# Fileset [2026MolPharm_BICNIC.pdf](https://mdr.nims.go.jp/filesets/a2ff2448-51d8-4e9e-92bf-8246aebdcd96/download) ## Creator Paulina Poloczek, [Justyna Knapik-Kowalczuk](https://orcid.org/0000-0003-3736-8098), Joanna Klimontko, Xue Han, [Kohsaku Kawakami](https://orcid.org/0000-0002-3466-9365), [Marian Paluch](https://orcid.org/0000-0002-7280-8557) ## Rights [Creative Commons BY Attribution 4.0 International](https://creativecommons.org/licenses/by/4.0/) ## Other metadata [Eutectic-Driven Recrystallization of Coamorphous Bicalutamide + Niclosamide Systems: Contrasting Stability above and below T _g](https://mdr.nims.go.jp/datasets/fce8ac6a-36e0-4c1d-b3a7-7e58dc65a647) ## Fulltext Eutectic-Driven Recrystallization of Coamorphous Bicalutamide + Niclosamide Systems: Contrasting Stability above and below TgEutectic-Driven Recrystallization of Coamorphous Bicalutamide +Niclosamide Systems: Contrasting Stability above and below TgPaulina Poloczek, Justyna Knapik-Kowalczuk,* Joanna Klimontko, Xue Han, Kohsaku Kawakami,and Marian PaluchCite This: Mol. Pharmaceutics 2026, 23, 3641−3653 Read OnlineACCESS Metrics & More Article Recommendations *sı Supporting InformationABSTRACT: Coamorphization is a promising strategy to enhance the physicalstability of poorly water-soluble drugs. However, the relationship betweencomposition, molecular dynamics, and long-term stability remains insufficientlyunderstood. Here, we investigate coamorphous systems composed of bicalutamide(BIC) and niclosamide (NIC), focusing on how the eutectic composition defined inthe crystalline state translates into molecular dynamics and long-term physical stabilityof the corresponding amorphous systems above and below the glass transitiontemperature (Tg). Thermal analysis revealed a eutectic point in the close vicinity of 25wt % NIC, enabling safe melt-based amorphization of NIC without thermaldegradation. Broadband dielectric spectroscopy showed that the addition of NIC doesnot significantly affect the molecular mobility of amorphous BIC, as reflected bycomparable Tg values oscillating around 328 K, fragility parameters in the range of85−92, as well as similar α-relaxation dynamics across all compositions. Despite thesesimilarities, the physical stability of the coamorphous systems exhibits a pronounced composition dependence. Under acceleratedconditions in the supercooled liquid state (T > Tg), the coamorphous system corresponding to the eutectic concentration displaysthe highest resistance to recrystallization. In contrast, long-term X-ray diffraction studies performed under glassy-state conditions (T< Tg) reveal a different stability ranking. These findings indicate that the stabilization observed for compositions corresponding tothe eutectic point depends on the thermal regime and emphasize the importance of evaluating physical stability under bothsupercooled liquid and glassy state conditions.KEYWORDS: bicalutamide, niclosamide, eutectic composition, coamorphous systems, physical stability, molecular mobility1. INTRODUCTIONNiclosamide (NIC) is an anthelmintic drug discovered in the1950s, initially employed as a molluscicide.1 Approximately adecade later, its efficacy in treating tapeworm infections wasestablished, leading to its approval by the United States Foodand Drug Administration (FDA) for human use in 1982.1,2 Inrecent years, drug repurposing research has revealed NIC’stherapeutic potential in the management of conditions such asParkinson’s disease, diabetes, and various viral and microbialinfections.1,2 Of particular interest is its emerging role inoncology, where it has demonstrated anticancer activity,especially in the treatment of prostate cancer and otherdrug-resistant malignancies through combination therapy.1−3 Anotable synergy has been observed when NIC is combinedwith bicalutamide (BIC), a nonsteroidal antiandrogencommonly employed in prostate cancer therapy due to itsinhibition of androgen receptor (AR) activity.3−7 Recentstudies have shown that this combination may help overcomeresistance to both BIC and enzalutamide (ENZ), enhancingtreatment outcomes and suppressing the progression of ENZ-resistant tumors.3,5Despite their pharmacological potential, the clinical utility ofthis drug combination is severely limited by the poor aqueoussolubility of both compounds, which adversely affects oralbioavailability.4,8,9 According to the Biopharmaceutics Classi-fication System (BCS), both NIC and BIC are classified asclass II drugs, characterized by low solubility and highpermeability.4,8−11 This class encompasses many activepharmaceutical ingredients (APIs). To overcome thislimitation, various strategies have been employed.11,12 Onewell-established approach is the conversion of crystallinecompounds into their amorphous forms.11−15 Amorphousmaterials exhibit enhanced aqueous solubility due to theabsence of long-range molecular order, which is associatedwith higher internal energy.13−15 However, the amorphousform of the BIC and NIC combination faces two significantReceived: December 29, 2025Revised: May 18, 2026Accepted: May 18, 2026Published: June 9, 2026Articlepubs.acs.org/molecularpharmaceutics© 2026 American Chemical Society3641https://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−3653This article is licensed under CC-BY 4.0Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/action/doSearch?field1=Contrib&text1="Paulina+Poloczek"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Justyna+Knapik-Kowalczuk"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Joanna+Klimontko"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Xue+Han"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Kohsaku+Kawakami"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Marian+Paluch"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Marian+Paluch"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/action/showCitFormats?doi=10.1021/acs.molpharmaceut.5c01958&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?goto=articleMetrics&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?goto=recommendations&?ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?goto=supporting-info&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=agr1&ref=pdfhttps://pubs.acs.org/toc/mpohbp/23/7?ref=pdfhttps://pubs.acs.org/toc/mpohbp/23/7?ref=pdfhttps://pubs.acs.org/toc/mpohbp/23/7?ref=pdfhttps://pubs.acs.org/toc/mpohbp/23/7?ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://pubs.acs.org?ref=pdfhttps://pubs.acs.org?