, Tween 80, Span 20 and Span 85) on water-induced phase separation in ASDs formulated with ritonavir and polyvinylpyrrolidone/vinyl acetate (PVPVA) was investigated using a variety of orthogonal analytical methods. Transparent films of ASDs with different compositions were prepared by spin coating. Fluorescence confocal microscopy in combination with an in situ humidity chamber was used to monitor the kinetics and morphology of phase separation following exposure to high relative humidity. Optical photothermal IR analysis of phase separated films enabled characterization of domain composition and surfactant distribution. Liquid-liquid phase separation concentration, zeta potential and solution nuclear magnetic resonance spectroscopy measurements enabled interpretation of interaction with and partition of surfactants into the drug-rich phase. It was found that phase separation kinetics and morphology were notably changed by the surfactants. Further, the surfactants showed different affinities for the drug-rich versus the aqueous/polymer-rich phases. The employed analytical techniques were found to be complementary in providing insight into surfactant location in phase separated systems. This study highlights the complexity of phase separation, especially in the presence of surfactants, and provides a foundation to understand the impact of AAPS on ASD performance.

Effect of Al2O3 content on amorphous phase-separation and self-limited crystallization of phosphosilcate glasses

Amorphous phase-separation and crystallization behavior of phosphosilicate glasses with different Al2O3 contents were systematically investigated. We demonstrate that nanophase-separation spontaneously occurs during cooling of all the glass melts. The two separated phases are found to be the phosphate-rich droplet phase with high ion movability and the rigid silicate-rich matrix. With increasing Al2O3 content, nucleation rate decreases whereas growth rate is enhanced in terms of nucleation-growth type phase-separation. In addition, for the compositions with 0 and 2 mol% Al2O3, sodium phosphate nanocrystals simultaneously form in the droplets in the cooling process, this is further confirmed from the micro-morphologies the samples heat-treated at 1.2 Tg for various durations. In this case, the growth of sodium phosphate is self-limited by the surrounding silicate-rich phase. Our results show that the addition of Al2O3 tends to inhibit nucleation of sodium phosphate rather than crystal growth. This work indicates that phase-separation can be used as a route to the preparation of amorphous/nanocrystal composites by adjusting Al2O3 content in phosphosilcate glass system.

Factors Influencing the Crystallization-Onset Time of Metastable ASDs.

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon–Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as “larger particles always crystallize later than smaller particles” are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.

Detecting Different Amorphous – Amorphous Phase Separation Patterns in Co-Amorphous Mixtures with High Resolution Imaging FTIR Spectroscopy

Detecting Different Amorphous – Amorphous Phase Separation Patterns in Co-Amorphous Mixtures with High Resolution Imaging FTIR Spectroscopy

Achieving fast hydrogenation by hydrogen-induced phase separation in Mg-based amorphous alloys

Mg-based amorphous alloys are one of the potential hydrogen storage materials. The challenges which are blocking application of such alloys involve unfavorable crystallization of amorphous phase in hydrogenation and dehydrogenation and sluggish low-temperature de/hydrogenation kinetics. To solve those challenges, the Mg60RExNi30−xCu10 (RE=La and Ce; x = 5, 7.5, 10 and 15) amorphous alloys were prepared by melt spinning and the structural transformation of amorphous phase and its correlation to hydrogenation kinetics has been investigated. It is observed that all the amorphous powders are able to absorb more than 3.0 wt%-H at 130 °C under 4.5 MPa-H2, and the hydrogen absorption rate of the Mg60RE10Ni20Cu10 amorphous alloys is much faster than other alloys by forming a dual amorphous phase structure during hydrogenation. XRD characterization of Mg60Ce10Ni20Cu10 hydrides proved that such dual amorphous phase structure is resulted by hydrogen-induced amorphous phase separation. According to EDX results, the dual amorphous phase structure consists of Ce-rich and Ni-Cu-rich domains with a size of about 5 nm which gradually form by element aggregation during hydrogen absorption. Meanwhile, it is also confirmed that the element aggregation is the precursor of hydrogen-induced crystallization as crystallization is observed in the Ni–Cu-rich domain. It is verified that the hydrogen-induced amorphous phase separation of the Mg-based amorphous alloys is tunable and can be used for obtaining superior hydrogenation performance. The hydrogen-induced structural evolution revealed in this work might inspire the development of new Mg-based hydrogen storage amorphous alloys.

