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[Xue Han](https://orcid.org/0000-0003-4812-1410), [Kohsaku Kawakami](https://orcid.org/0000-0002-3466-9365)

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[Influence of Pore Size of Mesoporous Silica on Physical Stability of Overloaded Celecoxib Glass](https://mdr.nims.go.jp/datasets/ff5f5d50-ab00-4159-b75a-6fcdcca8d7c2)

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Influence of Pore Size of Mesoporous Silica on Physical Stability of Overloaded Celecoxib GlassInfluence of Pore Size of Mesoporous Silica on Physical Stability ofOverloaded Celecoxib GlassXue Han and Kohsaku Kawakami*Cite This: Mol. Pharmaceutics 2025, 22, 2556−2567 Read OnlineACCESS Metrics & More Article Recommendations *sı Supporting InformationABSTRACT: The stabilization mechanism of mesoporous silica (MS) of twodifferent pore sizes (21 and 2.5 nm) on overloaded celecoxib (CEL) glass wasinvestigated. Differential scanning calorimetry (DSC) measurements revealedthe presence of three fractions with different molecular mobilities: free,intermediate, and rigid ones. The free fraction exhibited cold crystallizationduring DSC heating and was assumed to have almost the same properties asthose of the bulk molecules. The rigid fraction did not exhibit either glasstransition or cold crystallization behavior, which should be stabilized byinteractions with the MS surface. The remaining molecules exhibited glasstransition behavior without any tendency toward cold crystallization duringheating, which is called the intermediate fraction. The molecular dynamics ofeach fraction was investigated by using broadband dielectric spectroscopy(BDS). While the intermediate and free fractions exhibited comparablemobility, the rigid fraction demonstrated pore-size-dependent behavior:enhanced and suppressed molecular mobility was observed for the rigid fraction confined in 21 and 2.5 nm-pores, respectively.Isothermal crystallization of CEL glass was investigated using DSC and BDS at 95 °C. The results revealed that the CEL glass mixedwith MS with large pores exhibited slower crystallization compared to the CEL glass without MS, whereas accelerated crystallizationwas observed for the CEL mixed with a small amount of MS of small pores. The pore size of 21 nm was much larger than thecooperatively rearranging region (CRR) of the CEL glass, whereas the pore size of 2.5 nm was comparable to that. When the poresize was larger than that of the CRR, most of the loaded CEL molecules behaved as an intermediate fraction, presumably because themolecules could exchange inside and outside the pore. In contrast, the exchange was not likely to proceed when the pore size wascomparable to or smaller than that of the CRR, leaving a large free fraction. This finding provides a deep understanding of thestabilization mechanism of overloaded pharmaceutical glass by using mesoporous materials.KEYWORDS: glass, mesoporous silica, crystallization, cooperatively rearranging region, broadband dielectric spectroscopy,differential scanning calorimetry1. INTRODUCTIONDrugs with poor aqueous solubility often face challenges withlow oral bioavailability when the solubility or dissolutionprocesses limit absorption. A promising strategy for improvinglow bioavailability in such cases is transforming the crystallineform of the drug into glass.1−4 Because the glass state isthermodynamically unstable, it may crystallize during storageand/or immediately after contact with aqueous media.5 Anapproach to stabilizing drugs involves using porous materialssuch as mesoporous silica (MS).6−8 Its stabilization mecha-nism is generally assumed to include two factors: the directinteraction of guest molecules with the surface of the materialand the confinement effect in small pores.9 Hydrogen bondingbetween silanol groups on the surface and guest molecules ismainly responsible for the former mechanism. The capture ofmolecules in small pores influences their molecular mobility;this is known as the confinement effect. As molecular mobilityis an important factor that affects the crystallizationbehavior,10,11 molecules with limited mobility in the poresshould have a lower tendency to crystallize. Moreover, crystalscannot grow in pores unless the space provided is sufficientlylarge for nucleation and crystal growth.Understanding the influence of the properties of porousmaterial, including pore size, particle size, and surfacechemistry, on the physical stability of guest drugs is ofparamount importance. Surface adsorption mechanismsinclude hydrogen bonding, electrostatic interactions, andhydrophobic interactions. The effectiveness of drug loadingand release may be influenced by the adsorption mechanism.7Received: December 16, 2024Revised: March 18, 2025Accepted: March 19, 2025Published: April 4, 2025Articlepubs.acs.org/molecularpharmaceutics© 2025 The Authors. Published byAmerican Chemical Society2556https://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−2567This article is licensed under CC-BY 4.0Downloaded via 202.220.240.85 on May 13, 2025 at 07:05:19 (UTC).See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.https://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/showCitFormats?doi=10.1021/acs.molpharmaceut.4c01482&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?goto=articleMetrics&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?goto=recommendations&?ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?goto=supporting-info&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=tgr1&ref=pdfhttps://pubs.acs.org/toc/mpohbp/22/5?ref=pdfhttps://pubs.acs.org/toc/mpohbp/22/5?ref=pdfhttps://pubs.acs.org/toc/mpohbp/22/5?ref=pdfhttps://pubs.acs.org/toc/mpohbp/22/5?ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://pubs.acs.org?ref=pdfhttps://pubs.acs.org?