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-ashttps://pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://creativecommons.org/licenses/by/4.0/limitations: thermal degradation during melt-based amorphiza-tion processes, resulting from the thermal instability of NIC(Tdeg < Tm) and insufficient physical stability, arising from theinherently high recrystallization tendency of amorphousBIC.4,16During the manufacture of amorphous systems, particularlythrough techniques such as melt quenching or hot-meltextrusion, APIs are exposed to elevated temperatures thatapproach or exceed their melting points. Such thermal stressmay induce degradation pathways, leading to a reduction inpharmacological efficacy and the formation of undesirabledegradation products.17−19 Furthermore, the high free energyof amorphous phases renders them physically unstable,resulting in a propensity for recrystallization during processingor storage.13,14,20−23 This phenomenon is particularly evidentin the case of BIC, as previous studies have demonstrated itstendency to recrystallize both from the supercooled liquid andthe glassy state.4,20 Although multiple stabilization strategieshave been investigated, coamorphization with low-molecular-weight excipients, such as the antiandrogen flutamide (FLU),remains one of the most promising approaches for maintainingthe amorphous state of this API.4,20,24−26In this paper, we present a comprehensive physicochemicalcharacterization of the binary coamorphous systems composedof BIC and NIC. The study aims to elucidate howcoamorphization affects the thermal behavior, moleculardynamics, and physical stability of the BIC + NIC system,both in the supercooled liquid and glassy states. Differentialscanning calorimetry (DSC) and thermogravimetric analysis(TGA) were employed to investigate the thermal properties ofboth crystalline and coamorphous mixtures. The obtainedresults provided the basis for safe vitrification the BIC + NICsystems without thermal degradation. Broadband dielectricspectroscopy (BDS) was subsequently employed to investigatethe temperature-dependent molecular mobility and toquantitatively determine the recrystallization kinetics of thestudied systems under isothermal conditions performed atelevated temperature condition (T > Tg). Finally, long-termstability tests under standard storage conditions (T < Tg) werecarried out using X-ray diffraction (XRD) to evaluate thepreservation of the amorphous state over time. The combinedresults provide a molecular-level understanding of the interplaybetween composition, dynamics, and physical stability ofcoamorphous BIC + NIC system. The study revealed that theamorphous system with a composition corresponding to theeutectic point exhibits the highest physical stability whenexamined at temperatures above the glass transition (T > Tg).Interestingly, such a trend was not observed when the systemswere stored at the glassy state (T < Tg).2. MATERIALS AND METHODS2.1. Pure Compounds and Binary MixturesBicalutamide (BIC, crystalline white powder, purity ≥ 99%, Mw =430.37 g/mol) was purchased from Hangzhou Hyper ChemicalsLimited, China. BIC is chemically described as N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide. Niclosamide (NIC, pale yellow crystallinepowder, purity ≥ 99%, Mw = 327.12 g/mol) was purchased fromSigma-Aldrich, Germany. NIC is chemically describes as 2′,5-Dichloro-4′-nitrosalicylanilide. All materials were used as received.Binary mixtures were obtained by a mixing of neat substances using amortar, and grinding them gently for 5 min at room temperature. Theconcentration of NIC in the compositions varied from 10 wt % to 90wt % by weight. To achieve amorphous mixtures, the preparedpowders were heated above their melting point and subsequentlycooled to a glassy state.2.2. Thermogravimetric Analysis (TGA)Thermal stability of neat crystalline BIC and NIC was investigated bya Mettler TG 50 thermogravimetric analyzer (Mettler-Toledo,Switzerland) linked to a Mettler MT5 balance (Mettler-Toledo,Switzerland). The powder in open aluminum pans was placed in afurnace under nitrogen purge (50 mL/min) and heated at 10 K/min.Degradation of the sample was determined by the weight losspercentage.2.3. Differential Scanning Calorimetry (DSC)Thermal properties of neat, both crystalline and amorphous BIC andNIC, as well as their binary mixtures, were examined using DiscoveryDSC 250 system (TA Instruments Inc., USA) equipped with arefrigerated cooling system. For this purpose, powder samples of massbetween 3 and 10 mg, either of a neat API or mechanical binarymixtures, were placed into aluminum crucibles (40 μL). As areference, an empty aluminum crucible was utilized. All measurementswere performed under a nitrogen purge of 50 mL/min. Instrumentcalibration for temperature and enthalpy was performed using indiumand zinc standards. The melting point of neat substance and thesolidus transition in the binary mixture was determined as the onset ofthe peak, whereas in the case of liquidus transition the peak maximumwas detected. Glass transition temperature (Tg) was identified as themidpoint of the heat capacity increment. All samples were measuredwith a heating rate of 10 K/min, while the cooling rate was 20 K/min.Each experiment was conducted at least in triplicate.2.4. Broadband Dielectric Spectroscopy (BDS)Molecular dynamics of neat amorphous BIC and its coamorphousmixtures containing 10, 25, and 40 wt % of NIC was investigated witha Novo-Control GMBH Alpha dielectric spectrometer (NovocontrolTechnologies GmbH & Co. KG, Montabaur, Germany). Dielectricspectra were registered in a broad frequency range from 10−1 Hz to106 Hz. During the nonisothermal dielectric experiments the samplewas heated (with a step of 2 K) from 331 K up to 367, 379, 389, and379 K for neat BIC, BIC + 10 wt % NIC, BIC + 25 wt % NIC, andBIC + 40 wt % NIC, respectively. The temperature was controlled bya Quattro temperature controller with temperature stability betterthan 0.1 K. The examined systems were measured in a parallel-platecell made of stainless steel (diameter of 15 mm, and a 0.1 mm gapprovided by silica spacer fibers).2.5. X-ray Diffraction (XRD)XRD measurements of powdered samples, including neat crystallineBIC, neat crystalline NIC, neat amorphous BIC, as well as physicalmixtures and coamorphous BIC + NIC systems containing 10, 20, 25,30, and 40 wt % NIC, were performed using a Malvern PanalyticalEmpyrean diffractometer (Malvern Panalytical Ltd., Malvern, UK)equipped with a PIXcel3D ultrafast solid-state hybrid detector and aNi-filtered Cu Kα1,2 radiation source (λ = 1.5406 Å). Measurementswere carried out at room temperature (oscillating around 293−296K) in reflection mode using Bragg−Brentano geometry over a 2θrange of 5−45°. Prior to the first XRD measurement, amorphoussamples were freshly prepared by melt quenching and analyzedimmediately after vitrification. To ensure identical aging time,individual samples were prepared sequentially at intervals correspond-ing to the duration of a single XRD measurement. Following theinitial measurement, the samples were stored in SI SUBSTR 32 mmZERO BACKGROUND SAMPLE HOLDERS made from 32 mmdiameter silicon single crystal substrates and placed in the built-in 15-position Sample Changer. Between subsequent XRD measurements,the samples were kept under continuously monitored temperatureand relative humidity (35−38%) conditions.