Nanostructures and Dynamics of Isochorically Confined Amorphous

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Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial and Intermolecular Interactions Chen Zhang, Ye Sha, Yue Zhang, Ting Cai, Linling Li, Dongshan Zhou, Xiaoliang Wang, and Gi Xue J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b08545 • Publication Date (Web): 07 Nov 2017 Downloaded from http://pubs.acs.org on November 9, 2017

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The Journal of Physical Chemistry

Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial and Intermolecular Interactions.

Chen Zhang,† Ye Sha,† Yue Zhang,† Ting Cai,‡ Linling Li,† Dongshan Zhou,† Xiaoliang Wang*,† and Gi Xue*,†

†

Key Laboratory of High Performance Polymer Materials and Technology of Ministry of Education,

Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, P. R. China ‡

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic

Diseases, and Department of Pharmaceutics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China

ABSTRACT: The production and stabilization of amorphous drugs by the nanoconfinement effect has recently become a research hotspot in pharmaceutical sciences. Herein, two guest/host systems—indomethacin (IMC) and griseofulvin (GSF)—confined in anodic aluminum oxide (AAO) templates with different pore diameters (25-250 nm) are investigated by differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). The crystallization of the confined drugs is suppressed, and their glass transition temperatures show an evident pore-size dependency. Moreover, a combination of dielectric and calorimetric results demonstrates that the significant change in the temperature dependence of the structural relaxation time during the cooling process is attributed to the vitrification of the interfacial molecules and the local density heterogeneity under isochoric confinement. Interestingly, compared with the case of IMC/AAO, which can be described by a typical two-layer model, GSF/AAO presents an rare scenario of three glass transition temperatures under fast cooling (40-10 K/min), indicating that there exists a thermodynamic nonequilibrium interlayer between the bulk-like core and interfacial layer. In 1

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contrast, the slow cooling process (0.5 K/min) would lead confined GSF into the stable core-shell nanostructure. Using surface modification, the interfacial effect is confirmed to be an important reason for the different phenomena between these two guest/host systems, and intermolecular hydrogen bonding is also suggested to be emphasized considering the long-range effect of interfacial interactions. Our results not only provide insight into the glass transition behavior of geometrically confined supercooled liquids, but also offer a means of adjusting and stabilizing the nanostructure of amorphous drugs under two-dimensional confinement.

1.

INTRODUCTION Because of their distinctive structural characteristics and physical properties, such as

molecules present under confinement,1-3 nanomaterials are now widely studied and applied in the field of nanoscience and nanotechnology.4-18 Recently, the application of porous materials (silica-based materials and some metal-organic frameworks) in drug amorphization and delivery has attracted great interest by pharmaceutical scientists because of the materials’ nanosized capillaries and large surface area. In considering effective drug utilization, especially for an active pharmaceutical ingredient with poor solubility in aqueous media, the stable amorphous phase of a drug is required to offer high solubility, fast dissolution rate and increased bioavailability.19-20 Therefore, the stable nanostructure, molecular dynamics and thermodynamics of a confined amorphous drug would play a crucial role in pharmaceutical product performance. On the one hand, the complex consequences caused by the interactions of drug molecules and porous media are not well understood, which presents challenges to successful medicinal development. On the other hand, there has been much debate on how the glass transition behavior of a molecule changes under nanoconfinement. In pioneering studies, the confinement effects of some low-molecular-weight glass formers or polymers were investigated. Various confining media (such as zeolites, controlled porous glasses (CPGs), Vycor, regular porous silicates, anodic aluminum oxide (AAO) templates, etc.) were used in these studies. The glass transition temperature (Tg) and dynamics of molecules under two-dimensional confinement might increase, decrease or remain unchanged compared with the bulk, mainly depending on the pore size, surface interactions and details of the experimental 2


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conditions.21-31 In most cases, the negative influence of the finite-size effect (depends on pore size) on Tg could be discussed via the theories of the configurational entropy model,32 since the size of cooperatively rearranging regions (CRRs) would be suppressed under geometrical restrictions,33-34 leading to enhanced molecular mobility. Meanwhile, positive shifts of Tg and local frustrated dynamics are ascribed to the attractive interfacial effect, which tends to compete with the finite size effect.25,

29

Alternatively, the strongly perturbed orientation and translational motion of

confined molecules close to the curved pore surface should also be considered.35-36 However, It seems that the existing theories of Tg are unable to explain the variable behaviors at nanoscales perfectly.3 In principle, the finite-size effect can be considered as spatially uniform, whereas the interfacial effect decays with increasing distance from the surface of confining medium. Therefore, because of the competition and discrimination of these two effects, the confinement-induced variation in molecular dynamics may present a gradient or two-Tg scenario. There is growing evidence for the latter scenario, with observations including both positive and negative shifts of Tg, and dynamic processes with broadening relaxation times being reported for organic glass-forming liquids confined in nanopores by calorimetric and dielectric experiments.37-47 Kremer et al. first proposed

the

“two-state

model”

