Acceleration of Crystal Growth of Amorphous Griseofulvin by Low

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Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-concentration Poly (ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility Qin Shi, Chen Zhang, Yuan Su, Jie Zhang, Dongshan Zhou, and Ting Cai Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 26 May 2017 Downloaded from http://pubs.acs.org on May 30, 2017

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Molecular Pharmaceutics

Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-concentration Poly (ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility Qin Shi†, ‡, Chen Zhang§, Yuan Su†, ‡, Jie Zhang†, ‡, Dongshan Zhou§,*, Ting Cai†, ‡,* †State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China ‡Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China §Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China Abstract: This study aims to investigate the crystallization behavior and molecular dynamics of amorphous griseofulvin (GSF) in the presence of low-concentration poly (ethylene oxide) (PEO). We observe that the addition of 3 % w/w PEO remarkably increases the crystal growth rate of GSF by two orders of magnitude, in both the supercooled liquid and glassy states. The liquid dynamics of amorphous GSF in the presence and absence of PEO are characterized by dielectric spectroscopy. With an increase of the PEO content, the α-relaxation times of the systems decrease, indicating the increase of global molecular mobility. The couplings between molecular mobility and crystallization kinetics of GSF systems show strong time-dependences below Tg. The overlapping of α-relaxation times of GSF in presence and absence of PEO as a function of Tg/T suggests the "plasticization" effect of PEO additives. However, the crystallization kinetics of amorphous GSF containing low-concentration PEO do not overlap with those of pure GSF on a Tg/T scale. The remarkable accelerating effect of crystal growth of amorphous GSF by low-concentration PEO can be partially attributed to the increase of global mobility. The high segmental mobility of PEO is expected to strongly affect the crystal growth rates of GSF. These findings are relevant for understanding and ACS Paragon Plus Environment


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predicting the physical stability of amorphous pharmaceutical solid dispersions. Keywords: crystal growth; molecular mobility; dielectric spectroscopy; griseofulvin; poly (ethylene oxide)

Introduction: In the past decades or so, there is an increasing number of the new active pharmaceutical ingredients (APIs) exhibiting poor aqueous solubility.1-2 Amorphization of poorly water-soluble drugs becomes one of the most effective approaches to improve their solubility and hence bioavailability.3-4 However, from the thermodynamic perspective, amorphous materials are metastable, which have the higher free energies and tend to revert back to the more stable crystalline forms, negating their advantages.5-6 Therefore, it is crucial to maintain the APIs in the amorphous state during processing and storage in considering the potential risk of drug recrystallization. Polymers have been widely used to disperse non-crystalline APIs and improve their physical stability.7-13 Several mechanisms have been proposed to understand the role of the polymer governing physical stability of amorphous solid dispersions, including segmental mobility of polymers and formation of polymer–drug hydrogen bonding.8-9,14-15 Low-concentration polymers with high glass transition temperature (Tg) can significantly decrease the crystallization rate of amorphous drugs. For example, the crystal growth rate of amorphous nifedipine can be reduced by one order of magnitude in the presence of 1% w/w of various grades of polyvinylpyrrolidone (PVP).8 A study with more polymers by Powell et al. report that the inhibitory effect on crystal growth rates of amorphous nifedipine correlates remarkably well with the neat polymer's Tg, indicating the importance of polymer segmental mobility in crystallization inhibition.9 Specific interactions between polymers and drugs have been suggested to be another contributor to the stabilization effect on amorphous solid dispersion.13,16-18 For instance, Kestur et al. report that the power of a polymer dopant to inhibit crystal growth in the liquid felodipine depends on the strength/extent of drug-polymer hydrogen ACS Paragon Plus Environment

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bonding interactions.13 In a recent study, Kothari et al. demonstrate that the stronger drug-polymer hydrogen bonds interactions exhibit a better reduction effect on molecular mobility of nifedipine, and thus resulting of the higher resistance to recrystallization.16 Poly (ethylene oxide) (PEO) is one of the most extensively studied polymers with wide range of applications in the pharmaceutical field.19 In the delivery of poorly water-soluble drugs, PEO can serve as a hydrophilic matrix to enhance the solubility and modulate the release profile.20 PEO is also used as the matrix to formulate tamper-resistant tablets for deterring opioid abuse.21 However, unlike the most polymeric additives, PEO has been reported to accelerate the crystal growth in amorphous pharmaceuticals rather than inhibiting crystallizations.9,22 This phenomenon is analogous to the “plasticization” effect of water, where the water sorption can facilitate the crystallization of amorphous drugs through increasing the molecular mobility.23 Polyhydroxybutrate (PHB), a biocompatible polymer, has also been found to exhibit the accelerating effect on crystallizations specifically for the organic compounds with Tg’s 50°C higher than that of the polymer. 24 Very recently, Huang et al. reported that 1% w/w polymer additives could strongly alter the rate of crystal growth, from a 10-fold reduction to a 10-fold increase.25 The polymer effect on crystal growth rates of host molecules can form a master curve as a function of (Tg polymer – Tg host)/Tcryst, where Tcryst is the crystallization temperature.25 In this study, we systemically investigate the influences of low-concentration PEO on the crystal growth of amorphous griseofulvin (GSF). Under the cross-polarized microscope, we observe that the addition of 3 % w/w PEO remarkably increases the crystal growth rate of GSF by two orders of magnitude, in both the glassy and supercooled liquid states. In order to better understand the relation between crystallization kinetics and molecular dynamics, we examine the molecular mobility of amorphous GSF doped with low-concentration PEO by broadband dielectric spectroscopy (BDS). BDS has been widely used to explore different relaxation processes that may associate with the ACS Paragon Plus Environment


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physical stability of amorphous pharmaceutical solids.26 Experimental section: Materials Griseofulvin(2R,6'S)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H,4'H-spiro[1-benzofuran-2,1'-cyclohex [2]ene]-3,4'-dione) was purchased from J&K scientific Co., Ltd, China (Purity>99.0%) and used as received. The GSF received is the polymorph I. Poly(ethylene oxide) (PEO, Mv=100000, Tg = 226K) was purchased from Sigma-Aldrich (St Louis, MO) and used as received.