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533642Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-as3. RESULTS AND DISCUSSION3.1. Thermal Properties of Bicalutamide and NiclosamideCompositionsIn the initial stage of this work, the thermal behavior of theneat (as received) BIC and NIC was examined by differentialscanning calorimetry (DSC) and thermogravimetric analysis(TGA) to establish their fundamental thermal characteristics.The results�obtained during heating with a rate of 10 K/min�are presented in Figure 1. As shown in panel a of Figure1, the DSC thermogram of neat BIC displays a single sharpendothermic event corresponding to melting at Tm = 465 K,which is in agreement with the literature data.27 When themelting temperature is compared with the temperature atwhich a 0.5% mass loss is observed on the TGA trace(considered a reliable indicator of the onset of thermaldegradation), it becomes evident that BIC possesses asufficient thermal window for safe amorphization by meansof melt-based methods, such as vitrification. In contrast, panelb of Figure 1 presents the thermal profile of neat NIC. As canbe noted the compound begins to melt at Tm = 503 K, whatalso agrees with the literature melting point of this API.28,29 Itis worth pointing out that melting temperature overlaps withthe NIC’s onset of thermal decomposition, clearly indicatingthat NIC is thermally unstable at its melting point, andattempts to obtain its amorphous form via melt-based methodsmay result in partially degraded or chemically impure material.Moreover, it should be emphasized that our experimentalobservations revealed that even when NIC melts (with evidentpartial degradation) it rapidly recrystallizes upon cooling. Thiscrystallization behavior is documented in the SupportingInformation (Figure S1), where DSC heating and coolingthermograms of neat NIC are presented. Therefore, theamorphization of NIC is highly challenging. On the one handthe compound degrades upon melting, and on the other handit exhibits a strong tendency to recrystallize.As it has been mentioned in the introduction, recentpharmacological studies have demonstrated a therapeuticsynergy between BIC and NIC in the treatment of prostatecancer. Therefore, the next stage of our study focused onFigure 1. DSC (black) and TGA (green) heating scans of neat (A) BIC and (B) NIC recorded at a heating rate of 10 K/min. For BIC, a sharpmelting endotherm at Tm = 465 K is observed well below the onset of thermal degradation, indicating a sufficient thermal window for melt-basedamorphization. In contrast, for NIC the melting event at Tm = 503 K overlaps with the onset of thermal decomposition, as evidenced by a 0.5%mass loss (marked by dashed red lines), demonstrating its pronounced thermal instability. The shaded areas indicate the temperature rangesassociated with thermal degradation. Additional data for representative binary system (BIC + 25 wt % NIC) are provided in the SupportingInformation (Figure S2).Figure 2. (A) DSC heating thermograms of crystalline BIC, NIC, and their binary mixtures recorded at a heating rate of 10 K/min. Depending oncomposition, the thermograms reveal either two distinct endothermic events corresponding to eutectic melting followed by melting of the excesscomponent, or a single sharp endotherm characteristic of the eutectic composition (BIC + 25 wt % NIC, highlighted in red). (B) Phase diagram ofthe BIC + NIC system constructed from DSC data. Experimental melting points (symbols) are plotted together with liquidus lines calculated usingthe Schröder−van Laar equation (dashed lines).Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533643Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig2&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-aspreparing and investigating the thermal properties of binarymixtures of these APIs, aiming to address the followingquestions: How do BIC and NIC inf luence each other’s thermalbehavior when combined? Can these compounds form a eutecticsystem that would reduce NIC’s melting temperature andconsequently enable NIC’s amorphization in the presence of BICvia the melt-quenched method? If so, what is the eutecticconcentration for the NIC and BIC system, and in whichcompositional ranges would amorphization be feasible (safeagainst thermal decomposition)?To answer these questions, binary mixtures of BIC and NICat various weight concentrations were prepared (as describedin the Materials section) and investigated using DSC. Duringthe calorimetric experiments, the samples were heated from298 to 520 K at a rate of 10 K/min. The obtainedthermograms, alongside those of the neat APIs, are presentedin Figure 2a.As can be seen, the DSC traces of the binary BIC + NICmixtures reveal distinct thermal behavior depending on thecomposition. Mixtures containing 90 to 30 wt % NIC exhibittwo clearly separated endothermic events, corresponding toeutectic melting and the subsequent melting of the excesscomponent.30,31 At 25 wt % NIC, a single, sharp and narrowendothermic peak is observed, characteristic of the eutecticcomposition, where both components melt simultaneously at adepressed temperature. Interestingly, at lower NIC concen-trations (i.e., 20 and 10 wt %), only one broadenedendothermic peak is observed. The broadening, relative toboth the neat substances and the eutectic composition,suggests that this single thermal event is in fact an overlap oftwo unresolved transitions. To further verify this interpreta-tion, additional DSC measurements were performed at asignificantly reduced heating rate (0.5 K/min), which allowedimproved separation of overlapping thermal events (see FigureS3 in the Supporting Information). To accurately characterizethe thermal behavior of these compositions investigated with10 K/min HR, peak deconvolution was performed using adual-function fitting approach. The onset of the firstendotherm and the maximum of the second endotherm weredetermined and subsequently used for the construction of theBIC + NIC phase diagram. Moreover, a complementaryTammann analysis was carried out to further support thedetermination of the eutectic composition (see Figure S4 inthe Supporting Information). The resulting phase diagram isshown in Figure 2b, where the experimental data points areplotted together with the liquidus lines calculated using theSchröder−van Laar equation. This model describes the meltingpoint depression in binary mixtures of crystalline solids basedon the following formula:32−34=ikjjjjjy{zzzzzxHR T Tln( )1 1ifus im i,, (1)where xi is the mole fraction of component i, ΔHfus,i and Tm,irepresent the enthalpy of fusion as well as the meltingtemperature of the pure component, respectively, T is thetemperature of the mixture at equilibrium, while R is theuniversal gas constant. It needs to be pointed out that thetheoretical curves show good agreement with the experimentaldata confirming the eutectic point in the close vicinity of 25 wt% NIC and T = 455 K (based on the Tammann plot analysis(Figure S3), the eutectic composition was estimated to beapproximately 26.4 wt % NIC). The observed eutecticbehavior explains the visible melting point depression andproves that melt-based amorphization of NIC in the presenceof BIC is feasible and thermally safe within the NICconcentration range of 0 to 40 wt %.Considering both the melt-processing limitations of NIC-rich systems (i.e., thermal decomposition) and the described inthe Introduction proven therapeutic benefits of BIC-dominated compositions, we focused our further investigationson amorphous binary BIC + NIC systems with aFigure 3. (A) DSC heating thermograms of neat amorphous BIC and coamorphous BIC + NIC systems recorded at a heating rate of 10 K/min. Tgof the samples is indicated by the green shaded region, while arrows mark the onset of cold crystallization (Tc). Depending on composition, thesystems exhibit pronounced differences in recrystallization tendency. Notably, the eutectic composition (BIC + 25 wt % NIC, highlighted in red)does not show any crystallization event within the experimental temperature window, indicating enhanced physical stability. (B) Compositiondependence of the crystallization temperature (Tc, green squares) and glass transition temperature (Tg, red circles) for the investigated systems.The thermal gap ΔT = Tc − Tg, indicated by arrows, serves as a measure of stability and reaches its maximum at the eutectic composition,confirming its superior resistance to recrystallization under nonisothermal conditions.