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Glass-Crystal Growth Mode for Testosterone Propionate Alexander Shtukenberg,†,* John Freundenthal,† Erica Gunn,‡ Lian Yu,‡ and Bart Kahr† † ‡
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705-2222, United States ABSTRACT: The recently discovered glass-crystal (GC) growth mode in some glassforming liquids is characterized by strong and abrupt growth rate enhancement just in the vicinity of the glass transition temperature. GC growth previously has been observed in only 10 compounds. The data on testosterone propionate presented here indicate the fastest GC growth acceleration observed to date. Moreover, testosterone propionate is the first compound to show a helically twisted morphology concomitant with GC growth. It has been previously stated that an aryl ring is a prerequisite of GC growth, but testosterone propionate obviates that claim.
’ INTRODUCTION The growth velocity of a crystal into its melt is thought to be controlled by two factors: the rate of molecular fluctuation in the liquid immediately before the growth front that leads to correct registry with the crystal and the probability that the newly formed crystal is irreversibly attached into the crystal phase. The relevant molecular fluctuation for crystal growth is commonly believed to be similar to diffusion. Near the melting point Tm, where supercooling (ΔT = Tm T) is slight, the driving force for crystallization is small, diffusion is fast, and attachment of growth units is the rate-limiting step. If ΔT is large, diffusive mass transport is slowed and becomes rate-limiting; ultimately, rate is assumed to become proportional to the diffusion coefficient.1 Comparatively recently, it was shown that crystal growth from some glass-forming liquids near or below the glass transition temperature (Tg) can become faster by up to 4 orders of magnitude compared to the growth rates that are observed at slightly higher temperatures.2 4 This growth mode, termed glass-to-crystal or GC mode, was apparently first reported for o-terphenyl in 1967,5 and since 1995, it has been studied systematically by several research groups. To date, GC growth has been observed for 10 compounds: o-terphenyl,4 6 benzophenone, phenylsalicylate (salol), triphenylethane, toluene, diphenylphthalate, dimethylphthalate, isopropylbenzene,6 8 nifedipine,9 and 5-ethyl-2 2nitrophenylamino-3-thiophenecarbonitrile (ROY, so named for its red, orange, and yellow polymorphs).3,9,10 The key characteristics of GC growth mode can be summarized as follows:3,4 (1) It emerges suddenly near Tg upon cooling and disappears at the same temperature upon heating. (2) The growing crystals often form compact spherulites, although the GC growth mode can persist as fibers at higher temperature. (3) The growth rate is nearly independent of time. (4) The activation energy for growth can be smaller than the activation energy for diffusion-controlled growth. (5) All compounds showing GC r 2011 American Chemical Society
growth to date contain aryl rings, a structural feature that has been suggested to “help the realization” of GC growth.8 Although several mechanisms have been proposed to explain GC growth (see below), they do not explain all of the known features of this phenomenon. In the present article, we report an experimental study of testosterone propionate (TP), a compound without a phenyl ring that is able to crystallize in GC growth mode. This system shows some new features that might be important for refining our understanding of this mysterious growth phenomenon.
’ EXPERIMENTAL SECTION Testosterone propionate (TP) is the ester that is commonly abused by body builders. We happened to have a sample of TP in our chemical library from the Nutritional Biochemical Corporation. The sample was recrystallized from methanol and yielded elongated prisms. The structure was confirmed to be that previously described.11 Several milligrams of as-received or recrystallized TP was placed between a microscope slide and cover glass. The sample was melted on a hot plate (Tm = 120 °C) and then rapidly cooled to room temperature. Then, it was heated/cooled with a variable temperature stage (model FP90, MettlerToledo) to the desired temperature from 12 to 120 °C. Crystallization was observed using a conventional polarizing light microscope. Received: May 20, 2011 Revised: August 29, 2011 Published: August 29, 2011 4458
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Crystal Growth & Design An estimate of the thickness of the film based on the weight of TP and its area of spreading was usually in the range of 4 6 μm. TP does not degrade upon melting/crystallization cycling. The glass transition temperature was measured using a Q2000 differential scanning calorimetry (DSC) apparatus from TA Instruments. For each measurement, 3 5 mg of material was sealed in an aluminum Tzero pan and melted on a Linkam hot stage at 125 °C for 2 min. This sample was quenched on an aluminum block cooled to dry ice temperature and transferred immediately to the DSC cell waiting at 50 °C.