Poly(ethylene oxide)

Griseofulvin

Preparation of PEO/GSF mixtures Mixtures of GSF and PEO were prepared by cryogenic milling (SPEX SamplePrep 6770 Freezer/Mill). The cryogenic milling was found to reduce the particle size and mix components more efficiently than hand- and ball-milling.27 In a typical procedure, 1g of GSF and PEO mixture in an airtight tube was cryomilled at 10Hz for 5 cycles. Each cycle of milling time was 2min, followed by a 2-min cool-down process. Liquid nitrogen was used as a coolant. A two-step dilution was applied to achieve an uniform mixing for GSF containing low-concentration PEO. In this procedure, GSF and PEO were first mixed at the ratio of 9:1 or 7:3, and the resulting mixtures were mixed with GSF at the ratio of 1:9 to yield the mixtures containing 1% and 3% w/w PEO in GSF. Thermal analysis Differential scanning calorimetry (DSC) was conducted in aluminum pans using a TA Instruments DSC Q2000 equipped with a refrigerated cooling accessory under 50 mL/min N2 purge. For obtaining the solubility of GSF crystals in PEO, the annealing method reported by Yu and co-workers ACS Paragon Plus Environment

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was used.27-28 10~15 mg of cryomilled GSF/PEO (10/90,30/70,50/50,70/30, all in w/w ratio) mixtures were sealed hermetically in aluminum pans and annealed at a desired temperature for 4 hour then scanned at a standard heating rate of 10 K/min to determine whether un-dissolved GSF crystals still remained. This method facilitates the attainment of phase equilibrium, yielding more accurate measurement for determining the drug-polymer interaction parameter. Fourier transform infrared(FT-IR) spectroscopy The specific interaction between GSF and PEO was investigated using FT-IR spectroscopy (Thermo Fisher, Nicolet iS10). The spectra were recorded over a range of4000-400cm-1 with a resolution of 4cm-1, using 64 scans.10~15 mg of cryomilled GSF/PEO (30/70,50/50,70/30,all in w/w ratio) mixtures were melt at 503K and quenched to become the amorphous mixtures by liquid nitrogen. Each sample was dispersed uniformly in KBr and then compressed into a disc for analysis. Raman microscopy Raman Microscopy (ThermoFisher DXR) equipped with a 780nm externally stabilized diode laser was used to identify the polymorph of GSF crystals grown in the presence of PEO. Spectra were acquired using 2 seconds exposure time, 30 times, over the wavelength range of 3350-50cm-1, using a 50X objective, and laser power of 24 mW. The effect of low-concentration PEO on the crystallization of GSF at 333K The amorphous samples were prepared by melting 3~5mg of pure GSF powder, GSF doped with 1 and 3 % w/w PEO between two 15mm diameter round cover slips at 496~503K for 3 min on a hot stage (Linkam THMS 600), and subsequently quenched to the room temperature on an aluminum block. Samples prepared in this way were confirmed to be amorphous by the absence of birefringence under cross-polarized microscopy. The freshly made pure amorphous GSF and PEO doped samples were transferred to a desiccator and then stored in an oven maintained at 333K. After 10 days, the samples were removed from the desiccator for a side-by-side comparison. ACS Paragon Plus Environment


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Crystal growth morphology and kinetics The crystal growth morphology and kinetics were tracked by using a polarized light microscopy (Olympus BX53 microscopy equipped with an Olympus Digital Camera DP26). A Linkam THMS 600 hot stage was equipped on the polarized light microscope to achieve the temperature control. To study the bulk crystallization of GSF in the presence and absence of low-concentration PEO, amorphous samples were prepared by melting 3~5mg of samples between two 15mm diameter round cover slips at 496~503K for 3 min on a hot stage and subsequently quenched to the room temperature on an aluminum block. Sample prepared in this way was confirmed to be amorphous by the absence of birefringence under cross-polarized microscopy. The thickness of the liquid sandwiched between two cover slips was 10−15 µm. For crystal growth at 323, 333, 343, and 353 K, the melt-quenched samples were stored inside desiccators placed in an oven maintained at the desired temperature. For crystal growth at 363 K, the melt-quenched samples were partially crystallized at 353K on a hot stage and then transferred into a desiccator placed in an oven maintained at 363K. The procedure of forming crystals first at 353K as seeds saved time for the initiation of crystallization at 363 K. There was no difference between growth rates initiated by spontaneous nucleation or crystal seeding. To study crystal growth at 373, 383, 393 and 403K, the melt-quenched samples were placed on a hot stage maintained at the desired temperature. GSF bulk crystals crystallized spontaneously from the edge of the liquid. The crystal growth kinetics of GSF was monitored by tracking the advancing speed of a crystal front into the supercooled liquid or glass. For each measurement, we ensured that the steady-state growth rate was measured (the plot of length change vs. time was linear). The reported growth rate was the average of at least three measurements. It is worth mentioning that GSF has three polymorphs.29 Form I is the thermodynamically stable polymorph, showing a monotropic relationship with other two metastable polymorphs.29 In this study, all of the bulk crystals we examined were confirmed to ACS Paragon Plus Environment

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be Form I, as identified by Raman microscopy. Broadband dielectric spectroscopy (BDS) The melt-quenched sample was packed tightly between two cooper coated brass electrodes(20mm diameter) enclosed by a circular PTFE spacer(inner diameter 16mm, external diameter 20mm, height 0.5 mm) in a broadband dielectric spectrometer (Novocontrol Concept 80, Novocontrol Technologies GmbH & Co. KG, Germany). The circular spacer was used to confine the melt-quenching samples in the center of the gold plated copper electrodes without overflowing to the edge of electrodes. Dielectric measurements were conducted over the frequency range of 10-2 to 106 Hz, at temperatures from 361K to 412K with steps of 3K. The temperature control was achieved by a Quattro cryosystem temperature controller with temperature stability better than 0.01K. The Havrililak-Negami (HN) type dielectric function plus a term for dc-conductivity was used to fit the dielectric data for obtaining the average relaxation time(τHN) and shape parameters(α and β).30-31 △

∗ = − i″ = +

+

σ (1) ε

In this equation, ω is the angular frequency, ε*(ω) is the complex dielectric permittivity consisting of the real (ε′) and imaginary (ε″) components, and dielectric strength, ∆ε = εs - ε∞，where εs gives the low frequency limit (ω→0) of ε′ (ω) and ε∞ is the high frequency limit(ω→∞) of ε′ (ω). ε′ is a measure of the real part of the permittivity and ε″ is a measure of the imaginary of the permittivity. The exponents α and β (0 < α, β < 1) are shape exponents, corresponding to the asymmetry and width of the peak, respectively. The shape parameters provide a measure of the distribution of the relaxation time in the system. The value of σdc quantifies the level of dc-conductivity. A high conductivity contribution was observed in the low frequency region with increasing the temperature. And in the presence of PEO, the contributions of conductivity increased even more significantly. The effects of the conductivity are taken into consideration by including a term of the conductivity component, σdc/iε0ω, into the HN equation, where σdc is the contribution from the dc conductivity and ACS Paragon Plus Environment


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ε0 is the vacuum permittivity. Measurements were corrected for edge compensation, stray capacitance and spacer capacitance. Results and discussions： 1 State of mixing and drug-polymer molecular interactions The determination of the mixing state of GSF/PEO system is important and necessary for understanding the effects of PEO on the crystal growth and molecular mobility of GSF. Equation 2 is used to calculate the activity a of the drug in the saturated polymer solution.

lna=(∆Hm/R)(1/Tm - 1/T)

(2)

where ∆Hm and Tm is the enthalpy and temperature of melting of the pure drug, respectively. T is the temperature at which the drug's solubility is measured, which also equals to its depressed melting point.