to

interpret

the

dynamic

behavior

of

confined

low-molecular-weight glass-forming liquids, and calculate the molecular exchange between the bulk-like and interfacial phase.38-39 Soon afterwards, as Park and McKenna further summarized,41 the nanostructure of molecules confined in nanopores was described by a “two-layer” model: a shell with a high Tg and a core with a low Tg compared with that of the bulk. This phenomenon reveals a break in cooperativity at the core-shell boundary despite being seemingly counterintuitive. Recently, Paluch and co-workers confirmed this bifurcation in the molecular dynamics of a glass-forming liquid confined in AAO nanopores; even though the pore size was substantially larger than molecular dimensions and CRRs (in general, it is assumed to be several nanometers at Tg). They attributed this phenomenon to a local packing density heterogeneity arising from the vitrification of interfacial layer (or shell) under the isochoric confinement.46-48 From our previous works, during ultraslow cooling or long-time annealing, polymer oligomers can also form a stable core-shell structure when confined in AAO nanopores.49-53 It is worth noting that, when a fast cooling protocol was applied, the abnormal existence of a three-Tg phenomenon 3



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was observed for a poly(methyl methacrylate) (PMMA) oligomer/AAO system,50, 52 which could be interpreted by a metastable “three-layer” model. In this case, interfacial adsorption and molecular diffusion rates should be considered. Napolitano et al. demonstrated that many different aspects, such as the impact of thermal annealing condition on the interfacial molecular adsorption or the excess in the interfacial free volume related to the packing density, would play an important role on the dynamics of soft matter under nanoconfinement.54 However, a discussion involving the combination of factors mentioned above for the glass transition of low-molecular-weight glass formers confined in AAO nanopores and a comparison with the case of a confined polymer are hitherto scarce in the literature. In this work, we investigated the molecular dynamics and nanostructure of two amorphous drugs—indomethacin (IMC) and griseofulvin (GSF)—confined in AAO nanopores within different pore diameters (25~250 nm). Totally different glass transition behaviors for these two host/guest systems were observed by differential scanning calorimetry (DSC) techniques. And a decoupling between the core and interfacial molecular dynamics under isochoric confinement was demonstrated by broadband dielectric spectroscopy (BDS). We focused on the rare conversion between a metastable three-layer morphology and a stable core-shell nanostructure for the GSF/AAO system. The factors which play the crucial role in the stabilization of nanostructures of the confined amorphous drugs were revealed by adjusting the cooling procedure and the surface modification of the AAO nanopores. We believe that our research can provide a new insight into what kind of nanostructure does confined molecules prefer to form, which is significant for controlling drug release and delivery under nanoconfinement in biomedical applications.5-6

2. EXPERIMENTAL SECTION 2.1. Materials. Indomethacin (IMC) and griseofulvin (GSF) were purchased from Sigma-Aldrich (Purity>99.0%). Their chemical structures are presented in Scheme 1. The self-ordered AAO templates with average pore diameters of 25, 55, 130 and 250 nm respectively and a length of approximately 70 µm were provided by HeFei PUYUAN Nano, Ltd. All the templates were rinsed to remove possible impurities on the surface of the nanopores and then dried at 150 °C under vacuum for several hours before use. 4


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Scheme 1. Chemical Structures of IMC and GSF

2.2. Sample Preparation. The melt-quenched amorphous drugs were placed onto clean cover glasses, and annealed above their melting point (Tm, IMC ≈ 160 °C and Tm, GSF ≈ 220 °C) for 30 min to remove residual crystals and nuclei. Then, the AAO template was sandwiched between two cover glasses with a drug melt, and the whole system was maintained at a high temperature (170 °C for IMC and 230 °C for GSF) in vacuum for 12 h to allow the liquid to fill the nanopores via capillary forces. After the infiltration process, any excess sample on the surface of the template was removed with a sharp surgical blade. The AAO templates filled with glass-forming liquid are denoted as IMC/AAO and GSF/AAO.

2.3. Surface Modification of AAO. To study the influence of the interfacial effect, we modified the surface chemical composition of the AAO nanopores. Nanopores with a high concentration of surface hydroxyl groups (denoted as AAO-OH) were obtained by treating the pristine AAO templates with 30% H2O2 solution at 100 °C for several hours. Then, surface-modified hydrophobic AAO templates were fabricated by a liquid-phase reaction of AAO-OH

with

a

10

wt%

hexamethyl

disiloxane

(HMDSO)/chloroform

or

trichloro(1H,1H,2H,2H-perfluorooctyl)-silane (FOTS)/ chloroform solution at 50 °C for 24 h. The residual modifier was removed by washing with chloroform several times and finally drying in an atmosphere of nitrogen. The silanized AAO templates are denoted as AAO-R and AAO-F.

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2.4. Sample Characterization. 2.4.1. Scanning electron microscopy (SEM). The morphological characteristics were investigated by a scanning electron microscope (HITACHIS-4800). Taking the IMC/AAO as an example, Figure 1 shows SEM images of AAOs with different pore diameters filled with IMC.

Figure 1. SEM micrographs of the IMC/AAO top view: (a) 25, (b) 55, (c) 130 and (d) 250 nm.