Stress Corrosion Cracking in Amorphous Phase Separated Oxide Glasses: A Holistic Review of Their Structures, Physical, Mechanical and Fracture Properties

Stress corrosion cracking is a well-known phenomenon in oxide glasses. However, how amorphous phase separation (APS) alters stress corrosion cracking, and the overall mechanical response of an oxide glass is less known in literature. APS is a dominant feature concerning many multicomponent systems, particularly the ternary sodium borosilicate (SBN) glass systems. Its three constituent oxides have significant industrial relevance, as they are the principal components of many industrial oxide glasses. Simulations and experimental studies demonstrate the existence of a two-phase metastable miscibility gap. Furthermore, theory suggests the possibility of three-phase APS in these oxide glasses. Literature already details the mechanisms of phase separation and characterizes SBN microstructures. Realizing that glasses are structurally sensitive materials opens a number of other questions concerning how the mesoscopic APS affects the continuum behavior of glasses, including dynamic fracture and stress corrosion cracking. This paper reviews current literature and provides a synthetic viewpoint on how APS structures of oxide glasses alter physical, mechanical, dynamic fracture, and stress corrosion cracking properties.

Polymer-mediated drug supersaturation – A spotlight on the interplay between phase-separated amorphous drug colloids and dissolved molecules

HypothesisColloidal aggregation phenomena have been found responsible for the supersaturation of poorly water-soluble drugs, potentially leading to bioavailability enhancements. Unlike coarse precipitates, phase separation in the form of colloids, is expected to enhance drug supersaturation performance. Therefore, a high proportion of these colloids should correlate with the extent and the kinetics of supersaturation. The prime objective of the current study is to provide a mechanistic understanding on supersaturation for the model drug albendazole (ALB) in combination with twelve polymers. ExperimentsSpecies separated after a pH-shift were characterized by dynamic light scattering (DLS), freeze-fracture electron microscopy (FF-EM) and transmission X-ray diffraction (XRD). Laser diffraction (LD) in a liquid cell was introduced for a relative quantification of the colloidally separated species, described as colloid fraction. The pH-dependent supersaturation was assessed online using a miniaturized dissolution assay. FindingsHere, a measure of the extent of amorphous colloidal phase separation was established, and its impact on supersaturation was evaluated. As a result, a correlation was found between the extent of supersaturation and the colloid fraction. This confirmed the dependence of polymer-mediated enabling and preservation of supersaturation on the ability of polymers to stabilize colloid fractions. Furthermore, a fixed ratio was suggested between the dissolved drug and colloidally separated drug as the kinetic profiles of both species showed similar trajectories. In conclusion, colloid fractions were identified to be responsible for dissolved and potentially bioavailable drug molecules.

Predicting process design spaces for spray drying amorphous solid dispersions

Amorphous solid dispersions (ASDs) are commonly manufactured using spray-drying processes. The product quality can be decisively influenced by the choice of process parameters. Following the quality-by-design approach, the identification of the spray-drying process design space is thus an integral task in drug product development. Aiming a solvent-free and homogeneous ASD, API crystallization and amorphous phase separation needs to be avoided during drying. This publication provides a predictive approach for determining spray-drying process conditions via considering thermodynamic driving forces for solvent drying as well as ASD-specific API/polymer/solvent interactions and glass transitions. The ternary API/polymer/solvent phase behavior was calculated using the Perturbed-Chain Statistical Associating Theory (PC-SAFT) and combined with mass and energy balances to find appropriate spray-drying conditions. A process design space was identified for the ASDs of ritonavir and naproxen with either poly(vinylpyrrolidone) or poly(vinylpyrrolidone-co-vinylacetate) spray dried from the solvents acetone, dichloromethane, or ethanol.

Phase behavior of ASDs based on hydroxypropyl cellulose

Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies. The glass-transition temperature is a crucial attribute of a polymer, but in case of HPC hardly detectable by differential scanning calorimetry. By investigating the glass transition of HPC blends with a miscible polymer, we were for the first time able to estimate the HPC glass transition. Although both, fenofibrate and itraconazole reveal a very low crystalline solubility in HPC regardless of the HPC molecular weight, we observed that low-molecular weight HPC grades such as HPC-UL prevent fenofibrate crystallization for a longer period than the higher molecular weight HPC grades. As predicted, the ASDs with higher drug load underwent amorphous phase separation according to the differential scanning calorimetry thermograms. This work thus showed that it is possible to predict critical drug loads above which amorphous phase separation and/or crystallization occurs in HPC ASDs.

Combining crystalline and polymeric excipients in API solid dispersions – Opportunity or risk?