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533644Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig3&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-aspredominance of BIC. Selected mixtures containing 10, 15, 20,25, 30, 35, and 40 wt % NIC were prepared by melting thecrystalline powders in DSC crucibles followed by rapid coolingat a rate of 20 K/min. The resulting amorphous samples weresubsequently reheated with a rate of 10 K/min. The recordedthermograms are presented in panel a of Figure 3, along withthe trace of amorphous neat BIC for comparison.As can be seen, all binary mixtures exhibit a single glasstransition event, with Tg values identical to that of neat BIC,i.e., Tg = 328 K. This value (Tg of neat BIC) agrees well withpreviously reported literature data.4,20 The observed invariancein BIC’s Tg in the binary compositions suggests that NIC andBIC possess similar Tg values. It is worth noting that thisinterpretation is further supported by the empirical two-thirdsrule (Tg ≈ 2/3 Tm), which allows for a rough estimation of theglass transition temperature of NIC. Using the reportedmelting temperature of NIC (Tm = 503 K), the estimated Tg isapproximately 335 K. This value is in good agreement with theexperimentally observed Tg range for the investigated systems,thereby reinforcing the conclusion that NIC and BIC possesssimilar glass transition temperatures. Upon further heating ofneat BIC on the DSC thermogram, an exothermic peak wasregistered, confirming that the sample easily recrystallizes fromthe supercooled liquid state. This behavior is consistent withits classification as a second group of glass-formers (accordingto the classification system introduced in 2010 by Baird et al.),meaning that although it can be vitrified, it lacks the ability tomaintain the amorphous state upon heating.35 Binary mixtureswith 10 and 20 wt % NIC show slightly shifted to highertemperatures but still noticeable recrystallization exotherms,suggesting that NIC exerts a partial stabilizing effect.Interestingly, the composition being in the close vicinity toeutectic (25 wt % NIC) shows no recrystallization tendencythroughout the entire heating scan. This stabilizing effect doesnot persist with increasing NIC content, and the DSCthermograms of systems containing 30 and 40 wt % of NICagain exhibit an endothermic event, reflecting the recrystalliza-tion tendency of these compositions. To better quantify theFigure 4. Dielectric loss spectra (ε″) recorded in the glassy state (T < Tg�gray lines), and supercooled liquid region (T > Tg�black lines) for (A)neat amorphous BIC and coamorphous BIC + NIC systems containing (B) 10 wt % NIC, (C) 25 wt % NIC, and (D) 40 wt % NIC. Measurementswere performed upon heating in 5 K from 203 to 228 K and in 2 K temperature steps, starting from 331 K up to the temperatures indicated in eachpanel. Red dashed curves mark the spectra at which a rapid decrease in dielectric strength is observed, corresponding to the onset ofrecrystallization.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533645Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig4&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asobserved changes in recrystallization tendency, the thermal gapΔT = Tc − Tg was calculated for each composition and ispresented in panel b of Figure 3. This parameter serves as anindicator of kinetic stability of the investigated samples. Thehigher the ΔT value, the greater the resistance torecrystallization. As can be seen ΔT increases on both sidesas the composition approaches the eutectic ratio (∼25 wt %NIC), for which no recrystallization was observed within theexperimental window. This absence of crystallization suggeststhat the eutectic composition exhibits the highest physicalstability among all studied amorphous systems. Such behavior,i.e., the maximal physical stability of the amorphous systemcoincident with the eutectic composition, is consistent withrecent findings in the field of coamorphous pharmaceuticalsystems.36,37 To fully understand the origin of the observedimprovement in the physical stability of BIC and NIC in theirbinary compositions, it is essential to go beyond thermalanalysis. Thus, in the following sections, special attention isdevoted to the investigation of molecular dynamics andrelaxation processes in the studied systems, as well as to adetailed examination of how changes in composition influencethe recrystallization behavior and overall physical stability ofthe coamorphous BIC + NIC mixtures at isothermal Tconditions.3.2. Investigation of the Impact of Coamorphization onthe Molecular Dynamics of Neat BICTo investigate the impact of amorphous NIC on the moleculardynamics of amorphous BIC, broadband dielectric spectros-copy (BDS) was employed. The analysis focused on thetemperature dependence of the structural relaxation times andon the width of the structural relaxation peak. Notably, nowell-defined secondary relaxation processes (such as Johari−Goldstein relaxation) were detected in the temperature rangebelow Tg for any of the investigated systems. Instead, thedielectric response in the glassy state is dominated by a nearlyconstant loss (NCL) contribution. Therefore, the discussion isfocused on the structural (α) relaxation, which constitutes thedominant dynamic process governing molecular mobility inthese materials. The measurements were used also to verify thenonmonotonic changes in physical stability previouslyobserved in the DSC experiments. For this purpose, neatamorphous BIC as well as BIC-based coamorphous systemscontaining 10, 25, and 40 wt % NIC were investigated.Importantly, the thermal stability issues of neat NIC describedabove are no longer a limiting factor for the investigated onBDS BIC + NIC compositions, as the combined systemsexhibit sufficiently depressed melting temperatures, preventingthermal decomposition during melt-based processing. Themeasurements were carried out in the supercooled liquid andglassy state, heating the samples in 5 K step from 203 to 328 Kand in 2 K steps from 331 K up to 367, 379, 389, and 379 Kfor neat BIC, BIC + 10 wt % NIC, BIC + 25 wt % NIC, andBIC + 40 wt % NIC, respectively, with the resulting dielectricloss spectra presented in Figure 4. As can be seen in all cases, awell-defined α-relaxation peak, associated with the cooperativestructural dynamics, can be clearly identified. During heating,the α-relaxation shifts systematically toward higher frequencies,reflecting the acceleration of molecular dynamics withincreasing temperature. In addition to the main α-process, apronounced contribution from dc-conductivity is observed inthe low-frequency region, which becomes more significant afterthe addition of NIC to the system. It is also worth noting thatfor each investigated sample, the intensity of the dielectric lossspectra at some point begins to decrease rapidly. This drop isdirectly associated with the recrystallization process, duringwhich the number of dipoles contributing to the dielectricresponse is reduced (Δε ∼ Nμ2, where N is the number ofdynamically reorienting dipoles, while μ is their dipolemoment).38 Thus, the observed reduction in Δε reflects adecrease in the fraction of molecules participating in structuralrelaxation due to their incorporation into the crystalline phase.As can be seen in Figure 4, the onset of the aforementionedintensity decrease, i.e., the beginning of sample recrystalliza-tion, strongly depends on the concentration of the BIC + NICsystem. The earliest crystallization is observed for neat BIC,followed by the mixture containing 40 wt % NIC, then by theFigure 5. (A) Temperature dependence of the structural relaxation time (τα) determined based on BDS measurements for neat amorphous BICand coamorphous BIC + NIC systems containing 10, 25, and 40 wt % NIC. The solid lines represent fits to the VFT equation. (B) Comparison ofnormalized dielectric loss spectra (ε″/ε″max) recorded at T = 343 K for neat BIC and its coamorphous mixtures. All spectra exhibit a comparable α-relaxation peak shape, characterized by βKWW = 0.85.