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-ashttps://pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://acsopenscience.org/researchers/open-access/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/MS with the same pore size but different particle sizesexhibited different stabilization effects for overloaded simvas-tatin glass.12 This can be explained by the more effectiveinhibition of the crystal growth of bulk glass by small particlesand easier exchange of the inside and outside molecules of theMS for the smaller particles. Regarding the pore size effect,when prednisolone glass was entrapped within pores of 1.60and 2.16 nm, larger pores were reported to have a higherstabilization effect.13 In contrast, flufenamic acid glass wasfound to be stabilized in smaller pores including 3.2 nm poresof MCM and 7.1 nm pores of SBA, whereas crystallization wasobserved in the 29 nm pores of MCF silica.14 Similarly,nifedipine glass entrapped in pores smaller than 12 nmexhibited better stability than that in pores of 50−198 nm,15despite both pore sizes being significantly larger than themolecular size. These apparently contradictory observationsindicate that more systematic studies are required to providegeneral ideas regarding the stabilization mechanism ofmesoporous materials. A comparison of the relative poresizes is not likely to provide much information, but more focuson the relationship between the pore size and glass propertiesis required. Moreover, the stabilization effect only for theentrapped molecules in the pores is not sufficient for the use ofMS as a pharmaceutical excipient to avoid an increase in theformulation volume. The stabilization of overloaded drugs is ofpractical importance.Extensive efforts have also been made from a formulationviewpoint to demonstrate the effectiveness of MS in stabilizingpharmaceutical glasses. For example, oxidized porous siliconwas used to stabilize indomethacin;16 the loaded indomethacinwas stable at 40 °C/75% relative humidity (RH) for over sixmonths, whereas pure indomethacin recrystallized after onemonth. The physical stability of vortioxetine glass loaded inthree types of MS, namely MCM, SBA, and MCF, werecompared.17 The results revealed that the pure drug recrystal-lized in 1 day under 30 °C/56% RH, whereas the loaded drugexhibited better physical stability for 1 week. Notably, SBAprovided the highest stability over three months.In this study, the effect of MS addition on the physicalstability of overloaded celecoxib (CEL) glass is investigatedwith a focus on the effect of pore size. Although CEL glass hasbeen reported to be stabilized using a diameter of 2.5−3.7 μmand pore size of 23 nm,18 the detailed mechanism of thestabilization effect is still unclear. If surface adsorption andconfinement effects are the only stabilization mechanisms, thenMS cannot stabilize overloaded drugs. However, we demon-strated that the stabilization effect also worked for drugmolecules outside of the pores. The stabilization of theoverloaded CEL glass is discussed to provide clear guidance forthe selection of mesoporous materials as pharmaceuticalexcipients with an emphasis on the effect of pore size.2. MATERIALSCEL (Form III) was purchased from the Tokyo ChemicalIndustry (Tokyo, Japan) and used without further purification.MS (Sylysia350 and Sylysia730) was obtained from Fuji SilysiaChemical (Kasugai, Japan). The physical properties of MS arepresented in Table 1.2.1. Preparation of CEL/MS Physical Mixtures. CEL/MS binary mixtures were prepared by carefully mixing CELand MS for 20 min in various ratios using a mortar and pestlefor facilitating homogeneous mixing and loading of CEL intopores.19 Then, the samples were sieved using a 500-μm screen,melted at 170 °C on a hot plate, and then cooled by allowingthem to rest at 25 °C, resulting in the formation of the glassstate. The mixing ratios are expressed as the proportion of theMS in this study. For instance, the mixture of CEL and MSwith a weight ratio of 25:75 is expressed as a mixture with 75%MS. Sylysia350 and Sylysia730 are abbreviated as SYL350 andSYL730, respectively.2.2. Evaluation of Molecular States Using DifferentialScanning Calorimetry (DSC). The molecular mobility ofpure CEL and its mixtures with SYL730 or SYL350 weredetermined using DSC (Q2000, TA Instruments, New Castle,DE, USA). The instrument was calibrated using indium andsapphire, and dry nitrogen was supplied as an inert gas at aflow rate of 50 mL/min. Approximately 5 mg of each samplewas sealed in an aluminum pan and heated to 180 °C at aheating rate of 10 °C/min for melting. To observe the coldcrystallization behavior of CEL, the melt was cooled to −50 °Cat a rate of 10 °C/min to induce nucleation.19 The sample wasthen heated at a rate of 10 °C/min to observe the glasstransition, cold crystallization, and melting behaviors. Threeindependent samples of each composition were evaluated.2.3. Isothermal Crystallization of CEL Glass on DSC.The influence of MS on the isothermal crystallization of theCEL glass was evaluated at 95 °C. Approximately 5 mg of CELor its physical mixture with MS was sealed in aluminum pansand heated to 180 °C at a heating rate of 10 °C/min formelting. The samples were then cooled to −20 °C at 10 °C/min, followed by heating to 95 °C at a rate of 10 °C/min, andannealed at that temperature for predetermined periods. Theannealing for over 6 h was conducted in a temperature-controlled oven at 95 °C. The samples were then heated from25 °C at 10 °C/min to observe the glass transition behavior.The remaining glass fraction of the annealed samples wasdetermined by using the heat capacity change at the glasstransition temperature (ΔCp). Three independent sampleswere analyzed for each annealing period.2.4. Determination of the Size of the CooperativelyRearranging Region (CRR). The size of the CRR wasdetermined by DSC in temperature-modulated mode.Approximately 5 mg of CEL and its physical mixture withMS were sealed in Tzero pans and heated to 180 °C at a rate of10 °C/min for melting, followed by cooling at 10 °C/min to−50 °C. Then, the samples were heated at 2 °C/min undermodulation conditions with an amplitude of 0.5 °C and aperiod of 60 s. Three independent samples were analyzed foreach composition. The CRR size (L) was determined using thefollowing equation:20Table 1. Physical Properties of MSMS surface Area (m2/g) pore size (nm) pore volume (mL/g) particle size (μm)Sylysia 350 300 21 1.6 4Sylysia 730 700 2.5 0.44 4Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672557pubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asLkTd C C341 1Tg2pg pl1/3g=lmooonoooikjjjjjjy{zzzzzz|}ooo~ooo (1)where ρ and ΔdTg are the density and half of the glasstransition width, respectively; Tg is the onset glass transitiontemperature; k is Boltzmann’s constant; Cpg and Cpl are thespecific heat capacities of the glass and supercooled