Fast Crystal Growth of Amorphous Griseofulvin: Relations between

May 2, 2016 - *Address: Department of Pharmaceutics, College of Pharmacy, China ... A sudden 10-fold rise of bulk crystal growth rate was observed nea...
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Fast Crystal Growth of Amorphous Griseofulvin: Relations between Bulk and Surface Growth Modes Qin Shi and Ting Cai* 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, China ABSTRACT: Griseofulvin (GSF), a poorly water-soluble antifungal drug, is a model system for studying the physical stability of amorphous pharmaceuticals. In this study, we examined the crystallization kinetics of GSF in the bulk and at the surface as a function of temperature. A sudden 10-fold rise of bulk crystal growth rate was observed near Tg, a phenomenon similar to that observed in other molecular glasses and termed glass-to-crystal (GC) growth. Also analogous to other molecular glasses, GSF grows crystals much faster at the free surface than in the bulk. What distinguishes GSF from other systems is that surface crystallization can occur well above Tg (up to Tg + 62 °C). Another peculiar feature of GSF is that during bulk crystal growth at 130−150 °C, some crystals protruded well ahead of the normal growth front at the same growth rate as surface crystals. We suspect this protruding crystal growth is a surface-facilitated process through the formation of voids and free surfaces during bulk crystal growth. These new findings are important for understanding the mechanisms and connections for the bulk and surface crystallization in amorphous pharmaceutical solids.

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based (HNB) crystallization model,17 tension-induced interfacial molecular mobility,18,19 solid-state transformation by local mobility,13,15 percolative network nanocrystallization,20 and shear-stress-induced mobility.21 However, so far none of these models can explain all aspects of the GC growth phenomenon. The second mode of fast crystal growth, which occurs at the free surface, is even faster than the bulk GC growth. This phenomenon is uncommon for other materials.22−25 Despite their higher density than the glass, surface crystals of indomethacin (IMC) have been reported to rise hundreds of nanometers above the glass surface as they grew laterally.26 The upward-lateral growth of surface crystals is attributed to a growth mechanism aided by high surface mobility.6 Recent work showed that surface diffusivity (measured by surfacegrating decay experiment) correlates with surface crystal growth rate, indicating these two processes share a similar kinetic barrier.27,28 A few nanometers film coating can completely eliminate the fast surface crystal growth.29 Moreover, surface crystals were detected to be surrounded by depressed grooves or depletion zones, which further supported the view that surface crystal growth is a consequence of mass transport by surface self-diffusion.30 In this study, we systematically examined the bulk and surface crystallization of amorphous griseofulvin (GSF), a model system for studying physical stability of amorphous drugs.31,32 For the first time, we report that GSF shows GC growth with a sudden 10-fold rise of bulk crystal growth rate

INTRODUCTION Amorphous solids generally offer a higher solubility and faster dissolution rate than their crystalline counterparts, which makes them a good vehicle for delivering poorly soluble drugs whose bioavailability is limited by their low solubility.1−3 However, amorphous solids are thermodynamically unstable and tend to crystallize over time and subsequently negate their advantages.4 Therefore, understanding crystallization behavior of materials is of utmost importance in order to develop amorphous pharmaceutical solids.5,6 In general, amorphous pharmaceutical solids are stored in the glassy state, at the temperature below the glass transition temperature (Tg). This storage strategy was guided by the standard crystallization models that assume the molecular diffusion defines the kinetic barrier for crystal growth.7,8 According to these models, crystal growth should be extremely slow as molecules are difficult to reorganize in the glassy state.9 However, recent studies showed that crystal growth in organic glass can be much faster than the predictions by standard models.4 In the presence of free surfaces, crystal growth can be even faster.6 The fast crystal growth mode in the bulk, termed glass-tocrystal (GC) mode, is activated near Tg where growth rate is orders of magnitude faster than in diffusion-controlled growth mode. This phenomenon was first observed by Greet and Turnbull in 1967 and so far has been reported for about 14 organic glass formers.10−16 This fast crystal growth mode is known to date only for small-molecule glasses but not inorganic, metallic, or polymeric materials. Several theoretical models have been proposed for explaining the formation mechanism of GC growth, including homogeneous nucleation© XXXX American Chemical Society