Figure 1. The activity of GSF a versus PEO weight fraction w. The solid red line represents the Flory-Huggins fit. Figure 1 shows the result of this calculation for GSF dissolving in PEO. With an increase of the PEO weight fraction w in the mixture, the activity of GSF a decreases. The Flory-Huggins interaction parameter χ can be used to assess the miscibility and interactions between drugs and polymers.27-28 The activities of GSF dissolved in PEO are reasonably fitted to the Flory-Huggins ACS Paragon Plus Environment

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model, as shown by the solid curve in Figure 1. According to the Flory-Huggins theory, the activity of GSF in polymer solution is given by equation 3

lna = lnvdrug + (1-1/x)vpolymer + χvpolymer2

(3)

where vdrug and vpolyme is the volume fraction of GSF and PEO, respectively. x is simplified to the ratio of the molecular weight of PEO and GSF based on the assumption that volume fraction is the same as the weight fraction. χ is the drug-polymer Flory-Huggins parameter. The small negative value of Flory-Huggins interaction parameter χ (-0.29) for GSF/PEO mixtures suggests that GSF is thermodynamically favorable to be miscible with PEO.32 The miscibility of GSF/PEO mixtures is further suggested by the observation that PEO-doped GSF liquid is optically clear and has a single Tg at any composition, showing no evidence of phase separation. The χ value obtained for GSF/PEO mixtures is almost identical to the bifonazole/PEO system, consistent with the hydrophobic nature of both drugs.33 In addition, the χ value of GSF/PEO mixtures is comparable to those of GSF containing PVP-VA and or HPMC-AS.34 The interaction between GSF and PEO was further examined by the FT-IR spectroscopy, which is usually quite sensitive to drug-polymer hydrogen bonding interactions in amorphous solid dispersions.13,35 Given that GSF and PEO both contain hydrogen bond acceptors but no hydrogen bond donors,36 we expect no peak shift related to hydrogen bonds from the pure components to amorphous GSF/PEO dispersions. This is indeed the case: the carbonyl stretching region of IR spectra (Figure 2) is sensitive to hydrogen bonding, but no spectral shifts are observed.

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Figure 2. Effect of different concentration (0%, 30%, 50%, and 70% w/w) PEO on the carbonyl stretching region of the IR spectra of amorphous GSF.

2 Crystallizations of GSF in the presence of PEO

Figure 3. Effect of low-concentration PEO on the bulk crystallization of amorphous GSF. (a)fresh samples of amorphous GSF doping with different concentration of PEO (0, 1% and 3% w/w) between two 15mm diameter cover slips at 333K (Tg-28K), (b) same as (a), but 10 days later.

Amorphous samples of GSF with or without low-concentration PEO were prepared by melt quenching. The values of Tg determined by DSC for pure, 1% and 3% w/w PEO doped GSF are 361, 358 and 352 K, respectively. Figure 3 shows how small amounts of PEO affect the crystallization of amorphous GSF. All samples were stored at 333K (28K below Tg) in a desiccator. Figure 3a shows the freshly made pure amorphous GSF and PEO doped samples between two microscope coverslips. ACS Paragon Plus Environment

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Figure 3b shows the same samples as in Figure 3a after 10 days stored at 333K (Tg-28K). The pure GSF sample remains to be completely amorphous after 10 days. However, with the addition of 1 % w/w PEO, white GSF crystals appear along the glass perimeter and progressively grow into the interior. For the amorphous GSF sample doped with 3 % w/w PEO, it appears to be almost fully crystallized after 10 days at 333K (Tg-28K). This side-by-side experiment exhibits clearly that the crystallization process of amorphous GSF substantially speeds up in the presence of low-concentration PEO. Figure 4 shows the morphologies of GSF crystals grown in the presence or absence of low-concentration PEO at different temperatures. GSF grows as compact spherulites at 333K (Tg-28K) and 403K (Tg+42K). The growth morphology of GSF exhibits no significant change after doping with low-concentration PEO both below and above Tg. Fibers can be observed growing from compact crystals at the temperature near Tg (363K, Tg + 2K). The fiber-like crystal growth of pure GSF near Tg has been interpreted as the precursors of GC (glass-crystal) growth in the equilibrium liquid.37 GC growth is a fast crystal growth mode activated near Tg, which has been observed in several organic glass formers.10,38-40 In the presence of low-concentration PEO, these fast-growing fibers can still be observed at the advancing front of compact spherulites near Tg, as shown in Figure 4.



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Figure 4. Crystal growth morphologies of amorphous pure GSF or GSF doped with 1 and 3 w/w % PEO at 333, 363, and 403K.

The growth kinetics of GSF crystals alone and in the presence of low-concentration PEO as a function of temperature are shown in Figure 5. In general, the crystal growth rate of GSF decreases on cooling. However, the trend shows a discontinuity in the region of the glass transition temperature of GSF. We have previously described this sudden jump in growth rate at 360 K is due to the activation of GC growth, which can be much faster than the diffusion-controlled crystal growth.38 In the presence of 1% or 3% w/w PEO, the crystal growth rate of GSF increases by approximately 1 and 2 orders of magnitude respectively at different temperatures. The GC growth of GSF is not disrupted in the presence of low-concentration PEO, as suggested by the studies of both crystal morphologies and growth kinetics. Small amounts of PEO seem to be very effective in accelerating the crystal growth of GSF. The ACS Paragon Plus Environment

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strong influence on the crystal growth of amorphous pharmaceuticals by low-concentration polymer additives is quite remarkable. It has also been reported that the crystallization of amorphous nifedipine or felodipine can be significantly inhibited by small amounts of PVP.10,12 It is noteworthy that the crystal growth rates of both nifedipine and felodipine are reduced significantly in the presence of low-concentration PVP near or below Tg. But these inhibitory effects greatly diminish at temperatures well above Tg.9-10, 12 However, in the case of GSF, the accelerating effect of PEO on the crystal growth rate seems to be equally strong in the glassy and liquid states. Compared to the pure GSF, the crystal growth kinetics of PEO-doped systems show the similar temperature dependence.

Figure 5. Crystal growth kinetics of GSF without and with 1% or 3% w/w PEO. Blue empty triangles represent GSF with 3% w/w PEO, red empty circles represent GSF with 1% w/w PEO and black empty squares represent pure GSF.

3 Dielectric study Dielectric loss spectra of amorphous GSF in the presence and absence of PEO are measured in the supercooled liquid by means of the BDS technique. Dielectric spectra collected in the supercooled liquid state for pure and PEO doped amorphous GSF exhibit the well-pronounced structural ACS Paragon Plus Environment


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α-relaxation process (Figure 6). The α-relaxation peaks are observed in the temperature range from 364K to 409K. With increasing the temperature, the α-relaxation peaks progressively move toward to higher frequencies, indicating the reduction of α-relaxation time, i.e., the higher global mobility. At the temperatures above 409 K, the intensities of α-relaxation peaks decrease rapidly due to the crystallization of amorphous GSF. The average α-relaxation time for GSF at the experimental temperature range is determined by using the HN function (eq 1). The calculation of the α-relaxation time is based on the HN fitting parameters, as shown in the following equation.

τα=τmax=τHNsin

!

"

#/

sin

!

!