liquid,respectively. The specific heat capacities were determinedusing a previously established protocol.21 Briefly, 10 mg ofquenched glass was evaluated using Tzero pans in temperature-modulated mode, and the experiments were repeated 10 timesto obtain the mean values. Cpg and Cpl were determined to be1.62 and 2.07 J/(g°C), respectively. The glass transition widthwas determined from the difference between the onset and endpoints of Tg.2.5. Evaluation of Molecular Mobility on BroadbandDielectric Spectroscopy (BDS). Broadband dielectricmeasurements of pure CEL and its mixtures with MS wereperformed by using a Novo-Control GMBH Alpha dielectricspectrometer (Montabaur, Germany). The sample temperaturewas controlled by a Quattro temperature controller withtemperature stability better than 0.2 °C. The samples weremelted on a stainless-steel sample stage using a hot plateheated to 170 °C for 10 min and then quenched underambient temperature to obtain the glass samples. Thickness ofthe samples was controlled to 0.1 mm by inserting silica spacerfibers between the stainless-steel plates. The samples with thestage were immediately transferred to the instrument andheated at 190 °C for 1 h to remove residual moisture under aflow of nitrogen gas. The dielectric spectra were acquired in atemperature range from −120 to 140 °C, with an interval of 4°C (−120 to 0 °C) or 2 °C (0 to 140 °C) in a frequency rangefrom 10−2 to 107 Hz. All measurements were repeated twice toconfirm reproducibility. The data obtained at each temperaturewere analyzed by fitting the spectra to the Havriliak−Negami(HN) equation as follows:18,22,23ii( ) ( ) ( )1 ( )ka bHN* = = +[ + ](2)Here, ε*(ω) is the complex permittivity; ε’ (ω) and ε”(ω) arethe real and imaginary parts, respectively, of the complexpermittivity; ε∞ is the high-frequency limit permittivity; Δε isthe relaxation strength; τHN is the relaxation time; and a and bare exponents of the relaxation processes. ω is equal to 2πf,where f denotes frequency. σdc is the DC-conductivity, and ε0is the permittivity of a vacuum. The α relaxation time τa wasdetermined using the following equation:18,22,23abbabsin2 2sin2 2a aHN1/ 1/= ×+ +ÄÇÅÅÅÅÅÅÅÅÅikjjj y{zzzÉÖÑÑÑÑÑÑÑÑÑÄÇÅÅÅÅÅÅÅÅÅikjjj y{zzzÉÖÑÑÑÑÑÑÑÑÑ (3)2.6. Isothermal Crystallization of CEL Glass on BDS.BDS was also used to investigate the isothermal crystallizationof the glass samples at 95 °C. The isothermal dielectricresponse of the CEL glass was measured continuously at 600 sintervals. The frequency range in which the α relaxation peakappeared was investigated. The crystallization process wasmonitored by the intensity of the real (ε′) part of the complexdielectric permittivity because basically, only the glass phasecontributed to the dielectric response.24 Therefore, the relativepermittivity (ε′N) of CEL can be calculated using thenormalized change in dielectric dispersion. The equation isas follows:( )/( )N 0 t 0= (4)Figure 1. (a) First and (b) second heating DSC curves for pure CEL, its mixture with 25% SYL350, and its mixture with 25% SYL730. After thefirst heating, the samples were cooled to −50 °C to induce nucleation. (c) Second heating curves for the CEL mixtures with 33 or 50% MS.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672558https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig1&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig1&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-aswhere ε′0 is the initial static dielectric permittivity, ε′∞ is thelong-time limiting value, and ε′t is the value at time t. ε′N isalmost analogous to crystallinity; however, the calculatedvalues do not have strong physical meaning, as each fractionhas different strengths of dipole moment.2.7. X-ray Powder Diffraction (XRPD). The samples usedfor BDS and DSC measurements were collected afterevaluation and subjected to XRPD analysis. Data wereobtained on a Rigaku RINT Ultima X-ray diffraction system(Rigaku Denki, Tokyo, Japan) with Cu Kα radiation. Thevoltage and current were set to 40 kV and 40 mA, respectively.Data were acquired at a scan rate of 2 °C/min at 0.02°intervals.2.8. Density Measurement. The true density of the CELglass was measured by using an AccuPyc II gas pycnometer(Micromeritics, Norcross, GA, USA) using helium gas.Approximately 0.5 g of the sample was melted on a hot plateand then cooled under an ambient atmosphere. Subsequently,the obtained glass pellet was ground using a mortar and pestleand dried under a vacuum at 40 °C for 30 min. The powderwas confirmed to be in a completely glassy state by XRPD andDSC. The measurements were repeated ten times to obtain themean value.3. RESULTS3.1. Discrimination of Molecular State of CEL GlassUsing DSC. Figure 1a,b shows the first and the second DSCheating curves for pure CEL and its physical mixtures with25% MS, respectively. At this mixing ratio, the amount of CELexceeded the pore capacity (i.e., overloaded) of both types ofMS. The melting behavior of the mixture with SYL730 wassimilar to that of pure CEL during the first heating; however,the melting peak split into two for the mixture with SYL350.CEL is expected to penetrate the pores during the grind-ing.25,26 The appearance of the fraction that melted at a lowertemperature can be explained by the confinement effect of thepores, as described by the Gibbs−Thomson equation.27Presumably, the pore size of SYL730 was too small to allowthe crystalline CEL to penetrate during the grinding.The melted samples were cooled to −50 °C and then heatedagain to acquire the second heating curves (Figure 1b), wherethe onset Τg values were ca. 58 °C for all samples. A coldcrystallization peak appeared for pure CEL and the mixturewith 25% SYL730, whereas it was not observed for the mixturewith 25% SYL350. This observation indicates that SYL350 hasa stronger stabilization effect on CEL, despite its smallersurface area compared to that of SYL730. The proportion ofMS was increased to determine the effect of the mixing ratioon the stabilization of the CEL glass (Figure 1c). The thermalbehaviors for the mixture with SYL350 remained almost thesame, except for ΔCp, which decreased with an increasing MSamount. For the mixture with SYL730, in addition to thedecrease in ΔCp, the cold crystallization peak became smallerwith increasing MS amount. However, small crystallization andfollowing melting peaks were observed even for the mixturecontaining 50% SYL730.