Received: February 16, 2016 Revised: April 18, 2016

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identify the polymorph of crystal growing at the surface or in the bulk of melt-quenched amorphous films. Spectra were acquired using 2 s exposure time, 30 times, over the wavelength range of 3350−50 cm−1, using a 50× objective, and laser power of 24 mW. X-ray Diffraction (XRD). XRD analysis was conducted at room temperature using D8 Advance X-ray diffractometer (Bruker, Germany). Diffractometer was run at 40 kV and 40 mA with Cu Kα radiation (k = 1.5406 Å), and scans were carried out over a range of 3−40° (2θ) with a step size and step time of 0.02° and 1 s, respectively. Before analysis, the surface crystals were grown at different temperatures on the smooth round cover glass. Then the data were collected from these as grown thin film surface crystals. Scanning Electron Microscopy (SEM). The detailed morphologies of crystals grown at the surface were observed using a field emission scanning electron microscope (FE-SEM, S4800, Hitachi) with a maximum resolution of 1.0 nm. High-resolution SEM was operated at 15 kV and 5.2−7.1 mm working distance using an in-lens secondary electron detector. Prior to SEM analysis, the sample was coated with a gold film 10 nm thick (ScD5oo, Bal-Te). The gold film stopped surface crystal growth and prevented charging during SEM analysis. To further prevent charging, the sample was attached to a metal stub with a carbon tape. Crystallizations of Amorphous GSF in the Bulk. To study the bulk crystallization of GSF, 3−5 mg of crystalline GSF was melted between two 15 mm diameter round coverslips at 230 °C 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 free of crystals by a polarized light microscope. The thickness of the liquid sandwiched between two coverslips was 10−15 μm. GSF bulk crystals crystallized spontaneously from the edge of the liquid. Such crystals were used for growth-rate measurement 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. For crystal growth rate measurements at 50, 60, 70, and 90 °C, samples were partially crystallized at 80 °C and then transferred to the desired temperature. The procedure of forming crystals first at 80 °C as seeds saved time and ensured observation of crystal growth in a freshly made glass. There was no difference between growth rates initiated by spontaneous nucleation or crystal seeding.

near Tg, as well as fast surface crystal growth. In contrast to other systems, the surface crystal growth of GSF is not strongly disrupted by the onset of fluidity, able to persist up to 62 °C above Tg with smaller activation energy than the bulk crystallization process. In addition, we report a fast protruding crystal growth mode in the bulk liquid above Tg whose rate matches that of surface crystal growth. We suggest that the protruding crystal growth in the bulk is likely a surfacefacilitated process and discuss the relation between bulk and surface crystallization in GSF.

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EXPERIMENTAL SECTION

Griseofulvin (2R,6′S)-7-chloro-2′,4,6-trimethoxy-6′-methyl-3H,4′Hspiro[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. Differential Scanning Calorimetry (DSC). DSC measurements were conducted in an aluminum pan using a Q2000 (TA Instruments, New Castle, DE) unit under 50 mL/min N2 purge. A total of 3−5 mg of materials was loaded in a crimped low-mass aluminum pan. The heating rate used in the experiments was 10 °C/min. The glass transition temperature (Tg) of amorphous GSF was determined at 88 °C. Hot Stage Optical Microscopy (HSM). The crystal growth was tracked by using a polarized light microscope (Olympus BX53 microscopy equipped with a Olympus Digital Camera DP26). A Linkam THMS 600 hot stage was equipped on the polarized light microscope to achieve the temperature control. Raman Microscopy. Raman microscopy (ThermoFisher DXR) equipped with a 780 nm externally stabilized diode laser was used to