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533646Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig5&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-assystem with 10 wt % NIC, while the latest onset ofrecrystallization is recorded for the nearly eutectic composition(BIC + 25 wt % NIC). This nonmonotonic behavior is fullyconsistent with the trend observed and discussed in theprevious section based on the calorimetric studies.In order to assess whether, despite the absence of significantdifferences in Tg, the investigated samples differ in thetemperature dependence of the structural relaxation times(τα(T)), the asymmetric α-relaxation peaks were fitted usingthe Havriliak−Negami (HN) function with conductivitycorrection, defined as:39* == +[ + ]+ii i( ) ( ) ( )1 ( )HNHNa bDC0 (2)The conductivity contribution was treated as an additiveterm and did not affect the reliability of the HN fits, as the α-relaxation peak remained well-defined and could be clearlyseparated from the low-frequency conductivity contribution. Ineq 2, ε′(ω) and ε″(ω) are the dielectric responses in real andimaginary parts, respectively, ε∞ is the permittivity at highfrequencies, Δε is dielectric strength, τHN represent therelaxation time, characteristic of the process, while α and βare peak shape parameters. Employing the obtained fittingparameters the structural relaxation time of the α-process (τα)was calculated for each temperature in every investigatedcomposition by using the following formula:40−42= [+] [+]sin(2 2) sin(2 2)HN1/ 1/(3)It is worth pointing out that the values of τα calculated fromthe described above fitting procedure correspond to the inverseof the peak frequency (τα = 1/2πfmax), where fmax denotes thefrequency at which the maximum of the α-relaxation processoccurs. The temperature dependences of the structuralrelaxation times τα(T) determined for the investigated systems,i.e., neat amorphous BIC and the coamorphous BIC + 10, 25,and 40 wt % NIC mixtures, are compared in panel a of Figure5. As can be seen, all systems exhibit nearly identical τα(T)behavior, demonstrating that the addition of NIC to BIC doesnot practically modify its molecular dynamics, which mostlikely results from the very similar temperature dependence ofthe structural relaxation times of neat NIC to neat BIC. Inorder to parametrize this dependence, the Vogel−Fulcher−Tammann (VFT) equation was applied. The VFT relation isgiven by the following equation:43−45=ikjjjjjy{zzzzzTBT T( ) exp0 (4)where τ∞, B, and T0 are fitting parameters. Here, τ∞ representsthe pre-exponential factor related to the vibrational time scale,T0 is the Vogel temperature corresponding to the divergence ofrelaxation time, and B = DT0, with D being the parameter thatquantifies the deviation from simple Arrhenius behavior. Thevalues of the obtained VFT parameters for both neat BIC andits coamorphous mixtures with NIC are summarized in Table1. By extrapolating the VFT curves to τα = 100 s, thecorresponding glass transition temperatures were determinedfor all investigated systems (Tg = 326 K). As can be seen, theTg values derived from dielectric measurements are in goodagreement with these obtained from calorimetric studies.In the next part of the analysis of the dielectric loss spectra,the shape of the structural relaxation peaks was compared forall investigated systems. The spectra selected for this purpose,recorded at T = 343 K, are presented in panel b of Figure 5. Ascan be seen, the width of the dielectric loss peaks for allexamined materials�neat BIC and its mixtures containing 10,25, and 40 wt % NIC�can be satisfactorily parametrized usingthe same shape parameter βKWW = 0.85 suggesting comparabledegree of dynamic heterogeneity among the samples.46 Theonly noticeable difference between the compared spectra is thepreviously discussed increased contribution from dc-conduc-tivity, which becomes more pronounced upon the addition ofNIC.A comparative analysis of the dielectric loss spectra for neatamorphous BIC and its coamorphous mixtures containing 10,25, and 40 wt % NIC that has been presented in this sectionrevealed only minor differences among the investigatedsamples. The temperature dependence of the structuralrelaxation time (τα(T)), as well as the glass transitiontemperature (Tg), the fragility parameter (mp), and thestretching parameter (βKWW) were found to be nearly identicalfor all systems.12,13,41,47 Considering that molecular dynamicsoften play a crucial role in governing the physical stability ofamorphous pharmaceutical systems, the invariance of theseparameters could suggest a comparable tendency towardrecrystallization of all investigated systems. However, asdemonstrated by the experimental data, the samples begin torecrystallize at different temperatures during heating, indicatingthat they differ significantly in terms of physical stability. Thisobservation is fully consistent with the results obtained fromcalorimetric studies i.e., both DSC and BDS revealed anonmonotonic dependence of recrystallization tendency onthe NIC content in the binary amorphous BIC + NIC systems.It should be noted, however, that these conclusions are basedsolely on nonisothermal measurements. Therefore, to verifywhether the same trend persists when the samples aremaintained under identical thermal conditions, isothermalstability studies were carried out, as presented in the followingsections of this work.3.3. Physical Stability Studies of BIC + NIC CoamorphousSystems under accelerated T (T > Tg) ConditionsTo evaluate the physical stability of the amorphous BIC and itscoamorphous mixtures containing 10, 15, 20, 25, 30, and 40 wt% of NIC at isothermal conditions, and in this sectionparticularly at temperatures above the glass transition, time-Table 1. VFT Fit Parameters Derived from Dielectric Data for Neat BIC and Coamorphous BIC + NIC Systems, along withthe Corresponding Tg Values Determined from BDS, and mpSample: log τ∞ [s] B = DT0 [K] T0 [K] Tg,BDS [K] mpNeat BIC −16.4 ± 0.2 3015 ± 98 254.4 ± 1.9 325.5 85BIC + 10% NIC −15.1 ± 0.2 2452 ± 67 264.0 ± 1.2 326.3 89BIC + 25% NIC −14.7 ± 0.2 2235 ± 82 265.6 ± 1.5 325.9 92BIC + 40% NIC −16.3 ± 0.3 2919 ± 141 256.3 ± 2.2 325.5 86Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533647Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asresolved dielectric measurements were performed. Figure 6presents the evolution of the dielectric loss spectra recorded atT = 348 K for two representative samples: neat BIC (panel a)and for the amorphous composition of BIC and NIC havingeutectic concentration (i.e., BIC + 25 wt % NIC) (panel b).As can be seen, both systems show a gradual decrease indielectric strength (Δε ∝ N·μ2) with increasing measurementtime, which reflects the progressive loss of dipolar dynamicsassociated with recrystallization. In the case of neat BIC, thedielectric signal begins to