2.4.2. Thermal Analysis. The mass fraction of drugs filled in the AAO templates was determined by thermogravimetric analysis (Perkin-Elmer TGA-Pyris system). The samples were heated from 20 to 700 °C at 10 K/min under a nitrogen atmosphere, and the results are shown in Figure S1. Calorimetric measurements of bulk and confined samples were carried out by a Mettler-Toledo DSC1 STARe differential scanning calorimeter under a dry nitrogen atmosphere. The temperature and enthalpy were calibrated using indium and zinc standards before experiments. The IMC/AAO and pure IMC were sealed and scanned from -20 to 170 °C at 10 K/min; for GSF/AAO and pure GSF, the scanning temperature range was 20 to 230 °C. In the cooling rate-dependency experiment, the confined samples with different pore diameters were first heated above the respective melting points to eliminate thermal history, and then a cooling process across 6


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Tg was performed with different cooling rates of 40, 20, 10, 5, 2, 1, 0.5 K/min; glass transition temperature and ∆Cp values were determined from the subsequent heating curves with a heating rate of 10 K/min.

2.4.3. Broadband Dielectric Spectroscopy (BDS). The dielectric measurements were made in temperatures ranges of 15-115 °C for IMC/AAO and 65-160 °C for GSF/AAO using a Novocontrol Alpha dielectric spectrometer (Concept 80, Novocontrol Technologies GmbH & Co, KG) over a frequency range of 10-2 to 106 Hz at ambient pressure. The confined samples were measured between two gold-plated copper electrodes (20 mm diameter), for the bulk sample, a PTFE ring (outer diameter: 20 mm, area: 59.69 mm2, and thickness: 0.5 mm) was used as a spacer. Before the dielectric measurements, the confined samples were first heated above the melting point, and two cooling protocols were employed using a hot stage: fast cooling rate—10 K/min, slow cooling rate—0.5 K/min.

3. RESULTS AND DISCUSSION 3.1. Glass Transition of Amorphous Drugs Confined in Nanopores. DSC thermograms measured for quenched bulk drugs and drugs confined in AAO nanopores with different pore diameters are shown in Figure 2a and b. Under confinement, the crystallization of both drugs is suppressed during typical temperature scans. As model compounds for studying the physical stability of amorphous pharmaceutical solids, IMC and GSF both have rigid structures and low configurational entropy, and they can readily undergo crystallization.55-56 Confinement is an effective way to prevent the nucleation and crystal growth of crystallizable drugs, which ensures that pharmaceutical products remain in an amorphous state for the long term.57 Due to the reduced molecular mobility in the adsorbed layer originating from the interfacial effects, as well as the suppression effect on the nucleation at nanoscale, nanoconfinement ultimately leads to a slower crystallization kinetics compared to the bulk.58-59 For the confined IMC samples, two distinct glass transition processes located above and below the Tg of the bulk are observed, which are denoted as Tg, high and Tg, low , respectively. Some of the thermograms exhibit a tiny hump between the two major transitions, which could be ascribed to residual drugs remaining outside the nanopores. A similar phenomenon has been reported for 7



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supercooled liquids and polymers confined in nanopores by both experiments and simulations,3, 46-47, 49, 51, 60-62

which can be interpreted according to the two-layer model proposed by Park and

McKenna:41 The shell consisting of the molecules interacting with the nanopore walls would reflect the higher Tg, and the molecules in the core exhibit faster dynamics and the lower Tg. However, in the case of confined GSF samples, DSC heat traces exhibit a discontinuity at the high-temperature glass transition region. The appearance of three Tg values is unusual for nanoconfined supercooled liquids. There is another Tg (denoted as Tg, mid) with a higher value than that of the bulk but lower than Tg, high. In our previous research, the existence of three Tg events was revealed by calorimetric investigations for a poly(methyl methacrylate) (PMMA) oligomer confined in AAO nanopores.50, 52 The origin of Tg, mid can be attributed to the molecules between the core and shell, which are trapped in a nonequilibrium state. Figure 2c and d reveals the effect of pore diameter on the glass transitions of these two kinds of confined drug molecules. Clearly, Tg, high

and Tg, mid increase with decreasing pore diameter, but the opposite trend occurs with Tg, low.

The relationships between the confined Tg and the nanopore diameter are analogous to the results of other supercooled liquids confined in porous materials with small pore sizes.1

8


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Figure 2. Normalized DSC heating traces of (a) bulk IMC and IMC/AAO, (b) bulk GSF and GSF/AAO with different pore sizes. All samples were first cooled from their respective melt temperature at 10 K/min and then heated at 10 K/min. The DSC curves were normalized on the basis of the TGA results. The relationship between the nanopore diameter (d) and the values of the multiple Tg values of (c) IMC/AAO and (d) GSF/AAO.

3.2. Molecular Dynamics under Isochoric Confinement. To confirm the results of the calorimetry measurements, the molecular dynamics were 9