/

"

(4)

Temperature dependences of α-relaxation time in the region of supercooled liquids are most frequently described using the empirical Vogel−Fulcher−Tammann (VFT) equation (eq 5 ). +,

% = %& exp *,#, -

(5)

In the VFT equation, τ is the average α-relaxation time, τ0 is the relaxation time of the unrestricted material (10-14 s, the quasi lattice vibration period), T0 is the zero mobility temperature and D is the strength parameter for a measure of fragility.26, 41 The determined α-relaxation times are fitted to the VFT equation, as shown in Figure 7. The calculated dielectric Tg values of PEO-GSF system, which are commonly defined as the temperature where α-relaxation time is 100 s, are in good agreement with the calorimetric Tg values measured by DSC (Table 1). With increasing the content of PEO in the amorphous GSF, both of Tg determined from calorimetric and dielectric data show a progressive decrease, which is analogous to the water effect in amorphous solid dispersions.23 In the glassy state, the α-relaxation times are extremely long and very challenging to be experimentally measured by the dielectric spectrometer. A commonly used method for predicting the

α-relaxation time in the glassy state is based on the Adam-Gibbs-Vogel (AGV) equation (eq 6)

% = %& exp

+,

0 .,/# 23 01

(6)

where τ0, D, and T0 are the fitting parameters obtained from the VFT equation (eq. 5) for temperature ACS Paragon Plus Environment

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dependences of α-relaxation time in the region of the liquid state. Tf is the fictive temperature at which the value of configuration entropy of the glass would be its equilibrium value.42 The intersection point between the enthalpy of the equilibrium liquid extrapolated below Tg and the enthalpy of the glass defines Tf, which can vary between the Kauzmann temperature TK and the glass transition temperature Tg.26 Based on the literature, for the sake of simplicity, Tf is often estimated to be equal to Tg for the freshly prepared glass on the assumption that the configurational entropy changes insignificantly with temperature below Tg.5,26,43 For calculating the α-relaxation times of the glass at equilibrium liquid state (Inset of figure 7), Tf is applied as T, then the eq.6 reduces to the VFT equation (see Supporting Information). With the addition of small amounts of PEO, the contributions of dc conductivity signals on the value of dielectric loss ε″ increase dramatically (Figure 6 b-c). Kothari et al. also reported significant dc conductivity contribution to the dielectric loss spectra of amorphous nifedipine solid dispersion with adding more than 10% w/w PVP.44 The effects of the conductivity are taken into consideration by including an additional conductivity term into the HN model for calculating the α-relaxation times, which has been described in Experimental Section.

Figure 6. Normalized dielectric loss behaviors of (a) pure GSF, (b) GSF-PEO (1% w/w) and (c) GSF-PEO (3% w/w). All the dielectric loss curves have been normalized on the basis of dielectric loss curve of 385K.



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Figure 7. Temperature dependence of α-relaxation times for pure GSF, GSF-PEO (1% w/w) and GSF-PEO (3% w/w). Green circles, red and blue triangles represent the α-relaxation times above Tg determined experimentally using dielectric spectroscopy. Dotted lines represent temperature dependences of α-relaxation times in the supercooled liquid and the glass state described by VFT and AGV equation, respectively. The inset shows the effect of glass aging on the α-relaxation times.

. Figure 8. Normalized dielectric loss behaviors of pure GSF, GSF-PEO (1% w/w) and GSF-PEO (3% w/w) at 385K.

The temperature dependences of the α-relaxation times for pure amorphous GSF and amorphous GSF containing low-concentration PEO are shown in Figure 7. At a given temperature, there is a ACS Paragon Plus Environment

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decrease in the α-relaxation time with increasing the concentration of PEO. For example, as shown in Figure 8, in the presence of low-concentration PEO, the α-relaxation peak moves to a higher frequency at 385K, indicating a pronounced increase in molecular mobility of the system. At 385K, when compared with the pure GSF, the addition of 1% and 3% w/w PEO yield approximately 2 and 5.5 fold decrease in α-relaxation times, respectively. The accelerating effects on global mobility (α-relaxation) by additives have also been examined for some other systems, including amorphous sucrose doped with 2.5% w/w sorbitol and amorphous solid dispersions containing low contents of water.23,45-46 Based on the fitting parameters of the VFT equation and Tg determined from dielectric relaxation data, we estimate the fragility parameter m for measured samples.

m =

5678α g 5,9 ⁄, T=T

(7)

In the literature, the fragility parameter is of interest to the field since it has been often used to predict the glass-forming ability and the recrystallization tendency of amorphous pharmaceutical solids.47-48 Table 1 shows the fragility parameters of pure GSF and GSF doped with low-concentration PEO. The fragility parameter of pure GSF is determined as 84.6, which can be categorized as "moderately fragile" materials.26 The addition of 3% w/w PEO slightly increases the fragility parameter to 94.1. Some studies demonstrate that the increase of fragility parameter leads to a "fragile" material with a weaker glass-forming ability, and thus lower the physical stability of the amorphous system. However, due to the complicated properties of pharmaceutical compounds, the correlation between the fragility and the recrystallization tendency of amorphous pharmaceuticals is still debatable. For instance, the amorphous form of celecoxib is easier to recrystallize than etoricoxib despite the two pharmaceutical compounds share the roughly equal fragilities.49

Table 1 Values of Tg (from DSC and BDS), fragility parameters (m) determined from eq.7, and βKWW determined from eq.8 for GSF in the presence and absence of low-concentration PEO



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System

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βKWW

Tg(K)

Tg(K)

Fragility parameter

DSC

BDS

m

GSF

361

359

84.6

0.69

GSF-PEO (1% w/w)

358

357

87.6

0.60

GSF-PEO (3% w/w)

352

355

94.1

0.53

An alternative parameter βKWW, which is known as the stretching exponent of the Kohlraush-Williams-Watts(KWW) function, has been reported to have the potential connections with the physical stability of amorphous materials.50 βKWW is a measure of asymmetric distribution of structural relaxation times, which is derived from the HN peak width parameter αHN and βHN via the following equation in this work.

βKWW1.23 =αHNβHN

(8)

βKWW has been reported to correlate with the crystallization tendency of many amorphous pharmaceuticals. The physical and chemical stability are found to decrease as the value of βKWW decreases.51 In this study, the value of βKWW decreases with an increase in the content of PEO (Table 1), which is consistent with the observation that recrystallization of amorphous GSF tends to become faster in the presence of PEO. However, it should be noted that not all amorphous pharmaceutical systems satisfy the correlation between βKWW and physical stability. Similar to the fragility parameter, one single parameter is sometimes not sufficient to truly reflect the complex crystallization phenomenon. Some amorphous drugs have been reported to recrystallize easily despite they are characterized by relatively large values of βKWW.26,47,52

4 Correlations between molecular mobilities and crystallization kinetics In the literature, some linear correlations have been established to describe the potential coupling between different kinds of molecular mobility and crystallization kinetics by applying the following equation.26 ACS Paragon Plus Environment

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log τcr= ξxlog10X+A

(9)

where ξX, the coupling coefficient, can be used to describe the coupling between the measure of molecule motions X (relaxation times, diffusivities and viscosities) and the characteristic crystallization time τcr.26 In the literature, τcr has been examined in different manners, such as the onset time of crystallization, inverse overall crystallization rate, crystal growth rate and characteristic time for a certain degree of crystallization, etc.26 A value of ξX ≈ 1 is a strong indicator that the crystallization process can be mainly attributed to the investigated molecular mobility, whereas the smaller value of ξX means the investigated molecular mobility is less responsible for the crystallization. In this study, the coupling coefficients are determined by calculating the correlation between the structural relaxation time τα and the characteristic time for crystal growth, τu, defined as the time required for the crystal to grow one molecular layer 53. τu = a/u,39 where a is the calculated molecular diameter of GSF and u is the crystal growth rate of GSF obtained from Figure 5. Herein,

τα and τu are considered as the factors responsible for the molecular mobility and crystallization process, respectively.