ΔCp is assumed to be proportional to the mobile glassfraction of CEL. The dependence of ΔCp of each mixture onthe proportion of MS is shown in Figure 2a. Linearextrapolation of each data set provided the required amountof MS to erase the glass transition of CEL as 83.9 and 85.6%for SYL350 and SYL730, respectively. The disappearance ofthe glass transition behavior can be explained by the stronginteraction of CEL molecules with the MS surface. In the fieldof polymer chemistry, the amorphous part where the glasstransition cannot be observed is called the rigid amorphous.28Thus, the invisible CEL glass in this study is hereafter referredto as the rigid fraction. The rigid fraction may be expected tobe proportional to the surface area of the MS, which includesboth surfaces inside and outside pores. However, it was slightlylarger for SYL350 than for SYL730, indicating that the poreswere not filled completely, at least for SYL730.Although the amount of the rigid fraction was notsignificantly different for both MS, their stabilization effectswere completely different, as shown in Figure 1b,c, suggestingthe important roles of the mobile fraction on the physicalstability of CEL glass. For example, in the presence of 33% MS,the amount of rigid fraction was 15.2 and 6.7% for SYL350 andSYL730, respectively. Most of the CEL glass remained mobilein the presence of both MS. However, cold crystallization wasnot observed in the mixture with SYL350 during DSC heating,whereas most of the mobile CEL crystallized in the mixturewith SYL730. The fraction that exhibited cold crystallizationduring DSC heating was assumed to have a molecular mobilitysimilar to that of pure CEL and is hereafter termed the freefraction. The remaining fraction, which exhibits glass transitionbehavior but is unable to crystallize during heating, is called theintermediate fraction. The free fraction was calculated from thecold crystallization enthalpy. Figure 2b and Table 2 show theclassification of each fraction for various mixing ratios of MS.In the mixture with SYL350, most CEL molecules, except forFigure 2. (a) Changes in ΔCp (expressed as per gram of the mixture) as a function of the loading proportion of MS. (b) Rigid, intermediate, andfree fractions of CEL molecules in mixtures with SYL350 or SYL730. NT: not tested.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672559https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig2&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig2&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asthe rigid fraction, existed as the intermediate fraction,regardless of the mixing ratios. In contrast, most CELmolecules behaved as free fractions in the mixture withSYL730.The absence of proportionality of the rigid fraction to thesurface area of the MS indicated imperfect penetration of theCEL molecules into the small pores.29 Using the density of theCEL glass (1.41 g/cm3), the required amounts of SYL350 andSYL730 to completely capture the CEL molecules into thepores were calculated to be 31 and 61%, respectively, based onthe pore volume of MS. The strong stabilization effect isexpected on molecules adsorbed as a monolayer.30 Theadsorbed area per CEL molecule was calculated as ca. 0.59nm2 using the bulk density value under a simple assumption ofthe cubic shape of CEL molecules. Given that the surface ofMS is densely packed with monolayered CEL, SYL350, andSYL730 theoretically can load 5.1 × 1020 and 1.2 × 1021 CELmolecules per gram, respectively; thus, the required amounts ofMS to offer monolayer adsorption sites for all CEL moleculesare 76 and 57%, respectively. In the experiment, the requiredamounts of MS for changing all CEL molecules into the rigidfraction were 83.9 and 85.6%, respectively. Based on thiscalculation, approximately 9% and 33% of the pores in SYL350and SYL730, respectively, were unfilled. Because thiscalculation includes some assumptions, such as the use ofthe bulk density value to estimate the adsorption area per CELmolecule, SYL350 may be almost filled, whereas this is not truefor SYL730. Approximately one-third of the pores of SYL730were likely to be unfilled.3.2. Investigation of Molecular Mobility Using BDS.Figure 3 shows the normalized dielectric spectra obtained byBDS measurements of the CEL glass and its mixture with 25%MS, where all fractions are expected to coexist. Theintermediate fraction is dominant in the mixture withSYL350, whereas the free fraction dominates, but theintermediate fraction should also have a contribution in themixture with SYL730. All spectra fit well with the superpositionof the HN function (Figures 3a−c). Figure 4a shows the ταvalue as a function of temperature, where the Vogel−Fulcher−Tammann (VFT) equation was used to fit the data.31DTTTexp000= ikjjj y{zzz(5)where τ0 is the time scale of the vibrational motion, T is thetemperature, T0 is the temperature analogous to the Kauzmanntemperature, and D is a strength parameter. The data for pureCEL and its mixtures with 25% MS could be fitted by similarVFT functions, and the fitting parameters are reported in theSupporting Information. The shape of the α relaxation peakprovides information on the distribution of τα, which can bedescribed by the β parameter in the Kohlrausch−Williams−Watts (KWW) function.31Table 2. Calculated Rigid and Free Fractions of CEL Glassin the Mixture with SYL350 or SYL730mixture with SYL350 mixture with SYL730MS load (%) rigid (%) free (%) rigid (%) free (%)17 3.42 ± 3.77 0.00 N.T. N.T.20 6.47 ± 1.75 0.00 3.73 ± 3.93 78.9 ± 14.225 2.67 ± 1.90 0.00 4.28 ± 3.07 84.7 ± 6.033 15.2 ± 2.5 0.00 6.69 ± 0.78 74.6 ± 9.750 23.8 ± 3.4 0.00 8.36 ± 1.13 1.42 ± 2.4767 32.4 ± 9.6 0.00 28.9 ± 0.6 1.49 ± 1.2983 100 0 100 0Figure 3. Normalized dielectric spectra of (a) pure CEL, (b) its mixture with 25% SYL730, and (c) its mixture with 25% SYL350, respectively. TheKWW fitting at 74 °C is represented by break lines. ε″max is the maximum value of the α relaxation peak.