Figure 1. Crystal growth morphologies of GSF in the bulk (a) 210 °C, (b) 130 °C, (c) 100 °C, (d) 90 °C, (e) 80 °C, and (f) 60 °C. B

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Crystallizations of Amorphous GSF at the Free Surface. To observe crystal growth at a free surface, 2−5 mg of GSF was melted on a clean 22 mm square coverslip at 230 °C for 3 min, and subsequently covered with a 15 mm diameter round coverslip. After quenching to the room temperature, the 22 mm squared cover glass was detached from the GSF sample at 80 °C by gently bending its center toward the round cover glass to expose the free surface. In this way, fewer cracks were formed at the free surface to ensure the undisturbed crystal growth. Surface crystal growth rate was measured by tracking the crystals spontaneously nucleated at the free surface. In some studies, surface crystallization was initiated at 80 °C spontaneously, and the sample was transferred to a desired temperature for further measurement. The surface crystal growth was measured under N2 purge. Polymorphism of GSF. GSF has been reported to have three polymorphs with a melting point at 220, 214, and 205 °C, respectively.33 Form I (Tm = 220 °C) is the thermodynamically stable polymorph, showing a monotropic relationship with other two metastable polymorphs.33 In this study, all of the bulk and surface crystals we examined were confirmed to be Form I, as identified by DSC, XRD, or Raman microscopy.

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RESULTS

Bulk Crystal Growth. Figure 1 shows the morphologies of GSF crystals grown in the bulk at a wide range of temperatures, from 60 °C (Tg - 28 °C) to 210 °C (Tm - 10 °C). The morphology of GSF crystals changes with temperature. When the crystallization occurred near the melting point (e.g., 210 °C), the product was large, faceted single crystal (Figure 1a). If the liquid was cooled to 130 °C, a fine-grained polycrystalline material was produced. Interestingly, fast-growing protrusions were observed ahead the normal compact growth (Figure 1b). These protruding crystals grew substantially faster than the normal compact growth. For each of the protrusions, an air bubble was pushed forward at its tip. As we discuss later, the growth rate of the protrusion closely matched the surface crystal growth rate. We speculate that the protruding crystals grew along with the advancing air bubbles where the free surface was steadily created. As the liquid was further cooled toward Tg (88 °C), the crystal growth of GSF became very slow. At 100 and 90 °C, short and loose fibers were observed at the growth front (Figure 1c,d). Below Tg, the crystal morphology of GSF changed back to compact spherulites with a sharp interface with the glass (Figure 1e,f). Figure 2 shows the bulk crystal growth rate of GSF. The growth kinetics above Tg (90−210 °C) shows the familiar bellshaped curve, a result of the competition between thermodynamic and kinetic effects. At a small supercooling (170−210 °C), molecular diffusion is fast and crystallization is limited mainly by the thermodynamic driving force. The crystal growth rate increases with decreasing temperature and increasing thermodynamic driving force. Below 170 °C, the growth rate decreases sharply, a consequence of decreasing molecular mobility.15 The crystal growth rate of GSF decreases to approximately 10−10 m/s at 90 °C, where the liquid diffusivity is expected to be very small at the temperature near Tg. The growth kinetics of diffusion-controlled crystallization (90−160 °C) is Arrhenius, and the activation energy Ea is 236 kJ/mol (Figure 2b). With further cooling, a sudden 10-fold rise of growth rate occurs at 87 °C (Tg - 1 °C). Since the crystal growth occurred in the glassy state, this phenomenon is called GC growth mode, which had been reported for several other organic glass formers.10−16 The growth kinetics of GSF in the glassy state (T < Tg) is also Arrhenius, and the activation energy

Figure 2. (a) Crystal growth rate of GSF in the bulk. (b) Arrhenius kinetics of GSF crystal growth in diffusion-controlled mode (solid round) and GC mode (solid square).