Figure 9. Plots of characteristic crystallization time τu versus α-relaxation time τa above Tg in (a) pure GSF, (b) GSF-PEO (1% w/w) and (c) GSF-PEO (3% w/w). τu = a/u, where a is the molecular diameter and u is the crystal growth rate. The α-relaxation times above Tg are obtained by fitting the VFT equation as shown in Figure 7.



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Figure 10. Plots of characteristic crystallization time τu versus α-relaxation time τa in freshly made glass and equilibrated glass of (a) pure GSF, (b) GSF-PEO (1% w/w) and (c) GSF- PEO (3% w/w). The τa of freshly made glasses and equilibrated glasses are estimated by AGV equation as shown in Figure 7.

Table 2 Coupling coefficient ξX for structural relaxation time τa and characteristic crystallization time τu Material

Supercooled Liquid State

Glassy State (Freshly made glass)

Glassy State (Equilibrated glass)

Pure GSF

0.50

1.29

0.17

GSF-PEO (1%w/w)

0.39

1.10

0.14

GSF-PEO (3%w/w)

0.51

0.91

0.13

Figure 9 shows the coupling between τα and τu in the supercooled liquid state of GSF systems. The coupling coefficient ξX ranges between 0.39-0.51 in supercooled liquid state of pure GSF and PEO doped systems, indicating a weak response of molecular mobility to the crystal growth rate above Tg. These results also suggest that the additions of low-concentration PEO do not significantly affect the coupling between the relaxation and the crystallization rate of GSF. Recent studies reveal that at large supercooling, bulk diffusion becomes the kinetic barrier for the crystal growth, as evidenced by the proportionality of the growth rate to the liquid diffusion coefficient.54-56 For instance, in the studies of o-terphenyl55 and indomethacin,57 the temperature dependence of crystal growth rate well matches with that of translational self-diffusion coefficient Dtrans, despite translational diffusion is much faster than the Stokes-Einstein prediction near Tg. In the supercooled liquid state, both ACS Paragon Plus Environment

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rotational and translational motions contribute to the overall molecular dynamics, but dielectric spectroscopy usually only provide the measurement of rotational mobility.26 Thus, it is reasonable to argue that ξX in this study reflects the correlation between the crystal growth and molecular rotational mobility. As mentioned above, the translational motion is considered to be the major factor to influence the crystal growth in the supercooled liquid state. Therefore, the observed weak coupling between τu of GSF and the structural relaxation time is likely attributed to the decoupling between translational diffusion and rotational diffusion in the deeply supercooled regime near the glass transition for fragile liquids.57-60 Figure 10 shows the coupling between the τu and estimated α-relaxation time in the glassy state of GSF systems. Since the glassy state is a non-equilibrium state, τa of GSF below Tg is expected to keep changing during the glass aging. In contrast, the crystal growth rate in GC mode is known to exhibit much weak time-dependence than τa.53 In this study, the α-relaxation times of the freshly made glass and fully equilibrated glass are calculated separately to describe the two extreme situations of coupling between τu and τa below Tg. For the freshly made glass, the coupling coefficient values are 1.29, 1.10, and 0.91 for pure, 1% w/w PEO doped, and 3% w/w PEO doped GSF, respectively. The values of ξX obtained from the freshly made glass are close to 1 and larger than those obtained from the supercooled liquid state, suggesting that a stronger correlation between the α-relaxation times with growth rates of GC growth than those associated with diffusion-controlled crystal growth. However, as the aging progresses, the glass will keep relaxing towards the equilibrium liquid state, leading to a dramatic increase of τa (Inset of figure 7). The coupling coefficient values of the fully equilibrated glass are 0.17, 0.14, and 0.13 for pure, 1% w/w PEO doped, and 3% w/w PEO doped GSF, respectively. As shown in Table 2, structural relaxation time τa and characteristic crystallization time τu exhibit strong couplings between each other in the freshly made glasses (~1), but weak coupling in ACS Paragon Plus Environment


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the equilibrated glasses (~0.1). Theoretically, depending on the time when the crystal growth rates are measured in the glassy state, the respective τa should always lie between the values of the fresh prepared and equilibrated glasses. In this study, the timescale of crystal growth rate measurements below Tg (323, 333, 343 and 353K) ranges from 1 week to 4 weeks. We estimate that the τa at the time when crystal growth rates were measured would increase by a few orders of magnitude compared with values of freshly made glass, as shown in the inset of figure 7. In fact, the actual coupling coefficient ξx between the τu and τa at the time crystals grow in the glassy state should fall between 0.1~1 (between those of fresh and equilibrated glasses). Therefore, the couplings between the τu and τa in the glassy state seem to be strong at the beginning but become weak upon aging, due to the strong time-dependence of molecular mobility during structural relaxation. It is conceivable that the crystallization kinetic of GSF systems below Tg may also correlate with other molecular motions with weak or no time-dependence. Recent work by Yu and coworkers has found that despite the significant increase of bulk relaxation time during the physical aging, surface diffusivity of organic glasses remained unchanged.61 Surface mobility could be involved and better correlated with GC growth in organic glasses through the creation of voids and free surface.62-63

5 Effects of PEO on the structural relaxation times and crystal growth rates as a function of temperature scaled with Tg


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Molecular Pharmaceutics Figure 11. (a) Plots of crystal growth rate , (b) Plots of relaxation time as a function of Tg/T.