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obtained by dielectric measurement. To eliminate the influence of thermal history, before the tests, all the samples underwent the same thermal protocols (cooling rate was 10 K/min) as in the DSC experiments using a hot stage. Dielectric spectra were recorded during the heating process. Figure S2 presents the dielectric loss spectra of bulk (IMC and GSF) and confined drugs (for example, taking 55 nm drug-filled AAO samples) at the indicated range of temperature. For the bulk samples, the spectra display a prominent structural (α-) relaxation that shifts toward higher frequencies as the temperature increases because of the decrease in viscosity and enhancement in mobility. In the confined samples, two loss processes can be seen. The high-frequency dynamic process resembles the relaxation curve of the bulk sample, at least at high temperatures; therefore, this process should be attributed to the relaxation of bulk-like drug molecules in the core volume. In constrast, the slower process in the conductivity wing is proposed to be assigned to Maxwell–Wagner–Sillars (MWS) polarization (interfacial polarization) because its magnitude of relaxation strength far exceeds that of the intrinsic relaxation of the drug molecules. This phenomenon is related to the blocking of charge carriers at the inner pore wall-liquid interface, which is very common in the heterogeneous system.39-40, 63-64 In general, the relaxation process of interfacial molecules in AAO nanopores has the characteristics of a relatively broad distribution of relaxation times and a low dielectric loss peak height.46-47, 52 Unfortunately, the relaxation signal of the interfacial layer is concealed by the conductivity contribution and strong MWS process, which cannot be directly observed with dielectric spectroscopy here. Therefore, we focus on the variation of the relaxation process of the bulk-like drug molecules in the core volume. Figure 3 shows the dielectric loss spectra obtained for IMC and GSF confined in AAO templates with different pore size at representative temperatures. At temperatures significantly closer to the respective bulk values of the glass transition temperature, as shown in Figure 3a and b, the shift of the α-relaxation peak towards higher frequencies can be observed with the reduction of pore size. On the other hand, when the measured temperatures are above the glass transition temperature of the interfacial layer, the peak position of confined α-relaxation is nearly the same as that in bulk case and seems to be unaffected with the increasing geometrical confinement. In addition, the distribution of α-relaxation times becomes broad and furthermore depends on the pore size. Similar results have also been reported in the cases of other soft matters confined in AAO nanopores,30-31,

47, 52, 62, 65-66

which may be linked to the increased local heterogeneity of the 10


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confined system and the consequent variation of the local density.40, 67-68 Alternatively, the strong interaction between the interfacial and core molecules can also be a major factor behind the phenomenon. As the pore size decreases, the interfacial effect would dominate in this case because of the increased surface-to-volume ratio. Thus the broadening of the α-relaxation process, especially at the low-frequency side, can be observed.

Figure 3. Frequency dependence of the normalized dielectric loss (ε″) for (a) IMC/AAO at 45 °C, (b) GSF/AAO at 100 °C, (c) IMC/AAO at 75 °C and (d) GSF/AAO at 130 °C with different nanopore diameters.

The imaginary part of the dielectric permittivity is a function of frequency (ω) and temperature (T). To extract the relaxation times of α and MWS processes, the obtained isothermal spectra in Figure S2 were fitted using the empirical Havriliak-Negami (HN) function: 69

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ε ′′ (ω ) =

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∆ε (T ) σ dc + ε∞ + n ε 0ω 1 + ( iωτ ( T ) ) m  HN 

(1)



where ε∞ is the high-frequency limit value of the permittivity, ∆ε(T) is the dielectric strength of the relaxation process that depends on the amount of effective dipole under investigation, τHN(T) is the central relaxation time, m and n (m > 0, mn ≤ 1) are the shape parameters that characterize the symmetrical and asymmetrical broadening of the loss peak. For the ionic conductivity contribution, σ is the specific dc conductivity, and the ε0 is the permittivity of vacuum. While for the MWS polarization relaxation, which was detected in similar confined systems, the dielectric responses

were usually preferred to described by the special version of HN with n = 1 in equation (1).40, 63 This one-shape-parameter function is known as the Cole-Cole (CC) equation.70 Furthermore, the mean relaxation time (τmax) at the maximum of the dielectric loss is calculated by the following equation:



 −1/ m  π mn   sin    2 (1 + n )   2 (1 + n ) 

τ max = τ HN sin −1/ m 

πm

(2)

The HN and the CC fits were satisfactory and the temperature dependence of the relaxation times for bulk and confined drugs are summarized in Figure 4. Additionally, the fitting results of the dielectric loss curves (e.g., 55 nm) concerning the different relaxation processes and conductivity contributions are shown in the insets.

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Figure 4. Characteristic relaxation time (τmax) as a function of reciprocal temperature for the 13



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α-relaxation and MWS processes of (a) bulk IMC and IMC/AAO, (b) bulk GSF and GSF/AAO. The dashed lines correspond to the VFT fittings of the α-relaxation for the bulk sample. The insets show the frequency dependence of the dielectric loss (ε″) for IMC/AAO at 100 °C and GSF/AAO at 140 °C with 55 nm nanopores. The black circles represent the measurement data, the red solid lines represent the fitting curves, and the dashed lines represent the individual processes (the blue dashed lines are the conductivity contributions).

As can be seen, for the confined samples at high temperatures, the α-relaxation of core molecules has a behavior similar to that of the bulk samples. Additionally, their temperature dependence on α-relaxation can be described by the Vogel−Fulcher−Tammann (VFT) equation:

 DT0    T - T0 

τ max = τ 0 exp 

(3)

with infinite relaxation time (τ0), fragility parameter (D), and Vogel or “ideal” glass transition temperature (T0). In contrast, the MWS polarization process relaxation time follows an Arrhenius temperature behavior:

 ∆E    k BT 

τ max = τ 0 exp 

(4)