Ea is 185 kJ/mol (Figure 2b), which is smaller than the value of diffusion-controlled mode in the liquid state. Surface Crystal Growth. Figure 3 shows crystal growth morphologies of GSF at the free surface at temperatures both below and above Tg. Below Tg, amorphous GSF could spontaneously nucleate at the free surface. GSF grew as spherulite-like morphology at 60 and 80 °C (Figure 3a,b). We did not observe any loose fibrous crystals by avoiding the cracks on the free surface during the sample preparation.24 In this case, the boundaries between crystal growth front and amorphous region were better defined, and thus more accurate growth rate measurements could be achieved. SEM was used to examine the texture of surface crystal growth front. Figure 4 shows the GSF surface crystal grown in compact domains surrounded by depletion zones, which is similar to the surface crystal morphologies of IMC γ polymorph.34 Unlike many other systems,34 amorphous GSF shows fast crystal growth even well above Tg. Above Tg, the surface crystal layer becomes very thin and barely visible through a light microscope (see crystals grown at 100 °C in Figure 3b), indicating that the underneath bulk crystal growth is very slow. Another interesting feature of the surface crystal growth of GSF C

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Figure 3. Crystal growth morphologies of GSF at the surface (a) 60 °C, (b) 80 and 100 °C, (c) 115 °C, (d) 130 °C.

Figure 4. SEM images of GSF crystals at the surface at 80 °C. Figure 5. (a) Temperature-cycling experiment performed with GSF surface crystals grown at 120 and 130 °C. The sample was rapidly heated and cooled between 120 and 130 °C. Crystals that grew at 120 °C appeared as bright rings, crystals that grew at 130 °C appeared as dark rings. (b) SEM images of GSF surface crystals grown at 120 and 130 °C.

is the decreasing birefringence: compare crystals grown at 115 °C (Figure 3c) and 130 °C (Figure 3d); the latter is much less birefringent between crossed polarizers. To better understand the latter feature, a temperature-cycling experiment was performed. As shown in Figure 5a, the GSF surface sample was cycled between 120 and 130 °C. During each cycle, the sample was heated to 130 °C at a rate of 100 K/min, held for 1−2 s, and then cooled to 120 °C at a rate of 100 K/min for a holding time of 15−20 s. The surface crystals grown at 120 °C formed bright rings (high birefringence), whereas those grown at 130 °C formed dark rings (low birefringence). The dramatic transition of crystal birefringence seemed to occur at this narrow temperature range. SEM experiments were conducted to reveal detailed surface textures of GSF crystals grown at 120 and 130 °C (Figure 5b). The crystals grown at 120 °C showed smooth surface texture, whereas those grown at 130 °C exhibited a much coarser texture composed of irregular voids or channels. As we discuss later, the weak birefringence of the surface crystals that grew at 130 °C is possibly caused by the interference of the protruding growth in the bulk at high fluidity. The GSF surface crystals grown at different temperatures were all identified as polymorph I by XRD (see Figure 6). Figure 7 shows the surface crystal growth rates of GSF measured at different temperatures. The log u of GSF surface crystals changes almost smoothly from 50 °C (Tg - 38 °C) to 150 °C (Tg + 62 °C), with only a slight kink at Tg. This behavior is in contrast with the GSF bulk crystal growth, which shows an obvious discontinuity of growth rate at Tg (Figure 2a). Compared to the bulk, the surface crystallization of GSF shows weaker temperature dependence. At 50 °C, GSF surface

Figure 6. X-ray powder diffraction patterns of the powder of GSF polymorph I and GSF surface crystals that grew at 130, 120, and 115 °C.

crystals grow 2 orders of magnitude faster than bulk crystals. For the molecular glasses studied previously, the surfaceD

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Figure 7. Crystal growth rate of GSF in the bulk (solid squares) and at the surface (empty triangles).