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672560https://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.4c01482/suppl_file/mp4c01482_si_001.pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig3&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig3&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-astexp 0 1= <lmooonoooikjjjjjy{zzzzz|}ooo~oooikjjjjjjjjy{zzzzzzzz (6)where Φ and t are the remaining fractions of the excessenthalpy with reference to the extrapolation of the supercooledliquid to a lower temperature, and time, respectively. A large βvalue indicates homogeneity of the relaxation time, whichmakes the dielectric spectral peaks symmetric. The fitting ofthe BDS data revealed that pure CEL and the mixture with25% SYL730 shared similar β values of 0.69 and 0.66,respectively. However, the β for the mixture with 25% SYL350was 0.55, suggesting that the addition of SYL350 made themolecular mobility of CEL heterogeneous, most likely due to alarge proportion of the intermediate fraction.Figure 4b shows the normalized dielectric spectra of themixtures with 67% MS, where those for 25% mixtures areretained as a comparison. For the mixtures with 67% MS, thepresence of two components must be assumed for successfulfitting. Thus, τa values were obtained by applying deconvolu-tion to the spectra (Figure 4c,d). As almost no free fractionexists for both (Figure 2b), the obtained two τa values are likelyto be assigned to those of intermediate and rigid fractions. Aspresented in Figure 4a, one of the mean τα of CEL withSYL350 and SYL730 was both comparable to that of pureCEL. This observation aligns with previously reported resultsfor the CEL mixtures with SYL244FP, which has a pore size of23 nm, ranging from 9 to 45%.18 Furthermore, their resultsreported that the β values of the mixtures decreased from 0.65to 0.45 with increasing amounts of MS. Our observations alsorevealed a widening of the dielectric spectra, which suggested adecrease in β values. The β values of the intermediate fractionin the mixture with 67% SYL350 and SYL730 were determinedto be 0.31 and 0.57, respectively.The mobility of the rigid fraction was investigated usingmixtures with 83% MS (Figure 4e,f). The β values for the rigidfraction in the mixture with 67% SYL350 and 67% SYL730were 0.30 and 0.25, respectively. The mean τα values (Figure4a) were influenced differently by the addition of MS. Therigid fraction in SYL350 had higher molecular mobility relativeto free and intermediate fractions, whereas the opposite trendwas observed in the presence of SYL730. Thus, molecularFigure 4. (a) Relaxation time (τα) of CEL glass and its mixtures with various amounts of SYL350 or SYL730; all fractions exist for the mixtureswith 25% MS but the amount of rigid fraction is negligible; intermediate and rigid fractions exist for 67% MS, and only rigid fraction is available for83% MS. (b) Normalized dielectric spectra and KWW fitting (as presented by break lines) of the mixtures with 25 or 67% of MS at 70 °C. (c) Anexample of deconvolution of dielectric loss spectra of the mixture with 67% SYL350 at 68 °C into rigid and Intermediate + free fractions. (d) Anexample of deconvolution of dielectric loss spectra of the mixture with 67% SYL730 at 72 °C. (e) Dielectric loss spectra of a mixture with 83%SYL350 at 68 °C (1000/T = 2.93). (f) A dielectric loss spectra of a mixture with 83% SYL730 at 72 °C (1000/T = 2.90).Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672561https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig4&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig4&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asmobility of the rigid fraction was likely to be influenced bypore size. Although a decrease in molecular mobility is easy toimagine considering its interaction with the MS wall, anincrease in mobility appears to be unnatural. However, botheffects have been observed in previous studies. The mobility ofnaproxen glass encapsulated in MS with a pore size of 5.9 nmexhibited two α relaxation processes: a slower relaxationbelongs to molecules interacting with the pore surface and afaster relaxation that happens in the center, whereas suchmultimodal processes were not the observed for the naproxenglasses in 2.4 or 3.2 nm-pore.32 On the other hand, ibuprofenglass showed faster mobility inside MCM with pore sizes of 3.5and 11.6 nm,33 which may be explained by a decrease in thedimension of molecular motion.34−36 As for clotrimazole glass,density functional theory simulation proved that the highflexibility of the silica surface silanols made the glass moleculeshighly mobile in the MSU-H having 8.5 nm pores.37 Thus, anincrease in molecular mobility in nanopores has also been ageneral observation.3.3. Size of CRR of CEL Glass. Figure 5 shows the effect ofMS addition on the CRR size of the CEL glass. Because Τg wasthe same for the intermediate and free fractions, this estimationwas the average for the two fractions. Upon mixing withSYL730, it remained almost constant up to 33% MS, anddecreased beyond this ratio. This observation corresponded toa change in the intermediate/free fraction ratio (Figure 2b).Mixing with SYL350 significantly reduced the size of the CRR,even in small amounts. This analysis suggests that theintermediate fraction has a CRR smaller than that of thebulk molecules.3.4. Effect of MS on the Physical Stability of CELGlass. The effect of MS addition on the physical stability ofthe CEL glass at 95 °C was investigated using BDS and DSC.Representative BDS spectra of the three samples are presentedin Figure 6a−c. Unlike in DSC, a rigid fraction was detectablein the BDS study. However, the weak intensity of staticpermittivity (ε′s) in the mixture with SYL350 suggested areduction in the dipole moment of the intermediate and rigidfractions. During annealing, the CEL glass in all samplesshowed recrystallization, as reflected by the decreasing ε′s.However, for the mixtures with MS, the decrease of ε′s haltedbefore reaching 100% crystallinity. The evolution curves of ε′Nfor pure CEL and its mixtures with MS are shown in Figure 6d.The ε′N values of mixtures with 25% SYL350 and SYL730stopped growing at approximately 86 and 99%, respectively. Asthe rigid fraction is not expected to crystallize, the ε′N does notreach zero. However, the remaining is larger than theproportion of the rigid fraction for the mixture with SYL350,suggesting that a part of the intermediate fraction was notlikely to be crystallized. The time to reach 50% ε′N (t1/2) of themixture with 25% SYL350 was the longest at 14400 s, followedby pure CEL (10800 s) and the mixture with 25% SYL730(5400 s). Thus, the addition of