The plots of α-relaxation times and crystal growth rates versus the Tg scaled reverse temperature Tg/T are shown in Figure 11. Here, Tg is the dielectric Tg defined as the temperature where τα equals to 100 s. Figure 11a shows that once the temperature is scaled by Tg/T, the α-relaxation times of GSF with and without PEO collapse into a single master curve. The overlap of α-relaxation times verse Tg/T by additives is analogous to the observation of water effect on amorphous drugs and solid dispersions, where the α-relaxation times of the systems with different water contents overlapped as a function of Tg/T.23,47 Furthermore, several studies have demonstrated that the crystallization times of amorphous pharmaceutical systems vary linearly with the Tg/T ratio upon water sorption.23,47,64,65 The increased molecular mobility and decreased stability are attributable to the "plasticization" effect of water.23,47,64-66 In this study, from a liquid dynamic perspective, PEO additives behave like water to plasticize the systems and increase molecular mobility, as evidence of the overlapping of the α-relaxation times as a function of Tg/T (Figure 11a). However, unlike what have been reported in the water sorption, 23,64-66 the crystallization kinetics of amorphous GSF containing low-concentration PEO do not overlap with those of pure GSF on a Tg/T scale. Figure 11b shows that the crystallization rates of GSF in the presence of PEO increase to a greater extent than expected from the decreased Tg, indicating that factors other than molecular mobility could accelerate the crystallization rate. These results are similar to the study reported by Miyazaki et al., who have found that the effect Tg was not enough to account for the decreased crystallization rates of nifedipine by additions of PVP and HPMC.64 Korhonen et al. also observed moderate correlations between crystal growth rate and structural relaxation in phenobarbital and phenobarbital with PVP and L-proline, indicating factors other than the α-relaxation time may contribute to control of crystallization of amorphous systems.67 Compared with the small-molecule water, it has been demonstrated that various physicochemical properties of polymers can affect the crystallization process, such as hydrophobicity, ACS Paragon Plus Environment


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molecular weight and conformation etc.9,18,68 In addition, the molecular interactions and difference between the mobility of polymer and host molecules are found to affect the rate of crystal growth. In this case, the high segmental mobility of PEO chains could significantly enhance the mobility of GSF at the crystal/amorphous interface during the crystallization process. Zhao and Ediger have reported that the segmental dynamics of dilute PEO strongly correlated with the dynamics of both high and low molecular weight hosts on the basis of NMR measurements.69 Since no strong molecular interactions were found between GSF and PEO, it can also facilitate migrations of host and polymer molecules and impede the adsorption of polymers at crystal surfaces, thus lower the kinetic barrier of crystallization. Overall, the accelerating effect of crystal growth of amorphous GSF by low-concentration PEO can be partially attributed to the increase of global mobility characterized by the dielectric spectroscopy. More importantly, the high segmental mobility of PEO is expected to strongly affect the crystal growth rates of the host molecule GSF. These results also support the viewpoint of the polymer effect on crystal growth on the basis of fracture, surface diffusion, and host-polymer segregation on the surface.25

Conclusion We systemically investigated the effect of low-concentration PEO on the crystallization behavior and molecular mobility of amorphous GSF. The crystallization of amorphous GSF speeds up substantially in the presence of low-concentration PEO. At 3 % w/w PEO, the crystal growth rates of GSF increase significantly by two orders of magnitude in both the supercooled liquid and glassy states. The liquid dynamics of amorphous GSF in the presence and absence of PEO are characterized by dielectric spectroscopy. With increasing the PEO content, the α-relaxation times of the systems decrease, indicating the increase of global molecular mobility. The coupling between molecular mobility and crystallization kinetics of GSF systems exhibits strong time-dependences below Tg. The ACS Paragon Plus Environment

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overlapping of α-relaxation times of GSF in presence and absence of PEO as a function of Tg/T suggests the "plasticization" effect of PEO additives. However, the crystallization kinetics of amorphous GSF containing low-concentration PEO do not overlap with those of pure GSF on a Tg/T scale. Therefore, in addition to the increase of α-relaxation times, the high segmental mobility of PEO may also contribute to the accelerating effect on the crystal growth rate of GSF.

Supporting information Details of predicting α-relaxation times for the freshly made glass and equilibrated glass. This material is available free of charge via the Internet at http://pubs.acs.org

Author Information Corresponding Author

*Address: Department of Pharmaceutics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Tel: 86-025-83271123. E-mail: [email protected]. *Address: Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China, Tel: 86-25-89686136. E-mail: [email protected] Notes The authors declare no competing financial interest.

Acknowledgments The authors are grateful for financial support of this work by the National Science Foundation of China (No. 81402877, 21474049), the Program of State Key Laboratory of Natural Medicines-China Pharmaceutical University (No. SKLNMZZYQ201604), the Graduate Innovative Research Project of Jiangsu Province (KYLX16_1180) and the Program for Jiangsu Province Innovative Research ACS Paragon Plus Environment


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Team. We also thank Prof. Lian Yu (School of Pharmacy, University of Wisconsin, Madison) for helpful discussions.

References 1.

Vasconcelos, T.; Sarmento, B.; Costa, P. Solid Dispersions as Strategy to Improve Oral Bioavailability of Poor Water Soluble Drugs. Drug discovery today 2008, 39 (25), 1068-1075.

2.

Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Crystal Engineering of Active Pharmaceutical Ingredients to Improve Solubility and Dissolution Rates. Adv. Drug Deliv. Rev. 2007, 59 (7), 617-630.

3.

Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H. Solubility Advantage of Amorphous Pharmaceuticals: I. A Thermodynamic Analysis. J. Pharm. Sci. 2010, 99 (3), 1254-1264.

4.

Alonzo, D. E.; Zhang, G. G.; Zhou, D.; Gao, Y.; Taylor, L. S. Understanding the Behavior of Amorphous Pharmaceutical Systems During Dissolution. Pharm. Res. 2010, 27 (4), 608-618.

5.

Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Influence of Moelcualr Mobillity on the Physical Stability of Amorphous Pharmaceuticals in the Supercooled and Glasssy State. Mol. Pharmceutics 2014, 11(9), 3048-3055.

6.

Bhugra, C.; Pikal, M. J. Role of Thermodynamic, Molecular, and Kinetic Factors in Crystallization From the Amorphous State. J. Pharm. Sci. 2008, 97 (4), 1329-1349.

7.

Yu, L. Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization. Adv. Drug Deliv. Rev. 2001, 48(1), 27-42.

8.

Cai, T.; Zhu, L.; Yu, L. Crystallization of Organic Glasses: Effects of Polymer Additives on Bulk and Surface Crystal Growth in Amorphous Nifedipine. Pharm. Res. 2011, 28 (10), 2458-2466.

9.

Powell, C. T.; Cai, T.; Hasebe, M.; Gunn, E. M.; Gao, P.; Zhang, G.; Gong, Y.; Yu, L. Low-Concentration Polymers Inhibit and Accelerate Crystal Growth in Organic Glasses in Correlation with Segmental Mobility. J. Phys. Chem. B 2013, 117 (35), 10334-10341.

10. Ishida, H.; Wu, T.; Yu, L. Sudden Rise of Crystal Growth Rate of Nifedipine Near Tg Without and With Polyvinylpyrrolidone. J. Pharm. Sci. 2007, 96 (5), 1131-1138. 11. Sun, Y.; Zhu, L.; Wu, T.; Cai, T.; Gunn, E. M.; Yu, L. Stability of Amorphous Pharmaceutical Solids: Crystal Growth Mechanisms and Effect of Polymer Additives. AAPS J. 2012, 14 (3), 380-388. 12. Kestur, U. S.; Taylor, L. S. Evaluation of the Crystal Growth Rate of Felodipine Polymorphs in the Presence and Absence of Additives As a Function of Temperature. Cryst. Growth Des. 2013, 13 (10), 4349-4354. 13. Kestur, U. S.; Taylor, L. S. Role of Polymer Chemistry in Influencing Crystal Growth Rates From Amorphous Felodipine. CrystEngComm 2010, 12 (8), 2390-2397.