However, as the temperature decreases, the τα(T) dependence changes its character to an Arrhenius-like form. A similar variation also occurs to the free surface layer of a polymer thin film during the bulk-part vitrification.71-72 Interestingly, the temperatures of this crossover (Tcross) coincide well with the glass transition temperatures of the interfacial molecules determined from the DSC studies, which shift continuously to higher values with decreasing pore diameter. Moreover, below Tcross, the dynamics of core molecules becomes progressively enhanced in comparison with the bulk, which is ascribed to the increasing degree of confinement. According to the common definition (τα(Tg) = 100 s), the corresponding low glass transition temperature of the core molecules follows the same pore-size dependency as the DSC results. Similar phenomena were discussed by Paluch’s group,46-47,

62

who interpreted this

remarkable change in terms of a decoupling between the dynamics of the interfacial and core molecules. As they emphasized, the density fluctuations would play a crucial role in controlling dynamics of confined liquids and could be accurately quantified by the Ev/Hp ratio,48, 73 where 14


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Ev/Hp is equal to the ratio of the first derivatives of the τα(T) dependence under isochoric and isobaric conditions. The AAO nanopores are uniform and could be regarded as an isochoric confining environment upon cooling because of the nearly invariable thermal expansion coefficient of aluminum oxide. The glass-forming liquid confined in the AAO nanopores would enter the isochoric conditions after the vitrification of the interfacial molecules, in contrast to the bulk sample under constant ambient pressure. On the one hand, as the temperature decreases, the natural reduction in specific volume and the intermolecular interactions with the immobilized interfacial layer drive negative pressure effects and excess confinement on the dynamics of core molecules. Therefore, the confined liquids demonstrate the enhanced mobility compared with the bulk dynamics at the lower temperature. Furthermore, the sensitivity to the pressure changes is determined by the value of Ev/Hp for different confined materials.48 On the other hand, only a slight change in the packing density of molecules confined in nanopores may lead to remarkable changes in their relaxation and glass transition temperatures.74-75 Actually, the average density of the confined liquid is expected to decrease with increasing geometrical confinement.76 In addition, the molecules near the interface may exhibit strong spatial ordering and an enhanced packing density, which induces an increased Tg. Because of the isochoric glass formation conditions, the local packing density in the core volume would decrease correspondingly. In our previous work involving the polymer confined in the AAO nanopores, the pack density or the interchain proximity of polymer chains was proven to depend on the pore diameter by fluorescence resonance energy transfer (FRET) method.

51, 77

Here, in smaller pores, the higher Tg of the

interfacial layer is accompanied by a lower density and larger free volume for the core molecules, which results in a larger deviation from the bulk dynamics. In short, the changes of the dynamics-temperature dependency at the crossover temperature arise from the vitrification of the interfacial layer and consequent density variation of the core molecules, which is clearly affected by the pore size. According to the above results, we can confirm the existence of an interfacial relaxation process in the confined samples, although the corresponding loss peak is not directly observed in the dielectric spectrum.

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Figure 5. DSC heating traces of GSF confined in AAO templates with different nanopore sizes undergoing different cooling rates across Tg, low: (a) 25 nm, (b) 55 nm, (c) 130 nm, and (d) 250 nm. The DSC curves were normalized on the basis of the TGA results.

3.3. The Three- to Two-Layer Models Conversion of GSF/AAO System. To obtain a better understanding of the formation of the dynamic heterogeneity in the nanopores, the evolution of the interfacial layer, especially for metastable GSF/AAO, was investigated. With a traditional cooling rate of 10 K/min, IMC/AAO and GSF/AAO show 16


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different glass transition behaviors. IMC/AAO samples exhibit two Tgs corresponding to a typical two-layer model, while three Tgs are obtained for GSF/AAO samples. The “three-layer model” was first deduced by Gorbatschow and Kremer to explain the abnormally broad relaxation time distribution

of

H-bonded

liquids

confined

to

nanopores.78

However,

for

confined

low-molecular-weight glass-forming liquids, few of calorimetric evidences of this model were reported previously. For confined polymer, the heterogeneous nano-architectures in adsorbed layer and the possibility of formation of the interlayer adjacent to the adsorbed layer have been demonstrated.79-80 In general, the multi-Tg behavior verifies the mobility gradients, running along the confinement dimension. We speculate the GSF molecules in the interlayer are loosely packed compared with that in the adsorbed layer, but their mobility is still impeded through the interaction with the immobilized interfacial molecules. The nonequilibrium effect caused by non-repulsive interfacial interaction and interfacial adsorption would be dominant in this case, which lead a nonequilibrium adsorbed region. In our previous work, we demonstrated that the stabilization of nanostructure for PMMA oligomers confined in AAO nanopores is strongly affected by the thermal treatment.49-50, 52 Because the molecular orientation and dynamics in the interfacial region depend on the adsorption kinetics and layer aging procedure, the cooling rate may play a crucial role in the glass transitions behaviors of confined drugs. Herein, we did an investigation of the cooling rate-dependency of these two types of drugs confined in cylindrical nanopores. As shown in Figure S3 and Figure 5, a slower cooling rate results in a distinct enthalpy overshoot in the glass transition region, indicating the thermal responses in the heat flow curves are indeed glass transitions. In general, the amorphous drugs reveal a strong tendency toward recrystallization. However, due to confinement effects, no cold crystallization or melting process is observed for the confined samples heating from the glassy state (see Figure S4), even though the slowest cooling process (0.5 K/min) is applied. That indicates both confined drugs maintain in amorphous state during the cooling rate experiments. For the IMC/AAO samples, the glass transition always keeps with the two-layer model, irrespective of the cooling rate (see Figure S3). However, GSF/AAO shows a cooling rate-related glass transition behavior (see Figure 5). When the cooling rate is 40 K/min, the glass transition of confined GSF above Tg,bulk is split into two regions, which indicates the metastable thermal state of the interfacial layer. As the cooling rate slows down to 0.5 K/min, such two separated Tg values gradually merge into a single glass transition process. The cooling 17