SYL350 retarded thecrystallization of CEL glass, whereas the addition of SYL730accelerated it when a free fraction exists. The physical stabilityof CEL was enhanced by increasing the amount of MS. Thecrystallization of CEL was slower than that of pure CEL whenit was mixed with 67% SYL730, and the crystallization was notobserved with 67% SYL350 (Figure 6e). When 83% MS wasadded, crystallization never proceeded for both types of MSs.DSC was also used for investigating the isothermalcrystallization of the mixtures with 25% MS at 95 °C. Thecrystallization curves are shown in Figure 7. The crystallinity(X) of CEL was calculated by using ΔCp under the assumptionthat it is proportional to the amount of the remainingamorphous phase. The data were fitted using the Avrami−Erofeev equation:X k t d1 exp ( )n= { } (7)where k and d are the crystallization rate constant andinduction time, respectively. n is the Avrami exponent, whichreflects the dimensions of the crystal growth and nucleationmechanisms.The crystallization curves were very similar to thoseobtained from the BDS measurements (Figure 6d); that is,the addition of SYL350 and SYL730 retarded and acceleratedcrystallization, respectively, and a part of the amorphous phaseremained uncrystallized. The uncrystallized fraction as revealedby DSC was 6 and 4%, respectively, in the presence of SYL350and SYL730.The kinetic parameters obtained are given in Table 3. Theuncrystallized fraction was ignored in the fitting procedure ofthe Avrami equation. The Avrami exponents obtained wereapproximately 2 for both pure CEL and its mixture with MS,suggesting that the presence of MS did not influence thecrystallization mechanism. This may be due to the fiber-likegrowth properties of the CEL crystals38 that can fit the porestructure. The results show that k was smaller and larger in thepresence of SYL350 and SYL730, respectively, than in thepresence of pure CEL. As shown next, a small amount ofmetastable form III was included after crystallization withSYL350. Thus, the slow crystallization may partially beresponsible for the appearance of a different crystal form.The kinetic parameters obtained could be understood as thosefor the stable form I. As the crystallization of CEL glassfrequently proceeds into mixtures of form I and III,22 theseforms are likely to grow independently, that is, no interferenceis anticipated during the crystallization. Moreover, both stableand metastable forms (I and III) of pure CEL have almost thesame growth rate at 95 °C.38 Thus, the presence of a smallamount of form III does not have an impact on the kineticanalysis.Figure 5. Sizes of the CRR of CEL glass in its mixture with SYL350 orSYL730.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672562https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig5&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig5&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-as3.5. Physical Characterization of Recrystallized CEL.The recrystallized samples at 95 °C in the BDS study weresubjected to XRPD analysis (Figure 8a). CEL can exist in fivecrystal forms (Form I, II, III, IV, and V),22,39,40 where the moststable form at 95 °C is the Form I. The XRPD pattern of pureCEL was characteristic of Form I and represented by peaks at5.5°, 5.7°, 7.2°, and 16.6°. These peaks were observed in theXRPD patterns of the mixtures recrystallized in the presence ofSYL730 or SYL350. In addition, the characteristic peak ofForm III (19.2°) was observed for the mixture with SYL350.Figure 8b shows the DSC curves of the recrystallized CEL inthe presence of MS. The melting peak of Form I (ca. 164 °C)was observed for pure CEL and its mixture with 25% SYL730.Two endothermic peaks were observed at ca. 151 and 162 °Cfor the mixture with 25% SYL350. These peaks can beattributed to Forms III and I, respectively, under the influenceof pores, as observed for the physical mixture (Figure 1). Asmall endothermic peak with an enthalpy value of about 2.6 J/gwas observed for pure CEL at about 75 °C in a reproduciblemanner. Because a small endothermic peak indicates anenantiotropic polymorphic transformation,41 traces of othercrystal forms might exist in the recrystallized sample.4. DISCUSSION4.1. Molecular Mobility of CEL Molecules as Indicatedby BDS measurements. In this study, CEL glass was dividedinto three types based on its thermal behavior during DSCheating. A comparison with the BDS results provided furtherinsights. The mobility of free and intermediate fractions wassimilar in the BDS measurements, as proven by a similar meanτα (Figure 4a). The rigid fractions are likely to behave inopposite ways depending on the pore size. When the pore sizeis comparable to or smaller than CRR, the mobility of the rigidfraction seemed to be suppressed. However, the mobilityappeared to be enhanced in larger pores, presumably becauseof the easiness of exchange of molecules inside and outsidepores. In literature, water molecules inside the graphene slab,of which the pore size was 3.1 nm, were reported to exhibit fastdiffusion.42 The motion parallel to the pore wall was assumedFigure 6. Decrease of ε′s during isothermal annealing of the glass samples at 95 °C: (a) pure CEL, (b) mixture with 25% SYL350, and (c) mixturewith 25% SYL730. (d) and (e) ε′N of mixture with different amounts of MS determined by eq 4, as a function of time.Figure 7. Evolution of crystallinity of pure CEL, mixture with 25%SYL350, and mixture with 25% SYL730 at 95 °C, as determined byDSC.Table 3. Kinetic Parameters for the IsothermalCrystallization of Pure CEL Glass and the Mixture with 25%SYL350 or SYL730 from DSCsample k (s−1) d (s) nCEL 1.59 × 10−7 907 1.8mixture with 25% SYL350 4.64 × 10−8 0 1.8mixture with 25% SYL730 4.06 × 10−7 0 1.8Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672563https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig6&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig7&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig7&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asto be faster than that perpendicular to the surface, and thediffusion mostly occurs in a parallel direction to the wall in aconfined space.43 However, the diffusion was slower in thepore of 0.7 nm, most likely because of the suppression oftranslational motion.43 According to a dielectric relaxationspectroscopy study