decay rapidly after approximately 8100 s, and the recrystallization process is completed within 45000 s. In contrast, the amorphous mixture having the eutecticconcentration remains stable for a significantly longer periodi.e., the onset of recrystallization is strongly delayed. In panel bof Figure 6, the spectrum recorded at t = 45 000 s (i.e., thetime at which neat BIC becomes fully recrystallized) ishighlighted in green; at this t condition, in the case of the BIC+ 25 wt % NIC mixture, the recrystallization process has onlyjust begun, and the complete loss of dielectric response occursafter 213 000 s.As was noted above, the results presented in Figure 6 arerepresentative examples of the time-dependent dielectricresponse recorded for neat BIC and for the coamorphousBIC + NIC mixture corresponding to the eutectic concen-tration. However, analogous isothermal experiments were alsoperformed for several other compositions of the BIC + NICsystem in order to systematically evaluate the concentration-dependent physical stability. The dielectric data obtained forall studied mixtures were analyzed in terms of the normalizeddielectric strength, ε’N(t) which represents the normalizedprogress of the recrystallization process, where ε’N(t) = 0corresponds to the fully amorphous initial state and ε’N(t) = 1corresponds to the fully recrystallized state. The normalizationprocedure was performed according to the relation:48,49=tt( )(0) ( )(0) ( )N(5)where ε′(0) and ε′(∞) correspond to the initial and finalpermittivity values, respectively, and ε′(t) denotes thepermittivity recorded at a given time. This normalizationfacilitates a direct comparison of crystallization kinetics acrosssamples having different εs values. The resulting dependencesare presented in Figure 7.As can be seen, all investigated systems reveal a character-istic sigmoidal shape of the ε’N(t) curves, typical forcrystallization processes governed by nucleation and growthmechanisms. In order to describe and compare thecrystallization behavior of all the investigated samples, theirkinetic curves were fitted using the Avrami model, which is oneof the most established approaches for studying isothermalcrystallization processes. The model is expressed by thefollowing equation:50=t kt( ) 1 exp( )Nn (6)where k denotes the crystallization rate constant and nrepresents the Avrami exponent, which reflects the dimension-ality of crystal growth and the nature of the nucleation process.In most cases, the n parameter typically ranges between 2 and3, however, in the present study, n values were found to varywithin a broader range of 2 to 5, increasing as the compositionapproached the eutectic ratio. This trend suggests that themechanism of crystallization becomes more complex near theeutectic composition, as additionally evidenced by deviationsfrom ideal linear behavior observed in the linearized Avramiplots presented in Figure S5 (Supporting Information).Therefore, the Avrami analysis presented here should betreated as a semiquantitative description of the overallrecrystallization behavior rather than a strict mechanisticinterpretation based on an ideal single-step crystallizationmodel. The corresponding values of the Avrami exponent andcrystallization rate constant, are summarized in Table 2. It isworth pointing out that although the investigated systemsexhibit very similar molecular dynamics, as evidenced bycomparable glass transition temperatures, fragility parameters,and structural relaxation times, their crystallization kineticsdiffer significantly. This indicates that the crystallizationprocess is not governed solely by molecular mobility. InFigure 6. Time evolution of dielectric loss spectra (ε″) recorded at T= 348 K for (A) neat amorphous BIC and (B) the coamorphouseutectic composition (BIC + 25 wt % NIC). The measurementsillustrate the recrystallization process monitored isothermally by BDS.tend denotes the total experimental time, extending beyond thecompletion of recrystallization.Figure 7. Normalized dielectric strength (ε′N) as a function of timerecorded at T = 348 K for neat amorphous BIC and coamorphousBIC + NIC systems with different niclosamide contents. The decreasein ε′N reflects the progress of recrystallization under isothermalconditions. Symbols represent experimental data, while solid linescorrespond to fits using the Avrami model.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533648Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig7&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asgeneral, crystallization kinetics are determined by twocompeting processes: nucleation and crystal growth. Whilestructural relaxation reflects molecular mobility and is closelyrelated to crystal growth, nucleation is strongly influenced bylocal structural organization and intermolecular interactions. Inthe present system, the addition of NIC does not significantlyaffect the α-relaxation dynamics of BIC, suggesting thatmolecular mobility remains largely unchanged. However, thepronounced differences in crystallization half-times indicatethat nucleation processes are strongly composition-dependent.In particular, the eutectic composition exhibits the highestresistance to crystallization, which can be attributed toincreased structural disorder and frustration, hindering theformation of stable crystalline nuclei. At higher NIC contents,the decrease in stability suggests that local structuralarrangements may become more favorable for nucleation,despite similar molecular mobility.Importantly, the observed trend in stability is identical tothat found in the nonisothermal DSC and BDS experiments�the eutectic composition (BIC + 25 wt % NIC) exhibits thehighest physical stability, while the physical stability of theremaining systems decreases with increasing deviation from theeutectic ratio. This nonmonotonic concentration dependenceagain confirms that the maximum stabilization effect ariseswhen the intermolecular interactions and molecular packingreach their optimal balance, characteristic for the eutecticcomposition. To enable a quantitative comparison of thephysical stability among all investigated materials, thecrystallization onset (tonset) and half-life (t1/2) were determinedand compared in the Table 2. For a clearer illustration and tofacilitate direct comparison of the differences in physicalstability, the obtained tonset and t1/2 values were visualized inFigure 8 in the form of a red bar chart superimposed on thephase diagram of the BIC + NIC system.The diagram clearly illustrates that the eutectic point,corresponding to 25 wt % NIC, coincides with thecomposition exhibiting the highest physical stability underaccelerated conditions. It is worth noting that the observedcorrelation between the liquidus line of the crystalline BIC +NIC system and the crystallization half-life values of itsamorphous counterparts suggests a strong relationshipbetween the thermodynamic and kinetic properties of thesystem. The pronounced depression of the melting temper-ature at the eutectic composition facilitates molecular mixingand promotes the formation of a homogeneous amorphousphase, while the optimal intermolecular interactions betweenBIC and NIC appear to effectively suppress recrystallization.This combined thermodynamic-kinetic stabilization mecha-nism provides direct experimental evidence that the highestresistance to crystallization in coamorphous systems can beachieved when the composition corresponds to the eutecticpoint. It