Figure 1. DSC data showing glass liquid transition, crystallization, and melting of TP.
Figure 2. Metastable testosterone propionate (TPm) phase growing in standard “slow” growth mode (TPms). Degrees centigrade (°C) refer to temperatures of the marked areas during growth.
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The sample was heated at 10 °C/min from 50 to 20 °C, held for 2 min, and then cooled quickly to 50 °C and measured again. A typical DSC curve is shown in Figure 1. There was no significant difference in Tg between the first and second measurements. The reported value of Tg = 1 °C is the average of measurements for three individual samples. The heat of fusion is 21.0(2) kJ/mol. Polymorph identification was carried out using an X-ray Bruker AXS D8 DISCOVER GADDS microdiffractometer equipped with a VÅNTEC-2000 two-dimensional detector and a 0.5-mm MonoCap collimator (Cu Kα radiation). Because of the rapid conversion of metastable TP polymorph (see next section) in air at room temperature, it was impossible to scrape off the material from the glass slide and perform routine powder X-ray diffraction analysis. Instead, the data were collected from an as-grown thin film on a glass slide in reflection mode. The coverslip was removed immediately prior to data collection, and the sample was cooled to 10 °C with the cooling stage. Because the stage cap produced several strong diffraction maxima, we were able to get reliable data only in the narrow angular range of 2θ = 10 20°.
’ RESULTS TP crystallizes in two polymorphic modifications. The stable polymorph (TPs) belongs to the orthorhombic space group P21212111 and can grow from the melt above room temperature. A metastable (TPm) polymorph grows from the melt below 60 °C. TPm transforms to TPs at detectable rates when T > 0 °C, so that, at room temperature, the complete phase transformation takes just several hours in TP films prepared between two glass slides or only in a couple of minutes if the coverslip is removed. The GC growth mode was observed only for the metastable phase. TPm morphology is highly temperature-dependent. For T = 0 60 °C, the standard slow growth mode (TPms) is observed. We emphasize here, so as not to lose the reader in symbols, that subscript s specifies standard growth kinetics of the metastable (m) phase of the substance (TP). Crystal growth occurs in the form of compact spherulites, whose fibers are thicker and straighter at higher temperatures (Figure 2). The GC growth mode for TPm (labeled as TPmf, where subscript f means fast growth kinetics) emerges below 6 7 °C (Figure 3). We designate this onset temperature TGC (also called Tt previously). A new phase nucleates at the TPm/liquid interface in the form of thin fibers spreading radially from nucleation centers. In the first stage, fibers form bundles. Within a bundle, they grow at the same rate. However, the rate is not
Figure 3. Initial stages of the fast growth mode of the metastable phase (TPmf). Here, TPmf spherulites grow at 5.9 °C on the outer surface of TPms spherulites grown at ∼10 °C. The time t = 0 s corresponds approximately to the TPmf spherulite nucleation. The black circle is a gas bubble. The growth rate in the GC mode is ∼0.8 μm/s. 4459
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Crystal Growth & Design
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Figure 6. Growth morphologies of TPmf spherulites at different temperatures as marked in the figure. Note the hysteresis in the loss and recovery of the bands.
Figure 4. Outermost fibrous structure of TPmf spherulites. Note the different widths of the fibrous part in different spherulites, as well as in different parts of the same spherulite. (a) In situ observation, T = 5.5 °C. (b) Thickening of fibers on the spherulite surface that started after sample was removed from the refrigerator (T ≈ 5 °C) and stored for about 1 min at room temperature.