of ibuprofen glass in MCM-41, whosediameter is 3.6 nm, higher molecular mobility was likely to beretained near and below the Tg compared to that of bulkibuprofen,44 which was also verified by magic-angle spinningand pulsed-field gradient NMR techniques.45 In a study offlufenamic acid glass, the presence of a liquid-like layer that hashigh molecular mobility on the nanopore surface was proposedbased on investigation using 19F NMR spectroscopy.14Presumably, the high stability of the rigid fraction is notrelated to molecular mobility but to geometrical restriction inthe pores. In the isothermal crystallization study by BDS(Figure 6), the ε′N of the mixtures with 25% SLY350 andSYL730 reached 86 and 99%, respectively, whereas their rigidfractions were only 2.7 and 4.3%, respectively, in the DSCmeasurements. The higher final ε′N of the mixture withSYL730, compared to that expected based on the amount ofthe rigid fraction, may be understood as within experimentalerror; however, as the disagreement for the mixture withSYL350 was quite large, an additional explanation is requiredfor the apparent low ε′N. One possible explanation is thecontribution of the crystallized part to the dielectric spectra.The decrease in dielectric loss was caused by a reduction inactive dipoles after crystallization.46 However, the crystalmicrostructure can significantly influence the dielectric loss.47The remaining dielectric loss of the mixture with 25% SYL350could have originated from the orientation of the associateddipole located in defects, such as dislocations and vacancies,which exist in the form of loose crystallization in larger pores.48In fact, the final crystallinity in the DSC measurement reached94% (Figure 7).The crystallization of CEL with 67% SYL350 was completelyinhibited, whereas it was significantly retarded with 67%SYL730. Almost no free fraction was expected to exist at thismixing ratio for both MS. The ε′N reached 80% in the presenceof 67% SYL730, which is smaller than the amounts ofintermediate and free fraction (66%). This discrepancy may beexplained by the weak dipole moment of the rigid fraction.4.2. Influence of Pore Size of MS on the Stabilizationof CEL Glass. The physical stability of the CEL glass showedopposing trends, depending on the pore size in the presence of25% MS. The crystallization of CEL glass with 25% SYL730was faster than that of pure CEL, whereas 25% SYL350delayed the crystallization. Although SYL730 had a largersurface area than SYL350, its smaller pores did not allow easypenetration of CEL molecules, resulting in a similar amount ofrigid fraction in both MS. Considering the size of the CELmolecules, the number of molecules per cross-sectional area ofthe pores is estimated to be ca. 750 and 11 for SYL350 andSYL730, respectively. The most striking difference in themobility of the overloaded CEL molecules was the presence ofa large intermediate fraction in the mixtures with SYL350. It isdifficult to explain the delayed crystallization of CEL in thepresence of SYL350 solely based on molecular mobility, as themobility of free and intermediate fractions was similar (Figure4a). Thus, the steric hindrance of the nanopores for crystalgrowth should also be responsible for stabilization, although alarge fraction of CEL molecules existed outside the pore.Accelerated crystallization in the presence of SYL730 was aninteresting observation. In the literature, both physicalstabilization and destabilization of pharmaceutical glasseshave been reported for MS, suggesting a complicated influenceon the stability. The stabilization mechanism includes theinteraction of the drug with the MS surface and theconfinement effect of the pores. In addition, MS seems tohave a destabilizing effect, which may be explained by itstemplating property. Notably, the same MS can either stabilizeor destabilize the system depending on the mixing ratio, asobserved for aripiprazole glass.49The size of the CRR of the CEL glass was smaller than thepore size of SYL350 but comparable with that of SYL730(Figure 5). Therefore, the size of the CRR may explain thedifficulty in the exchange of inside and outside molecules forSYL730. The three fractions of CEL glass and their possibleexchange behaviors inside and outside the pores are presentedin Figure 9. The CEL molecules near the surface form a rigidfraction. When the pore size is sufficiently larger than the sizeof the CRR, the molecules inside and outside the pores appearto be easily exchanged. Crystallization was delayed in thepresence of SYL350, mainly because of geometrical restric-tions, as only molecules outside the pores were allowed togrow into large crystals. The molecules in the pores must“wait″ until they are released outside the pores, which causes adelay in crystal growth. Moreover, nuclei formed outside thepore may diffuse into the pores to inhibit their growth intolarge crystals. When the pore size is comparable to or smallerthan that of the CRR, as in the case of SYL730, the exchange ofmolecules inside and outside the pores is expected to beFigure 8. (a) XRPD patterns for pure CEL and its mixture with 25% MS after the isothermal crystallization study at 95 °C by using BDS. (b) DSCcurves for pure CEL and its mixture with MS after 14400 s (4 h) of annealing at 95 °C.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672564https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig8&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig8&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asextremely slow. No stabilization effects were expected based onthe geometrical restriction for the molecules outside the pores.Previously, the difference in the particle size of MS wasfound to influence the stabilization effect; simvastatin glass wasphysically stabilized by mixing it with MS of small particlesize.12 The MS with a large particle size did not offer astabilization effect despite having the same pore size of 23 nm,which can be explained in a similar manner. If the particle sizeis small, then the exchange of molecules is easy because of thelarge surface area of the particles. If the particle size is toolarge, then only entrapped molecules near the surface areinvolved in the stabilization effect. In summary, exchangeablemolecules, which can be quantified as intermediate fractions,are likely to play an important role in the