130 °C. For the protruding crystal, the tip growth velocity (ut) was much faster than the velocity of lateral growth (ul). As shown by Raman spectra in Figure 8b, crystals of normal bulk growth (region I), lateral growth (region II), and tip growth (region III) were identified to be the same polymorph. Figure 8c compares the growth rates of the protruding crystals, normal bulk crystals, and surface crystals. Interestingly, the tip velocity of protruding crystals in the bulk matches well with the velocity of crystals growing on the free surface. Meanwhile, the lateral growth of protruding crystals has a similar rate as normal bulk crystals. It was noteworthy that the phenomenon of protruding crystal growth in the bulk was only observed between 130 and 150 °C. This growth mode was not observed below 120 °C. As indicated earlier, the GSF surface crystals grown at 130 °C exhibited lower birefringence than those grown at 120 °C. This phenomenon might be related to the protruding crystal growth mode observed between 130 and 150 °C in the bulk. It is possible that, at high temperature with enough fluidity, the protruding growth in the bulk strongly interfered with surface crystallizations by creating voids and tunnels, yielding the coarse surface texture.

enhanced crystallization is generally sensitive to the passage of Tg, with the onset of fluidity disrupting the crystal growth process.34 In contrast, the surface crystals of GSF could grow steadily at a constant rate up to 150 °C (Tg + 62 °C), eventually reaching the same rate of the bulk growth. Relation between Protruding Crystal Growth in the Bulk and Surface Crystal Growth. As described earlier, in the bulk crystallization, some fast growing crystals protrude ahead of the normal compact growth as fluidity increases (Figure 1b). To understand why this phenomenon occurs, careful growth rate measurements and characterizations were conducted for the protruding crystals. Figure 8a shows three consecutive images during the growth of a protruding crystal at

DISCUSSION GC (Glass-to-Crystal) Growth in GSF and Other Molecular Glasses. We now compare GC growth in GSF and other molecular glasses. The rate of crystal growth from a one-component liquid at small supercooling is limited by the thermodynamic driving force. At large supercooling, the rate of crystal growth is found to be limited by molecular mobility in the liquid. For many systems, it has been established that diffusion in the liquid defined the kinetic barrier for the crystal growth. This is evident from the proportionality of the growth rate to the self-diffusion coefficient (D).7,8 If the temperature of liquid is further reduced to near or below the Tg, the viscosity in the supercooled liquid is so great (η > 1013 poise) that the

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Figure 8. (a) Photomicrographs of GSF bulk crystal growth at 130 °C, ut is the tip growth velocity, and ul is the lateral growth velocity of the protruding crystal. (b) Raman spectra of the normal bulk crystal (I), the lateral growth (II), and tip growth (III) of the protruding crystal. (c) Comparison of growth rates of protruding crystals versus normal bulk and surface crystals. E

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system starts to freeze into a solid-like glassy state. According to the current view that crystallization is controlled by diffusion, an organic glass should not crystallize readily because molecular diffusivity is greatly reduced in the glass. However, it has been reported that many organic systems can grow in a fast mode (GC growth) with a growth rate that is orders of magnitude faster than the growth under the bulk diffusion control below or near Tg. In this study, the bulk crystal growth rate of GSF shows an abrupt 10-fold increase as the temperature is decreased from above to below Tg. The fast GC growth of GSF in the bulk is activated at 87 °C (Tg - 1 °C) and continues deep in the glassy state (T < Tg). For comparison, Table 1 Table 1. Kinetic Parameters for Crystal Growth under GC Modea system

Tg cal, K

Tt, K

log u at Tt, m/s

Ea, kJ/mol

ref

ROY-YT04 ROY-Y ROY-OP ROY-R TP (TPm) NIF (β) IMC (γ) OTP DPCP DPCH salol IPB toluene GSF

260 260 260 260 272 315 315 246 222 230 222 129 118 361

269 265 265 261 280 316 306 249 225 233 226 127 116 360

−7.2 −7.4 −7.5 −8.2 −6.1 −8.5 −10.4 −7.8 −7.8 −8.1 −7.1 −9.5 −8.3 −8.5

83 76 88 71 127 126 131 65 30 45 57

13 13 13 13 14 12 16 17 15 15 13 11 13 this work

50 185

Figure 9. u at the termination temperature Tt versus Tt/Tg for GC growth in 12 liquids; the plot is reconstructed from ref 16; GSF data (red star) is from this work. (ROY: 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile; OTP: o-terphenyl; DPCP: 1,2diphenylcyclopentene; DPCH: 1,2-diphenylcyclohexene TP: testosterone propionate; IPB: isopropylbenzene; NIF: nifedipine; DMP: dimethyl phthalate; IMC: indomethacin; GSF: griseofulvin).