should be emphasized, however, that so far thephysical stability of the investigated systems has beencompared only in the supercooled liquid state.3.4. Physical Stability Studies of BIC + NIC CoamorphousSystems under Standard Storage T (T < Tg) ConditionsTo verify whether the physical stability trend observed for thecoamorphous BIC + NIC systems in the supercooled liquidstate is preserved when the materials are stored in the glassystate�specifically, under standard storage conditions atTroom�long-term stability tests were performed using X-raydiffraction (XRD). For this purpose, six representative sampleswere selected: neat BIC, BIC + 10 wt % NIC, BIC + 20 wt %NIC, BIC + 25 wt % NIC (corresponding to the eutecticcomposition), BIC + 30 wt % NIC and BIC + 40 wt % NIC.All these coamorphous systems were obtained by vitrificationand subsequently powdered prior to the first XRD measure-ment, which was performed immediately after their prepara-tion. The structural evolution of the materials was thenmonitored during storage: during the first 4 days, XRDmeasurements were carried out every 12 h, and afterward themeasurement frequency was gradually reduced. The obtaineddiffraction patterns are presented in Figure 9.As expected, the least stable material among the investigatedsamples was neat amorphous BIC. The first weak but distinctsharp Bragg reflection was detected as early as 6 h afteramorphization, indicating the onset of recrystallization. AfterTable 2. Avrami Crystallization Parameters (k and n) Obtained from Fits to the Isothermal Dielectric Crystallization DataRecorded at T = 348 K for Neat Amorphous BIC and Coamorphous BIC + NIC Systems with Different Niclosamide ContentsTogether with the Corresponding Crystallization Onset (tonset) and Half-Life (t1/2) TimesSample k [s−n] n C = k1/n [s−1] tonset [min] t1/2 [h]Neat BIC 4.94 × 10−17 ± 1.11 × 10−18 3.73 ± 0.02 3.6 × 10−5 70 5.71BIC + 10% NIC 5.42 × 10−17 ± 9.54 × 10−18 3.63 ± 0.02 4.0 × 10−5 90 7.56BIC + 15% NIC 1.32 × 10−19 ± 6.82 × 10−21 3.92 ± 0.00 1.5 × 10−5 182 16.41BIC + 20% NIC 2.29 × 10−22 ± 1.32 × 10−23 4.31 ± 0.01 8.2 × 10−6 275 26.69BIC + 25% NIC 7.78 × 10−25 ± 3.68 × 10−26 4.67 ± 0.00 4.4 × 10−6 456 38.01BIC + 30% NIC 2.17 × 10−16 ± 1.12 × 10−17 3.15 ± 0.00 7.0 × 10−6 224 22.78BIC + 40% NIC 3.41 × 10−14 ± 3.42 × 10−15 2.85 ± 0.01 1.7 × 10−5 97 13.32Figure 8. Red filled bars represent the crystallization half-times (t1/2),red patterned bars represent the crystallization onset (t0) determinedfrom isothermal dielectric measurements at T = 348 K, illustrating thestrong composition dependence of physical stability and themaximum stabilization at the eutectic composition. For clarity thebars are superimposed on the phase diagram of the BIC + NIC binarysystem constructed from DSC data.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533649Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig8&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-as24 h, the XRD pattern of BIC already exhibited well-defineddiffraction peaks, confirming advanced crystallization of thesample. The addition of 10 wt % NIC leads to a noticeableimprovement in physical stability, with the first signs ofrecrystallization observed after approximately 36 h of storage.Interestingly, further increase in NIC content results in anonmonotonic change in stability. For the sample containing20 wt % NIC, the onset of recrystallization is accelerated, withthe first small sharp Bragg peaks detected already after 24 h.Most notably, the composition corresponding to eutectic (i.e.,BIC + 25 wt % NIC) exhibits the lowest physical stability inthe glassy state, with the onset of recrystallization observed asearly as 12 h after amorphization. Upon further increase inNIC content, the stability trend reverses again: the sampleFigure 9. XRD patterns recorded during storage at Troom for (A) neat amorphous BIC and coamorphous BIC + NIC systems containing (B) 10 wt% NIC, (C) 20 wt % NIC, (D) 25 wt % NIC, (E) 30 wt % NIC, and (F) 40 wt % NIC. Diffraction patterns were collected immediately after samplepreparation and at selected time intervals during storage. The appearance of sharp Bragg peaks indicates the onset of recrystallization. The greencurves highlight the diffraction patterns recorded at the time when the first crystalline reflections were detected for each sample.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533650Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig9&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-ascontaining 30 wt % NIC begins to recrystallize after 24 h,whereas the system with 40 wt % NIC shows significantlyimproved stability, with the first detectable crystallinereflections appearing only after approximately 5 days ofstorage. This finding clearly indicates the absence of a directcorrelation between the recrystallization tendency of theinvestigated coamorphous BIC + NIC systems when evaluatedabove and below the glass transition temperature i.e., undersupercooled liquid (T > Tg) and glassy state (T < Tg)conditions. To the best of our knowledge, this is the first reportshowing that the composition-dependent physical stability of acoamorphous system corresponding to eutectic varies withtemperature. These results highlight the importance ofinvestigating physical stability under both accelerated andstandard storage conditions, as the mechanisms governingrecrystallization may differ substantially between the super-cooled liquid and glassy states.At the end of this section, it is worth discussing the nature ofthe solid material obtained after long-term recrystallization ofthe investigated systems. Figure 10 presents a comparison ofthe XRD patterns shown in Figure 9 for the BIC + NICmixtures containing 10, 25, and 40 wt % NIC recorded after 1year of storage, together with reference diffractograms of neatcrystalline (as-received) BIC and NIC, as well as BICrecrystallized from the amorphous state after 22 days ofstorage. As can be seen, recrystallization in the investigatedcoamorphous systems involves both components. Theobserved diffraction features can be assigned to crystallineNIC in its original crystalline form and to BIC crystallizing intoa form resembling that obtained upon recrystallization fromthe amorphous state, rather than the as-received crystallineBIC. This interpretation is supported by the presence ofdiffraction peaks characteristic of crystalline NIC and byreflections corresponding to the metastable, amorphous-derived polymorph of BIC. Importantly, no additionaldiffraction peaks appearing at new 2θ positions are detectedfor any of the investigated compositions. This observationindicates that recrystallization does not lead to the formationof a new crystalline phase, such as a cocrystal.To complement the XRD analysis and further assess thepossible formation of new crystalline phases during long-termstorage, additional DSC measurements were performed onsamples stored for 29 days at room temperature. Thecorresponding thermograms, recorded upon heating (HR =10 K/min), are presented in the Supporting Information(Figure S4) together with data for freshly prepared amorphoussamples. All investigated systems exhibit a characteristicenthalpy overshoot at Tg due to physical aging, followed bycold crystallization and subsequent melting. Notably, the DSCtraces reveal complex, multistep thermal behavior, includingadditional endothermic events at lower temperatures, whichmay suggest the in the glassy