Amorphous solid dispersions (ASDs) are often metastable against crystallization of the active pharmaceutical ingredient (API) and thus might undergo unwanted changes during storage. The crystallization tendency of ASDs is influenced by the API crystallization driving force (CDF) and the mobility of the molecules in the ASD. Low molecular weight-excipients are known to stabilize amorphous APIs in so-called co-amorphous formulations. Due to their success in stabilizing co-amorphous APIs, low-molecular weight excipients might also enhance the stability of polymeric ASDs. In this work, we investigated the potential of combined low-molecular weight excipient/polymer formulations with in-silico tools and validated the predictions with long-term stability tests of the most promising excipient/polymer combinations. The considered critical quality attributes for the ASDs were the occurrence of amorphous phase separation, API CDF, and molecular mobility in the ASD.As an example, carbamazepine/polyvinylpyrrolidone ASDs were investigated combined with the excipients fructose, lactose, sucrose, trehalose, saccharin, tryptophan, and urea. Although all excipients had a negative impact on the ASD stability, saccharin still turned out to be the most promising one. Long-term stability studies with ASDs containing either saccharin or tryptophan verified -in agreement to the predictions- that API crystallization occurred faster than in the reference ASDs without additional excipient.This work showed that the addition of crystalline excipients to polymeric ASDs might not only offer opportunities but might also bear risks for the long-term stability of the ASD, even though the crystalline excipient stabilizes the polymer-free API. Consequently, excipients should be evaluated based on the thermodynamic phase behavior of the individual mixture of API/polymer/excipient, rather than based on pure-component properties of the excipient only. In-silico predictions proposed in this work remarkably decrease the number of screening tests for identifying suitable formulation excipients.

An experimental and theoretical approach on stability towards hydrolysis of triethyl phosphate and its effects on the microstructure of sol-gel-derived bioactive silicate glass

The sol-gel method is versatile and one of the well-established synthetic approaches for preparing bioactive glass with improved microstructure. In a successful approach, alkoxide precursors undergo rapid hydrolysis, followed by immediate condensation leading to the formation of three-dimensional gels. On the other hand, a slow kinetics rate for hydrolysis of one or more alkoxide precursors generates a mismatch in the progression of the consecutive reactions of the sol-gel process, which makes it difficult to form homogeneous multicomponent glass products. The amorphous phase separation (APS) into the gel is thermodynamically unstable and tends to transform into a crystalline form during the calcination step of xerogel. In the present study, we report a combined experimental and theoretical method to investigate the stability towards hydrolysis of triethyl phosphate (TEP) and its effects on the mechanism leading to phase separation in 58S bioactive glass obtained via sol-gel route. A multitechnical approach for the experimental characterization combined with calculations of functional density theory (DFT) suggest that TEP should not undergo hydrolysis by water under acidic conditions during the formation of the sol or even in the gel phase. The activation energy barrier (ΔG‡) showed a height of about 20 kcal·mol−1 for the three stages of hydrolysis and the reaction rates calculated for each stage of TEP hydrolysis were kFHR = 7.0 × 10−3s−1, kSHR = 6.8 × 10−3s−1 and kTHR = 3.5 × 10−3s−1. These results show that TEP remains in the non-hydrolyzed form segregated within the xerogel matrix until its thermal decomposition in the calcination step, when P species preferentially associate with calcium ions (labile species) and other phosphate groups present nearby, forming crystalline domains of calcium pyrophosphates permeated by the silica-rich glass matrix. Together, our data expand the knowledge about the synthesis by the sol-gel method of bioactive glass and establishes a mechanism that explains the role played by the precursor source of phosphorus (TEP) in the phase separation, an event commonly observed for these biomaterials.

Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations

The present study evaluates the effect of molecular mobility and molecular interactions in the physical stability of rivaroxaban (RIV) – soluplus® (SOL) amorphous solid dispersions (ASDs). Initially, the use of Adam-Gibbs approach revealed that RIV's molecular mobility (below its glass transition temperature) is significantly reduced in the presence of SOL, while the use of ATR-FTIR spectroscopy showed the formation of hydrogen bonds (HBs) between the two ASD components, indicating that these two mechanisms can be considered as responsible for system's physical stability. Contrary to previously published reports, the utilization of ATR-FTIR spectroscopy in the present study was able to clarify, for the first time, the type of intermolecular interactions formed within the examined ASD system, while the presence of a separate drug-rich amorphous phase (significantly increasing as the content of the drug increases) was also identified. Furthermore, in order to gain an insight into the intermolecular interactions responsible for drug's amorphous phase separation, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems. Analysis of the obtained trajectories showed that the formation of strong intermolecular HBs between RIV's secondary amide proton and its three carbonyl oxygens (originating from the οxazolidone, oxomorpholin and carboxamide part of the drug molecule) as well as the significant reduction of the available HB acceptors in SOL due to copolymer's chain shrinkage, were responsible for the formation of a separate drug-rich amorphous phase within the ASD.