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rate experiment of the GSF/AAO samples demonstrates the evolution of confined molecules from a three-layer model to a two-layer model accompanied with the stabilization of the interfacial layer. A similar transformation was reported in the PMMA/AAO system.52 When a fast cooling rate was applied (such as 40~10 K/min), most of the confined PMMA chains were in a thermodynamic nonequilibrium state and presented a quite broadened glass transition with a Tg slightly higher than the bulk value. Furthermore, in that case, only a primitive interfacial layer had formed without the bulk-like core. With a decrease in the cooling rate, because of the sufficient dynamic molecular exchange, the contents of the interfacial layer and emerging bulk-like core both gradually increase and are accompanied by the disappearance of the metastable interlayer. However, compared with the PMMA/AAO system, the Tg evolution of the confined GSF does not involve a variation of bulk-like core content. This indicates that, for both confined GSF and IMC, the interfacial and core regions have completely separated, even with a rapid cooling treatment. Therefore, for the glass transition of GSF/AAO, the conversion of the two-layer model to the three-layer model should be considered as the self-adjustment of molecular conformation and packing density in the thermodynamic nonequilibrium interfacial region. We propose that the mentioned distinction between small molecule and polymer systems is associated with the different molecular structures. Because of the complex long-chain structure, the rearrangement of nonequilibrium chain conformation requires significantly longer times. Additionally, adsorption essentially involves the diffusion of molecules towards the interface. Compared with polymers, small molecules have a lower viscosity, which means a higher diffusion rate.

18


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Figure 6. The percent ∆Cp of the interfacial layer, Φads, as a function of cooling rate for GSF confined in AAO templates with different pore diameters.

Considering the content of the bulk-like core is almost constant (see Figure S5), the thickening of the adsorbed layer (Tg,high) should be appropriate and sufficient to reveal the effect of cooling rate on the formation of the stable core-shell nanostructure. In order to determine the structural evolution of interfacial layer quantitatively, the content of interfacial layer can be deduced from the change in heat capacity in the Tg, high region, as equation 5 shows:

Φ ads =

∆C p ,high ∆C p ,high + ∆C p ,inter + ∆C p ,low

(5)

The detailed calculation results are summarized in Figure 6. The interfacial layer gradually thickens with the decrease of cooling rate, and the interlayer disappears concomitantly. Even at high temperatures, there should already exist a very thin layer of molecules with frustrated dynamics adjacent to pore walls due to the restriction of the rigid surface. Molecules distributed in the interlayer and interfacial layer undergo exchange because of dynamic heterogeneity at a 19



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specific temperature.35,

38, 81

Such an exchange process would become irreversible during

continuous cooling accompanied with the migration of interlayer molecules toward the pore wall, and the interfacial layer thickens. The percent ∆Cp of the interfacial layer, Φads, (which is proportional to the thickness of the irreversible adsorbed layer) evolves with an exponential growth and would reach a plateau finally if the cooling rate further slows down. The similar phenomenon has been discussed by Napolitano et al. involving the impact of annealing time on the kinetics of thickening of the polymer layer irreversibly adsorbed onto the substrate.54, 82 In addition, it can be seen that the evolution of the interfacial layer in the 25 nm AAO nanopores is more rapid than that in the 250 nm AAO nanopores. This is consistent with the DSC curves of the cooling rate-dependency experiment. When the cooling rate decreases to 2 K/min, the glass transition of GSF confined in the 25 nm nanopores roughly conforms to the two-layer model; however, an evident three Tg values are still detected in the 250 nm samples. This is because increased geometrical confinement results in an enhanced interfacial effect, which sped up the stabilization of the interfacial region.

20


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Figure 7. The Tg evolution of (a) IMC and (c) GSF confined in the 55 nm nanopores undergoing different cooling rates across Tg, low, and the relaxation maps of (b) IMC/AAO and (d) GSF/AAO samples. The insets of panel b and panel d are comparisons of the dielectric spectra measured near the Tg,bulk for the samples undergoing fast cooling (~10 K/min) and slow cooling (0.5 K/min).