polymorph), NIF, and OTP, the surface crystal growth becomes slower and unstable above Tg.34 In contrast, this phenomenon is not observed for γ IMC, which can grow steadily at a constant rate at the surface up to 20 °C above Tg.34 Hasebe et al. argue that crystal morphologies play an important role for the different responses of surface growth as glasses are heated to become fluids, where needle-like surface crystals are more at risk to be disrupted than the crystals with compact morphology.34 In this study, the SEM images show that GSF grows in compact domains at the free surface. This is similar to the observation of γ IMC and is the second system exhibiting a small disruption of surface crystal growth at the onset of liquid flow. In contrast to the GC growth of GSF in the bulk, the less disruption of surface crystal growth by fluidity further supports the view that the surface-enhanced crystallization is sustained by surface diffusion. The crystal growth rates for GSF at the surface are well decoupled with the bulk growth rates from the glassy state to 150 °C (Tg + 62 °C). This indicates that surface diffusion is still active in the liquid state and can support fast surface crystal growth even at high fluidity. The crystal growth rate data also suggest a possible merging of surface diffusivity with bulk diffusivity at 150 °C. Relations between Bulk and Surface Crystallizations above Tg. Similar to other GC systems, the GSF bulk crystal changes growth morphologies with temperature, from faceted single crystals near the melting point (217 °C), to fiber-like crystals near Tg (88 °C), and to compact spherulites in the GC mode. In addition, some crystals are observed to protrude from the normal growth at 130 °C (Tg + 42 °C) in the bulk crystallization. We find that the tip growth velocity of these protruding crystals in the bulk surprisingly matched with the crystal growth velocity at the free surface. This similarity suggests a possible connection between the protruding crystal growth and the surface process. In general, the difference between the specific volume of supercooled liquid and crystal increases with increasing the temperature above Tg.36 Crystals with higher density are expected to build up tension at the advancing interface with the surrounding supercooled liquid. It is suspected that during the GSF bulk crystallization at 130 °C or above, voids and free surface can be continuously created at the growth front through the release of tension caused by liquid

a

Key: ROY: 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile; TP: testosterone propionate; NIF: nifedipine; IMC: indomethacin; OTP: o-terphenyl; DPCP: 1,2-diphenylcyclopentene; DPCH: 1,2diphenylcyclohexene; IPB: isopropylbenzene; DMP: dimethyl phthalate. Tg cal: calorimetric Tg measured at 10 K/min.

summarizes the kinetic parameters of the GC growth of GSF along with other reported GC systems.11−17 The termination temperature Tt represents the temperature below which compact crystalline domains expand at a constant velocity and above which the GC growth mode is disrupted. As seen from Figure 9, the velocity of GC growth at Tt for GSF can be perfectly fitted into the plots against Tt/Tg,16 which is consistent with the general conditions for GC growth (D/u < 7 pm) and further supports the view that GC growth is an inherently solid state process disrupted by fluidity.16 It is noteworthy that GSF has the largest activation energy for GC growth among these systems. Surface-Enhanced Crystal Growth in GSF and Other Molecular Glasses. The surface-enhanced crystallization of GSF in the glassy state was previously reported by Zhu et al.24 In this study we focus mostly on the surface crystal growth morphologies and kinetics of GSF above Tg. Remarkably, unlike other systems the surface crystallization is readily disrupted by the onset of fluidity above Tg,34 and the surface crystal growth of GSF can persist at a steady rate up to 150 °C (Tg + 62 °C). Yu and co-workers have revealed that the fast surface crystal growth for organic glasses is attributed by the higher surface mobility.27 This view is supported by the proportionality of surface crystal growth rate and surface diffusivity below Tg, measured for IMC, NIF, and OTP.28,35 However, for α IMC (α F