physical stabilizationof overloaded glass. A sufficiently large pore size and smallparticle size are required to exert the stabilization effect.From a practical point of view, the perfect filling of smallpores is anticipated to be difficult by any means. In fact, ourmodel calculation revealed that one-third of the pores ofSYL730 was assumed to be unfilled even in the mixture with asufficiently large amount of CEL. If guest molecules penetratefrom both sides of a connected pore, the pressure inside thepore increases, which should inhibit further penetration of theguest molecule. If the loading of drug molecules is done underhigh-temperature conditions, a decrease in temperature shouldallow additional loading of the guest molecules due to adecrease in pressure in the pores. However, even with thisscenario, perfect loading cannot happen as the pore environ-ment is not a vacuum. This is also a reason for the poorstabilization effect of MS with too small pores.4.3. Influence of the Pore Size of MS on the CrystalForm of CEL Glass. Form III is the most stable crystal formfor CEL at room temperature, whereas Form I is the moststable at temperatures higher than about 60 °C.22 In this study,only Form I appeared in the mixture with 25% SYL730 at 95°C. In contrast, Form III was likely to be formed in a mixturecontaining 25% SYL350. Similar observations, where nano-confinement influenced the form of the recrystallized drug,have been frequently reported. In the case of the crystallizationof phenyl salicylate, an unstable (monoclinic) form waspreferred in the presence of anodic alumina oxide membraneswith 150 nm pores, whereas a stable (orthorhombic) crystalwas found in that with 100 nm pores.50 When bulk probucolcrystallizes into Form I, unstable Form II is found innanochannels with a 40−120 nm pore size.51 This observationrevealed the usefulness of mesoporous materials for control ofthe crystal forms. In addition, our study indicated that a largerpore size is required relative to that of the CRR for thecontrolled crystallization as well as for the stabilization of theamorphous state. The slow crystallization in the presence ofSYL350 may be related to the occurrence of the metastableform, although its amount was small.5. CONCLUSIONSIn this study, the stabilization effects of two MS with differentpore sizes on the overloaded CEL glass were compared. CELglass in the presence of MS was classified using DSC into free,intermediate, and rigid fractions based on its molecularmobility. The intermediate fraction appears to play aninfluential role in the stabilization effect. The MS with alarge pore size (SYL350) significantly retarded the crystal-lization of the CEL glass, most likely because most of theoverloaded CEL molecules could exist as an intermediatefraction. In contrast, the crystallization of CEL glass wasaccelerated in the mixture with SYL730, when the amount ofMS was not sufficient, where most of the overloaded CEL glassremained as the free fraction. This difference likely originatedfrom the difference in the ease of exchange of CEL moleculesinside and outside of the pores. The pore size of SYL350 wassufficiently larger than the size of CRR of the CEL glass, but itis not true for SYL730, which might affect the exchangedynamics of the CEL molecules. These findings offer valuableinsights into the effect of pore size on the stabilization effect ofoverloaded pharmaceutical glass.■ ASSOCIATED CONTENT*sı Supporting InformationThe Supporting Information is available free of charge atht tps ://pubs .acs .org/doi/10 .1021/acs .molpharma-ceut.4c01482.Comparison of Τg, fragility, VFT parameters of pureCEL, and mixture with MS of different concentrations(PDF)■ AUTHOR INFORMATIONCorresponding AuthorKohsaku Kawakami − Research Center for Macromoleculesand Biomaterials, National Institute for Materials Science,Ibaraki 305-0044, Japan; Graduate School of Science andTechnology, University of Tsukuba, Ibaraki 305-8577,Japan; orcid.org/0000-0002-3466-9365; Phone: +81-29-860-4424; Email: kawakami.kohsaku@nims.go.jpAuthorXue Han − Research Center for Macromolecules andBiomaterials, National Institute for Materials Science, Ibaraki305-0044, Japan; Graduate School of Science andTechnology, University of Tsukuba, Ibaraki 305-8577, JapanComplete contact information is available at:https://pubs.acs.org/10.1021/acs.molpharmaceut.4c01482Figure 9. Schematic presentation of the influence of pore sizes on thedynamics of glass molecules. Rigid, intermediate, and free fractions arepresented by blue/cyan, yellow, and red, respectively. The rigidfraction exists as monolayers on the wall. It has a higher mobility inSYL350 but a lower mobility in SYL730. The intermediate fractionretains bulk-like mobility and is exchangeable inside and outsidepores. The stabilization effect based on the confinement effect iseffective for the outside molecules as well as for the inside molecules,as the molecules are easily exchangeable inside/outside pores. Whenthe exchange is slow, no stabilization effect is exerted on the freefraction outside the pores, as observed for SYL730.Molecular Pharmaceutics pubs.acs.org/molecularpharmaceutics Articlehttps://doi.org/10.1021/acs.molpharmaceut.4c01482Mol. Pharmaceutics 2025, 22, 2556−25672565https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?goto=supporting-infohttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?goto=supporting-infohttps://pubs.acs.org/doi/suppl/10.1021/acs.molpharmaceut.4c01482/suppl_file/mp4c01482_si_001.pdfhttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Kohsaku+Kawakami"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://orcid.org/0000-0002-3466-9365mailto:kawakami.kohsaku@nims.go.jphttps://pubs.acs.org/action/doSearch?field1=Contrib&text1="Xue+Han"&field2=AllField&text2=&publication=&accessType=allContent&Earliest=&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig9&ref=pdfhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c01482?fig=fig9&ref=pdfpubs.acs.org/molecularpharmaceutics?ref=pdfhttps://doi.org/10.1021/acs.molpharmaceut.4c01482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-asNotesThe authors declare no competing financial interest.■ ACKNOWLEDGMENTSThe authors thank Fuji Silysia Chemical for providing the MSmaterials.■ REFERENCES(1) Brouwers, J.; Brewster, M. 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