On the other hand, the value of the multiple Tg values of the confined drugs also depends on the cooling rate. Drug molecules confined in the 55 nm nanopores are selected as example. As shown in Figure 7a and c, Tg, high and Tg, mid are slightly reduced (within 1-2 °C) for the IMC/AAO and GSF/AAO samples, whereas Tg, low is elevated by 6-8 °C with a decreased cooling rate. This indicates the presence of the metastable state of confined molecules under rapid cooling treatment. Since the glass transition is a kinetic phenomenon, the glass transition of molecules would be influenced by the heat treatment process. And a slow cooling is equivalent to a longer annealing process. For these confined systems, when the interfacial layer vitrified, the packing density of residual molecules in the core area of the nanopores would be strongly perturbed because of the isochoric effect. The molecules in the core volume would have enough time to locally rearrange when a slow cooling is applied, resulting in a densely packed morphology and an increased Tg. Similar phenomena by annealing experiments to increase Tg have been reported in polymer thin films and nanochannel-confined small molecules or oligomers.47, 49, 62, 82-83 For the molecules in the interfacial layer, we propose that the restricted pore wall and the interfacial effect would hinder molecular rotational and translational motions, so their local rearrangement requires higher cooperativity and a longer time scale. Additionally, the preferred localized molecular orientation near the surface and intrinsic higher packing density of the interfacial layer would also suppress the changeability in Tg,high. The change in the glass transition of the molecules confined in 55 nm AAO nanopores with different thermal histories was confirmed by dielectric investigation. The samples were placed on a heating stage to control the cooling rate. After vitrification at low temperature, they were placed in the dielectric spectrometer, and the followed heating analysis was performed. As shown in Figure 7b and d, comparing the fast cooling case (10 K/min) with the slow cooling case (0.5 K/min), the relaxation times of α-relaxation show a 0.5~1 magnitude of deviation below Tcross. This demonstrates that during the slow cooling the mobility of molecules located in the core 21



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volume becomes slower. Actually, quenching samples confined in nanopores can lead to tension within the liquids and acceleration of the structural dynamics.84 This result is exactly the same as that from DSC. Meanwhile, at higher temperatures, no apparent effects of thermal history on τα(T) can be observed. Furthermore, it is worth noting that the relaxation time of the slower relaxation process suggests the absence of cooling rate dependence, which serves as evidence to prove that this process should be attributed to interfacial polarization rather than the structure relaxation of interfacial molecules. Otherwise, this relaxation process, especially for the GSF/AAO, would change dramatically with the decrease in cooling rate due to the conversion from the three-layer model to the two-layer model.

22


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Figure 8. Taking the samples with 55 nm nanopores as an example. DSC heating traces of (a) GSF/AAO and GSF/AAO-OH, (c) IMC/AAO, IMC/AAO-R and IMC/AAO-F. All samples were first cooled from their respective melt temperature at 10 K/min. The heating traces of (b) GSF/AAO-OH and (d) IMC/AAO-R undergoing different cooling rates across the the Tg, low. All the DSC curves were normalized on the basis of the TGA results.

3.4. Effect of Interfacial and Intermolecular Interaction on Stabilization of 23



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Confined Amorphous Drugs. DSC analysis reveals that the glass transition behaviors of IMC/AAO and GSF/AAO exhibit different cooling rate-sensitivities. Although the intrinsic reason remains obscure, it is easy to ascribe the result to the interfacial effect. The importance of interfacial effects has been consistently emphasized for the supercooled liquid/nanopore system and polymer thin films, which can depend strongly on the physical and chemical properties of the interface.42, 64, 85-90 A common surface modification is used to alter the chemical property of the pore wall via silanization. According to our previous work on PMMA oligomers confined in AAO nanopores, a stronger interfacial interaction can accelerate the stabilization of the interfacial layer.52 IMC is an acid that contains both a hydrogen bonding donor and acceptor, whereas GSF is a neutral molecule that only contains a hydrogen bonding acceptor. Since the surface of pristine AAO nanopores contains hydroxyls, the interaction between IMC and the inner wall of AAO nanopores would be stronger than the interfacial interaction in the GSF/AAO case. Here, we modify the interfacial interaction to determine whether the glass transition behavior of confined drugs can transform between a three-layer model and a two-layer model. Figure S6 shows the scheme of a pristine AAO template and surface-modified AAO templates, i.e., hydroxylated AAO (AAO-OH), HMDSO modified AAO (AAO-R) and FOTS modified AAO (AAO-F). The hydrophobicity of these templates is characterized by measuring their contact angle with water. As summarized in Table S1, the graphical change in contact angle indicates the changed surface hydroxyl density or successful silanization. Then amorphous pharmaceutical molecules were confined in these modified AAO templates, and the respective calorimetric heating curves are detailed in Figure 8. For GSF/AAO-OH, compared with the pristine nanopore case at a 10 K/min cooling rate, this demonstrates a two-layer model. Therefore, we can deduce that a stronger interfacial interaction can promote the formation of a stable interfacial layer. However, once the cooling rate increases, as shown in Figure 8b, GSF/AAO-OH still exhibits three Tg values (such as with cooling rates of 40 K/min and 20 K/min). For IMC/AAO-R, although the interfacial hydrogen bond interaction is substantially weakened, it still indicates a two-layer model (Figure 8c) when the cooling rate is 10 K/min. Additionally, a faster cooling rate, even with 40 K/min, cannot result in a three-layer model, as our original assumption. It appears that weaker interfacial interactions are not the crucial reason behind the peculiar 24


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three-layer

model

for

glass

transition

behavior.

It

should

be

noted

that

the

trimethylsilane-modified nanopore wall has weak interactions with confined molecules that are non-negligible, thus, leading to the formation of an interfacial layer.41,

52

However, for

IMC/AAO-F, the repulsive interfacial interaction is dominant, and Tg, high is completely hindered, as

shown

in

Figure

8c.