Page 26 of 31

Page 27 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics 14. Taylor, L. S.; Zografi, G. Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions. Pharm. Res. 1997, 14 (12), 1691-1698. 15. Mistry, P.; Suryanarayanan, R. Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions. Cryst. Growth Des. 2016, 16 (9), 5141-5149. 16. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. The Role of Drug–Polymer Hydrogen Bonding Interactions on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Mol. Pharmaceutics 2015, 12 (1), 162-170. 17. Kestur, U. S.; Eerdenbrugh, B. V.; Taylor, L. S. Influence of Polymer Chemistry on Crystal Growth Inhibition of Two Chemically Diverse Organic Molecules. Crystengcomm 2011, 13 (13), 6712-6718. 18. Trasi, N. S.; Taylor, L. S. Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide. Cryst. Growth Des. 2012, 12 (6), 3221-3230. 19. Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S. Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives. Angew. Chem., Int. Ed. 2010, 49 (36), 6288-6308. 20. Jamzad, S.; Fassihi, R. Development of a Controlled Release Low Dose Class II Drug-Glipizide. Int. J. Pharm. 2006, 312 (1-2), 24-32. 21. Maincent, J.; Feng, Z. Recent Advances in Abuse-deterrent Technologies for the Delivery of Opioids. Int. J. Pharm. 2016, 510 (1), 57-72. 22. Miyazaki, T.; Aso Y.; Kawanishi, T. Feasibility of atomic force microscopy for determining crystal growth rates of nifedipine at the surface of amorphous solids with and without polymers. J. Pharm. Sci. 2011, 100(10), 4413-4420. 23. Mehta, M.; Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. Mol. Pharmaceutics 2016, 13 (4), 1339-1346. 24. Sato, T.; Taylor, L. S. Acceleration of the Crystal Growth Rate of Low Molecular Weight Organic Compounds in Supercooled Liquids in the Presence of Polyhydroxybutylate. CrystEngComm 2017, 19, 80-87. 25. Huang, C.; Powell, C.T.; Sun, Y.; Cai, T.; Yu, L. Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for the Polymer Segmental Mobility Relative to Host Dynamics. J. Phys. Chem. B 2017, 121, 1963-1971. 26. Grzybowska, K.; Capaccioli, S.; Paluch, M. Recent Developments in the Experimental Investigations of Relaxations in Pharmaceuticals by Dielectric Techniques at Ambient and Elevated Pressure. Adv. Drug Deliv. Rev .2016, 100, 158-182. 27. Tao, J.; Sun, Y.; Zhang, G. G.; Yu, L. Solubility of Small-Molecule Crystals in Polymers: D-mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA. Pharm. Res. 2009, 26 (4), 855-864. 28. Sun, Y.; Tao, J.; Zhang, G. G.; Yu, L. Solubilities of Crystalline Drugs in Polymers: An Improved Analytical ACS Paragon Plus Environment


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Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 2010, 99 (9), 4023-4031. 29. Mahieu, A.; Willart, J. F.; Dudognon, E.; Eddleston, M. D.; Jones, W.; Danede, F.; Descamps, M. On the Polymorphism of Griseofulvin: Identification of Two Additional Polymorphs. J. Pharm. Sci. 2013, 102 (2), 462-468. 30. Havriliak, S.; Negami, S. A Complex Plane Representation of Dielectric and Mechanical Relaxation Processes in Some Polymers. Polymer 1967, 8 (67), 161-210. 31. Iglesias, T. P.; Carballo, M.; Fernández, J. P. Broadband dielectric spectroscopy. Springer: 2003 32. Marsac, P. J.; Shamblin, S. L.; Taylor L. S. Theoretical and Practical Approaches for Prediction of Drug-Polymer Miscibility and Solubility. Pharm. Res. 2006, 23(10), 2417-2426. 33. Chen, Z.; Liu, Z.; Qian, F. Crystallization of Bifonazole and Acetaminophen Within the Matrix of Semicrystalline, PEO-PPO-PEO Triblock Copolymers. Mol. Pharmaceutics 2015, 12 (2), 590-599. 34. Chen, Y.; Liu, C.; Chen, Z.; Su, C.; Hageman, M.; Hussain, M.; Haskell, R.; Stefanski, K.; Qian, F. Drug-Polymer-Water Interaction and Its Implication for the Dissolution Performance of Amorphous Solid Dispersions. Mol. Pharmaceutics 2015, 12 (2), 576-589. 35. Trasi, N. S.; Baird, J. A.; Kestur, U. S.; Taylor, L. S. Factors Influencing Crystal Growth Rates From Undercooled Liquids of Pharmaceutical Compounds. J. Phys. Chem. B 2014, 118 (33), 9974-9982. 36. Zhu, L.; Jona, J.; Nagapudi, K.; Wu, T. Fast Surface Crystallization of Amorphous Griseofulvin Below Tg. Pharm. Res. 2010, 27 (8), 1558-1567. 37. Sun, Y.; Xi, H.; Ediger, M.D.; Yu, L. Diffusionless Crystal Growth from Glass Has Precursor in Equilibrium Liquid. J. Phys. Chem. B 2008, 112(3), 661-664. 38. Shi, Q.; Cai, T. Fast Crystal Growth of Amorphous Griseofulvin: Relations between Bulk and Surface Growth Modes. Cryst. Growth Des. 2016, 16(6), 3279-3286. 39. Sun, Y.; Xi, H.; Chen, S.; Ediger, M. D.; Yu, L. Crystallization near Glass Transition, Transition from Diffusion-Controlled to Diffusionless Crystal Growth Studied With Seven Polymorphs. J. Phys. Chem. B 2008, 112(18), 5594-5601. 40. Musumeci, D.; Powell, C. T.; Ediger, M. D.; Yu, L., Termination of Solid-State Crystal Growth in Molecular Glasses by Fluidity. J. Phys. Chem. Lett. 2014, 5 (10), 1705-1710. 41. Angell, C. A.; Ngai, K. L.; Mckenna, G. B.; Mcmillan, P. F.; Martin, S. W. Relaxation in Glassforming Liquids and Amorphous Solids. J. Appl. Phys. 2000, 88 (6), 3113-3157. 42. Moynihan, C. T.; Easteal, A. J.; De Bolt, M. A.; Tucker, J. Dependence of the Fictive Temperature of Glass on Cooling Rate. J. Am. Ceram. Soc. 1976, 59(1-2), 12-16. 43. Zhou, D.; Geoff G, Z. Z.; Law, D.; David J.W, G.; A.schmitt, E. Thermodynamic, Molecular Mobility and ACS Paragon Plus Environment