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volume contraction. This is further suggested by the observation of air bubbles continuously pushed at the tip of protruding crystals. This phenomenon of gas bubbles released from the interface as the crystal grows into the melt has been studied extensively.37 For example, bubbles can be either generated from the advancing ice−water interface or incorporated into a growing ice crystal.38 The mechanism of protruding crystal growth in this study could arise from a surface-facilitated process. A possible scenario may be that the fast growth of crystal in the bulk above Tg generates bubbles; the fast surface diffusion at the airsupercooled liquid interface then sustains the continuous growth of crystals at the advancing front, which is comparable to the surface growth rate. Meanwhile, crystals formed at the interface initiate the bulk crystal growth laterally, as evidenced by the similar crystallization rates for the lateral growth and normal bulk growth. In short, GSF crystals grow faster along the air-supercooled liquid interface created by the advancing bubbles than perpendicular into the bulk, as protruding from the normal bulk growth. It is noteworthy that this protruding growth is analogous to the fast crystal growth along cracks observed in the OTP glasses.39 Paeng et al. report that the molecular mobility of OTP at the advancing growth front can be enhanced by a factor of 4 as a result of the tension built up with the progress of GC growth near Tg.40 Powell et al. suggest that fast GC growth is possibly facilitated by the voids created at the growth front where free surface exists.39 As shown in Figure 5a, the birefringence of GSF surface crystals grown in the liquid state exhibits a shape variation between 120 and 130 °C under polarized light microscope. The SEM images illustrate that the surface texture of crystals grown at 120 °C is quite smooth, whereas surface of crystals formed at 130 °C is comprised of many voids and channels. Given the fact that the bulk crystal growth occurs simultaneously with surface growth,34 the weak birefringence of surface crystals grown at 130 °C can be explained by the voids and tunnels formed in the bulk, as supported by the emerging of the protruding crystal growth at this temperature.

Article

AUTHOR INFORMATION

Corresponding Author

*Address: Department of Pharmaceutics, College of Pharmacy, China Pharmaceutical University, No. 24 Tongjiaxiang Rd. Nanjing 210009, China. Tel: 86-025-83271123. E-mail: tcai@ cpu.eud.cn. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for financial support of this work by the National Science Foundation of China (No. 81402877) and the Program for Jiangsu Province Innovative Research Team. We also thank Prof. Lian Yu (School of Pharmacy, University of Wisconsin, Madison) for helpful discussions.

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CONCLUSIONS In conclusion, we report the crystallization kinetics of GSF in the bulk and at the free surface as a function of temperature. The bulk crystal growth rates of GSF increase suddenly by 10fold at 87 °C (Tg −1 °C) on cooling. This finding sets another GC growth system that crystal growth far exceeds the diffusionlimited rate in the glass state. Surface-enhanced crystal growth of GSF can occur above and below Tg. Unlike other reported systems where surface crystallizations are active in the glassy state but disrupted above Tg, the surface crystal of GSF could grow steadily up well above Tg. The crystal growth rates for GSF at the surface are well decoupled with the bulk growth rates from the glassy state to 150 °C (Tg + 62 °C), indicating that the fast surface diffusion is active in the liquid state even at high fluidity. The fast protruding crystal growth in the bulk liquid is believed to be a surface-facilitated process. The creation of voids and free surface can be a result of liquid volume contraction and release of bubble at the advancing interface during the crystallization process. The observation of the connection between GSF bulk and surface crystallizations in this study is beneficial for understanding the mechanism of these two processes and the stability of amorphous pharmaceutical solids. G

DOI: 10.1021/acs.cgd.6b00252 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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DOI: 10.1021/acs.cgd.6b00252 Cryst. Growth Des. XXXX, XXX, XXX−XXX