A similar

phenomenon

was

reported

for

poly

n-butyl

methacrylate/AAO-F51 and polycarbonate/AAO-F91. The lack of attractive interfacial interaction makes it difficult to form an interfacial layer. Indeed, interfacial interactions can influence the formation and stabilization of the interfacial layer. However, there must be some other factors in IMC/AAO and GSF/AAO to cause their totally different glass transition behaviors. We suppose that intermolecular interactions might play an important role. Interface modification can modulate the interaction between the nanopore wall and confined molecules, but the interfacial interactions only occur straightforwardly on the monomolecular layer adjacent to the nanopore walls. For the system of molecules confined in AAO nanopores, the thickness of the interfacial layer is usually significantly larger than the intrinsic molecular size,46,

50, 62

which indicates that the interfacial interaction may exhibit a

prominent long-range effect. The interfacial interactions extend radially into the interior part via intermolecular interaction between small molecules, whereas for the polymer, such process can be easily realized due to their long chain structure and interchain coupling. It is easy to form intermolecular H-bonding interactions between IMC molecules. Most of the time, the dimer or trimer exists in bulk IMC. The initial surface-restricted IMC molecules could draw the other IMC molecules to get close to the nanopore wall rapidly via attractive intermolecular H-bonds, which is beneficial for interfacial adsorption. In terms of GSF, only weak intermolecular interactions exist. Actually, in comparison with IMC, although GSF has a relatively higher Tg, it has a substantially larger free volume and faster molecular mobility due to the lack of a hydrogen bonding capability.56 On the other hand, considering the weaker interfacial interactions of GSF/AAO, GSF molecules relatively far from the pore wall would be less confined. Therefore, during a rapid cooling process, a portion of the GSF molecules in the interfacial region cannot adjust their packing morphology sufficiently, thus, leading to the metastable interlayer with Tg, mid. When the cooling rate is slow, these interlayer molecules can be modulated into a more stable packing configuration. 25



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Page 26 of 33

In addition, referring to the calculations in the relevant literature,46, 50, 62 the thickness of the interfacial layer decreases with the reduction of the AAO nanopore size (herein, for GSF/AAO samples, pore diameter/interfacial layer thickness: 250 nm/36.5 nm, 130 nm/20.0 nm, 55 nm/8.4 nm, and 25 nm/4.1 nm). It is worth noting that, for molecules confined in other porous media (such as Gelsil and Vycor glasses) with smaller pore sizes (approximately or less than 10 nm), the interfacial layer thickness was evaluated to be in the range of 1 nm.41, 92 We suspect that the three-layer model may occur in nanopore confined systems with a large pore size or thick interfacial layer (such as a supercooled liquid/AAO system). As the pore size decreases, the glass transition of the interlayer becomes obscure, as shown in Figure 2b, due to the enhanced interfacial effect with a shorter extension distance of interfacial interactions and reduced impact of intermolecular interactions.

4. CONCLUSION In this manuscript, the Tg dynamics of IMC and GSF confined in AAO cylindrical nanopores with different pore diameters were investigated by using DSC and BDS. When the cooling rate is 10 K/min, calorimetric curves reveal a two-Tg scenario for IMC/AAO, which can be described by a two-layer model. However, GSF/AAO presents a conversion between three-Tg behavior and the more stable two-Tg behavior depending on the thermal treatment process. These two systems both demonstrate a pore size-dependent Tg value. Tg,

low

decreases whereas and Tg,

high

(or Tg,

mid)

increases with the reduction of pore diameter, indicating that the glass transition behavior of confined molecules is mediated by the counterbalance of interfacial effects and size effects. BDS experiments reveal that the dependence of relaxation time versus temperature of the bulk-like core molecules changes when the interfacial layer vitrifies, reflecting the local packing density heterogeneity under confinement as well as the interplay between the core and interfacial molecules. Fast cooling results in a thermodynamic instability for the confined molecules which can be adjusted via slow cooling, coinciding with the BDS results. Additionally, by surface modification of the AAO nanopores, we demonstrate that non-repulsive interfacial interactions are the dominate factor in forming the core-shell structure whereas the unstable three-Tg scenario originates from the other factor, i.e., a deficient extension of the long-range interfacial effect via 26


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weak intermolecular interactions. This work might contribute to a more comprehensive understanding of the physics and nanostructure of two-dimensionally confined molecules that are controlled by the interfacial effect, size effect, thermal treatment and intermolecular interactions. We believe that, for the glass transition of molecules confined in AAO nanopores with diameters significantly larger than molecular dimensions, stronger interfacial and intermolecular interactions lead to a stable two-layer model, while weaker interactions lead to the unstable three-layer model, and a one-layer model may occur with repulsive interfacial interactions.

■ AUTHOR INFORMATION Corresponding Author *Xiaoliang Wang, E-mail: [email protected] *Gi Xue, E-mail: [email protected]

Note The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (grant nos. 516730 94, 2179340025, 21574063, 21474049, 51133002, 21404055 and 21304003).

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TOC

Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial and Intermolecular Interactions Chen Zhang,†Ye Sha,†Yue Zhang,† Ting Cai,‡Linling Li,†Dongshan Zhou,†Xiaoliang Wang*,†and GiXue*,†

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Nanostructures and Dynamics of Isochorically Confined Amorphous

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