Page 28 of 31

Page 29 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics Crystallization Kinetics of Amorphous Griseofulvin. Mol. Pharmaceutics 2008, 5(6), 927-936. 44. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. The Role of Polymer Concentration on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Mol. Pharmaceutics 2015, 12 (5), 1477-1484. 45. Bhattacharya, S., Suryanarayanan, R. Molecular Motions in Sucrose-PVP and Sucrose-Sorbitol Dispersions: I. Implications of Global and Local Mobility on Stability. Pharm. Res. 2011, 28 (9), 2191-2203. 46. Mehta,M.; Suryanarayanan, R. Accelerated Physical Stability Testing of Amorphous Dispersions. Mol. Pharmaceutics 2016, 13 (8), 2661-2666. 47. Grzybowska, K., Paluch, M., Grzybowski, A., Wojnarowska, Z., Hawelek, L., Kolodziejczyk, K. Molecular Dynamics and Physical Stability of Amorphous Anti-Inflammatory Drug: Celecoxib. J. Phys. Chem. B 2010, 114(40), 12792-12801. 48. Kawakami, K.; Harada, T.; Yoshihashi, Y.; Yonemochi, E.; Terada, K.; Moriyama, H. Correlation between Glass-Forming Ability and Fragility of Pharmaceutical Compounds. J. Phys. Chem. B 2015, 119 (14), 4873-4880. 49. Rams-Baron, M.; Wojnarowska, Z.; Grzybowska, K.; Dulski, M.; Knapik, J.; Jurkiewicz, K.; Smolka, W.; Sawicki, W.; Ratuszna, A.; Paluch, M. Toward a Better Understanding of the Physical Stability of Amorphous Anti-Inflammatory Agents: The Roles of Molecular Mobility and Molecular Interaction Patterns. Mol. Pharmaceutics 2015, 12(10), 3628-3638. 50. Alvarez, F.; Alegra, A.; Colmenero, J. Relationship Between the Time-Domain Kohlraush-Williams-Watts and Frequency-Domain Hvriliak-Negami Relaxation Functions. Phys. Rev. B 1991, 44 (14), 7306-7312. 51. Tombari, E.; Ferrari, C.; Johari, G. P.; Shanker, R. M. Calorimetric Relaxation in Pharmaceutical Molecular Glasses and Its Utility in Understanding Their Stability Against Crystallization. J. Phys. Chem. B 2008, 112 (35), 10806-10814. 52. Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Hawelek, L.; Sawicki, W.; Wlodarski, K.; Markowski, J.; Paluch, M. Physical Stability of the Amorphous Anticholesterol Agent (Ezetimibe): the Role of Molecular Mobility. Mol. Pharmaceutics 2014, 11 (11), 4280-4290. 53. Sun, Y.; Xi, H.; Ediger, M. D.; Richert, R.; Yu, L., Diffusion-Controlled and "Diffusionless" Crystal Growth near the Glass Transition Temperature: Relation between Liquid Dynamics and Growth Kinetics of Seven ROY Polymorphs. J. Chem. Phys. 2009, 131 (7), 074506. 54. Fujara, F.; Geil, B.; Sillescu, H.; Fleischer, G. Translational and Rotational Diffusion in Supercooled Orthoterphenyl close to the Glass Transition. Z. Phys. B: Condens. 1992, 88 (2), 195-204. 55. Mapes, M. K.; Swallen, S. F.; Ediger, M. D. Self-Diffusion of Supercooled O-terphenyl near the Glass Transition Temperature. J. Phys. Chem. B 2006, 110(1), 507-511. 56. Ediger, M. D.; Harrowell, P.; Yu, L. Crystal Growth Kinetics Exhibit a Fragility-Dependent Decoupling from ACS Paragon Plus Environment


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Viscosity. J. Chem. Phys. 2008, 128 (3), 034709. 57. Swallen, S. F.; Ediger, M. D. Self-Diffusion of the Amorphous Pharmaceutical Indomethacin near Tg. Soft Matter 2011, 7 (21), 10339-10344. 58. Tarjus, G.; Kivelson, D. Breakdown of the Stokes–Einstein Relation in Supercooled Liquids. J. Chem. Phys. 1995, 103 (8), 541-545. 59. Cicerone, M. T.; Ediger, M. D. Enhanced Translation of Probe Molecules in Supercooled O-terphenyl: Signature of Spatially Heterogeneous Dynamics? J. Chem. Phys .1996, 104 (18), 7210-7218. 60. Edmond, K. V.; Elsesser, M. T.; Hunter, G. L.; Park, H. J.; Pine, D. J.; Weeks, E. R. Decoupling of Rotational and Translational Diffusion in Supercooled Colloidal Fluids. Proc. Natl. Acad. Sci. 2012, 109 (44), 17891-17896 61. Brian, C. W.; Zhu, L.; Yu, L. Effect of Bulk Aging on Surface Diffusion of Glasses J. Chem. Phys. 2014, 140 (5), 054509. 62. Powell, C. T.; Xi, H.; Sun, Y.; Gunn, E.; Chen,Y.; Ediger, M. E.; Yu, L. Fast Crystal Growth in o-Terphenyl Glasses: A Possible Role for Fracture and Surface Mobility., J. Phys. Chem. B 2015, 119 (31),10124-10130. 63. Yu, L. Surface Mobility of Molecular Glasses and its Importance in Physical Stability. Adv. Drug Deliv. Rev. 2016, 100, 3-9. 64. Miyazaki, T.; Yoshioka, S.; Aso, Y.; Kawanishi, T. Crystallization Rate of Amorphous Nifedipine Analogues Unrelated to the Glass Transition Temperature. Int. J. Pharm. 2007, 336 (1), 191-195. 65. Greco, S.; Authelin, J. R.; Leveder, C.; Segalini, A. A Practical Method to Predict Physical Stability of Amorphous Solid Dispersions. Pharm. Res. 2012, 29 (10), 2792-2805. 66. Yoshioka, S.; Aso, Y. Correlations between Molecular Mobility and Chemical Stability during Storage of Amorphous Pharmaceuticals. J. Pharm. Sci. 2007, 96 (5), 960-981. 67. Korhonen, O.; Bhugra, C.; Pikal, M. J. Correlation between Molecular Mobility and Crystal Growth of Amorphous Phenobarbital and Phenobarbital with Polyvinylpyrrolidone and L-proline. J. Pharm. Sci. 2008, 97 (9), 3830-3841. 68. Kestur, U. S.; Lee, H.; Santiago, D.; Rinaldi, C.; Won, Y.-Y.; Taylor, L. S. Effects of the Molecular Weight and Concentration of Polymer Additives, and Temperature on the Melt Crystallization Kinetics of a Small Drug Molecule. Cryst. Growth Des. 2010, 10 (8), 3585-3595. 69. Zhao, J.; Ediger, M. D. Segmental Dynamics of Dilute Poly(ethylene oxide) in Low and High Molecular Weight Glass-Formers. Macromolecules 2011, 44 (22), 9046-9053.


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Table of Contents Graphic

Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-concentration Poly (ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility Qin Shi†, ‡, Chen Zhang§, Yuan Su†, ‡, Jie Zhang†, ‡, Dongshan Zhou§,*, Ting Cai†, ‡,* †State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China ‡Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China §Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China


Acceleration of Crystal Growth of Amorphous Griseofulvin by Low

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