state formation of additionalcrystalline fractions (ex. cocrystal). However, due to thepartially amorphous nature of the samples and the occurrenceof recrystallization during heating (T > Tg), these resultscannot be unambiguously attributed to phases formed duringisothermal storage at T < Tg. Therefore, while DSC indicatesthe possibility of additional structural transformations, XRDremains the more reliable technique for phase identificationunder the investigated conditions. Importantly, the overalltrends observed in DSC remain consistent with the XRDresults, suggesting that recrystallization predominantly leads tothe formation of the original crystalline components.4. CONCLUSIONIn this work, a comprehensive physicochemical study of thebinary coamorphous systems composed of bicalutamide (BIC)and niclosamide (NIC) was carried out in order to investigatethe relationship between composition, molecular dynamics,and physical stability. The constructed phase diagram of BIC +NIC confirmed the formation of a eutectic system with aeutectic point at 25 wt % NIC, enabling the vitrification ofNIC in the presence of BIC without thermal degradation. Thenonisothermal calorimetric studies revealed that the coamor-phous composition having eutectic concentration exhibits thelowest tendency toward recrystallization among all investigatedcoamorphous binary systems. This result was further validatedby nonisothermal dielectric investigations performed in thesupercooled liquid state.Broadband dielectric spectroscopy (BDS) showed that theaddition of NIC to BIC does not significantly alter themolecular mobility of the system, as reflected by nearlyidentical values of Tg, mp as well as βKWW across allcompositions. Nevertheless, the physical stability of theamorphous systems strongly depends on composition,exhibiting a distinct nonmonotonic trend with a maximum atthe eutectic ratio. Isothermal dielectric experiments demon-strated that the eutectic mixture possesses the longestcrystallization half-life and the most delayed onset ofrecrystallization, confirming its superior stability underaccelerated (T > Tg) conditions. The strong correlationbetween the eutectic melting depression and the enhancedamorphous stability indicates that both thermodynamic andkinetic factors contribute cooperatively to the stabilizationeffect.Interestingly, long-term X-ray diffraction (XRD) studiesperformed under standard storage conditions (T < Tg)revealed a markedly different behavior, i.e., samples containing20 and 30 wt % of NIC recrystallized after a comparableFigure 10. Comparison of XRD patterns recorded after 1 year ofstorage for coamorphous BIC + NIC systems containing 10, 25, and40 wt % NIC with reference diffractograms of neat crystalline (as-received) BIC, neat crystalline NIC, and BIC recrystallized from theamorphous state after 22 days of storage. Shaded regions highlightcharacteristic diffraction features attributed to crystalline NIC (green)and to BIC recrystallized from the amorphous state (red).Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.5c01958Mol. Pharmaceutics 2026, 23, 3641−36533651Downloaded from pubs.acs.org/mpohbp/article-pdf/23/7/3641/65374922/acs.molpharmaceut.5c01958.pdf by NATL INST FOR MATLS SCIENCE (NIMS) user on 19 August 2026https://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.5c01958/suppl_file/mp5c01958_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig10&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig10&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig10&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c01958?fig=fig10&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.5c01958?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asstorage time, whereas the eutectic composition was no longerthe most stable. To the best of our knowledge, this is the firstreport showing that the composition-dependent physicalstability of a coamorphous system that forms a eutectic in itscrystalline state varies with temperature. These findingsdemonstrate that the mechanisms governing recrystallizationin the supercooled liquid and glassy states differs andunderscore the necessity of assessing the physical stability ofcoamorphous pharmaceuticals under both accelerated andambient storage conditions.■ ASSOCIATED CONTENT*sı Supporting InformationThe Supporting Information is available free of charge atht tps ://pubs .acs .org/doi/10 .1021/acs .molpharma-ceut.5c01958.Additional thermal and structural characterization datasupporting the conclusions of this study; including DSCheating/cooling thermograms of neat niclosamide;complementary DSC and TGA measurements of theBIC + NIC system; low-heating-rate DSC experimentsenabling improved resolution of overlapping meltingevents; Tammann plot analysis confirming the eutecticcomposition; DSC thermograms of aged amorphoussamples; and linearized Avrami plots used for semi-quantitative analysis of crystallization kinetics (PDF)■ AUTHOR INFORMATIONCorresponding AuthorJustyna Knapik-Kowalczuk − Institute of Physics, Universityof Silesia in Katowice, Chorzów 41-500, Poland; ResearchCenter for Macromolecules and Biomaterials, NationalInstitute for Materials Science, Tsukuba, Ibaraki 305-0044,Japan; orcid.org/0000-0003-3736-8098;Email: justyna.knapik-kowalczuk@us.edu.plAuthorsPaulina Poloczek − Institute of Physics, University of Silesia inKatowice, Chorzów 41-500, PolandJoanna Klimontko − Institute of Physics, University of Silesiain Katowice, Chorzów 41-500, PolandXue Han − Research Center for Macromolecules andBiomaterials, National Institute for Materials Science,Tsukuba, Ibaraki 305-0044, Japan; Graduate School ofScience and Technology, University of Tsukuba, Tsukuba,Ibaraki 305-8577, JapanKohsaku Kawakami − Research Center for Macromoleculesand Biomaterials, National Institute for Materials Science,Tsukuba, Ibaraki 305-0044, Japan; Graduate School ofScience and Technology, University of Tsukuba, Tsukuba,Ibaraki 305-8577, Japan; orcid.org/0000-0002-3466-9365Marian Paluch − Institute of Physics, University of Silesia inKatowice, Chorzów 41-500, Poland; orcid.org/0000-0002-7280-8557Complete contact information is available at:https://pubs.acs.org/10.1021/acs.molpharmaceut.5c01958NotesThe authors declare no competing financial interest.■ ACKNOWLEDGMENTSThe authors P.P., J.K.-K., J.K., and M.P. are grateful for thefinancial support of the National Science Center, Poland,within Project no. 2023/51/B/ST5/02317 (OPUS 26). J.K.-K.also acknowledges the co-funding of the research activity fromfunds granted under the Research Excellence Initiative of theUniversity of Silesia in Katowice. The studies wereimplemented as part of the strategy of the University of Silesia− Inicjatywa Doskonałosći (POB 1 − Priorytetowy ObszarBadawczy 1: Harmonijny rozwój człowieka − troska o ochronęzdrowia i jakosć ́ życia).■ REFERENCES(1) Chen, W.; Mook, R. A.; Premont, R. T.; Wang, J. Niclosamide:Beyond an Antihelminthic Drug. Cell. Signalling 2018, 41, 89−96.(2) Kadri, H.; Lambourne, O. A.; Mehellou, Y. Niclosamide, a Drugwith Many (Re)Purposes. ChemMedchem 2018, 13 (11), 1088−1091.(3) Ren, J.; Wang, B.; Wu, Q.; Wang, G. Combination ofNiclosamide and Current Therapies to Overcome Resistance forCancer: New Frontiers for an Old Drug. Biomed. Pharmacother. 2022,155, 113789.(4) Pacult, J.; Rams-Baron, M.; Chmiel, K.; Jurkiewicz, K.; Antosik,A.; Szafraniec, J.; Kurek, M.; Jachowicz, R.; Paluch, M. 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