Figure 5. Band spacing (P) in TPmf spherulites as a function of growth temperature (T). Symbols indicate different growth runs.
constant; periods of relatively slow growth alternate with periods of very fast growth. With time, not only the length of fibers but also their density in the bundle increases, and bundles fill the space around the nucleus, forming a spherical growth front (i.e., a spherulite). Spherulites are compact within the temperature range of our study, from 12 to +6 °C, but they can be accompanied by radially directed fibers of varied density on the spherulite rim. These fibers constitute the foremost part of the spherulite growth front (Figure 4). They might be present at T > 2 °C, but at lower temperatures, they are always observed. At T < 2 °C, the width of the fibrous zone increases as the temperature decreases. Compact spherulites are typically characterized by noncrystallographic branching and are lacking skeletal or dendritic forms.12 For all testosterone propionate phases studied here, neither skeletal nor dendritic growth was observed. Both the fibers decorating the outer spherulite boundaries and the fibers composing the compact spherulites are twisted, as indicated by optical banding observed between crossed polarizers. Many other molecular crystals behave similarly.13 As temperature decreases, the twist period slightly increases; at 0 2 °C, it attains a maximum; and then it decreases (Figure 5). Below 7 °C, the
Figure 7. Evolution of the TPmf spherulite when the temperature was raised above 7 °C: (a) tangential versus (b) radial growth. (a) Loose fibers existing on the growing surface strongly slow their propagation in length, thicken, and coalesce forming a growth front exhibiting different orientations of fibers. (b) Maintenance of radial crystallographic orientation observed for a “smooth” TPmf spherulite. A couple of loose fibers growing in fast growth mode are also visible.
pitch can no longer be observed optically (Figure 6). Typically, the twist period decreases as supercooling increases because the fibers become finer.14 In this respect, the P(T) behavior is consistent with the literature for growth below 1 °C, but the decreasing pitch at higher temperature indicates some change in crystal growth mechanism near TGC. If the temperature exceeds TGC, the morphology of previous established GC growth changes abruptly. Loose fibers on the spherulite surface rapidly slow their elongation but thicken at rates comparable to the TPms phase. Initially, thickened fibers preserve their twists, but after some time, they transform into individual spherulites, which compete with each other for the growth space (Figure 7a). If TPmf spherulite surfaces are not decorated by fibers, the transition to slow growth mode occurs through development of competing TPms spherulites directly on the TPmf spherulite surface (Figure 7b). Organized, well-patterned GC growth does not exist above TGC, but fast-growing, loose fibers can be observed up to 35 °C (Figure 8). Their structure is very similar to the structure of TPmf 4460
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Crystal Growth & Design fibers that turn into TPms spherulites at T > TGC (Figure 7a), when fast-growing extremely fine fibers stop growing in length and start thickening. Both types of fibers often grow in pulses showing alternating periods of fast and slow growth. The single difference is that fibers forming below TGC are usually straight (Figure 4), whereas those forming at higher temperatures are bent irregularly and even coiled (Figures 7b and 8). Although fast-growing banded spherulites strongly differ from coexisting TPms spherulites and look like a new polymorphic
Figure 8. Loose fibers of TPms phase growing at 21 °C on the outer boundary of TPms spherulites formed at 30 40 °C.
Figure 9. X-ray powder diffraction patterns of TPs spherulites (upper spectrum), TPmf spherulites (middle spectra from two runs), and TPms spherulites (lower spectra for two runs). The lowest TPms spectrum was collected from spherulites grown at room temperature (highly misoriented fibers; see Figures 2 and 8), whereas the higher one was collected from spherulites grown at 46 °C (similar fiber orientations that resulted in a texture and strong maximum at 2θ = 13.4°; see Figures 2 and 8). For the lowest TPms spectrum, some admixture of TPs phase was also detected.
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modification, continuous morphological changes (Figure 7) argue for the phase identity and presence of only one metastable TP polymorph. This conclusion is supported by a similarity in X-ray powder diffraction patterns (Figure 9). However, TPmf spherulites are more birefringent than TPms spherulites, suggesting that different fiber elongation directions manifest when the GC mode takes hold. The crystal growth kinetics is plotted in Figure 10. The red circles are typical growth rates for the stable TPs polymorph. The TPms polymorph has similar but slightly higher growth rates, whereas the GC growth mode, TPmf, is characterized by much higher (up to 300 times) growth rates. An Arrhenius activation enthalpy measured for the TPms phase at T < 50 °C is 177(6) kJ/mol. The growths of TPs and TPms have comparable activation energies in the same temperature range. In the GC mode, the temperature dependence of the crystal growth rate apparently becomes weaker with increasing temperature. The growth rate of the same spherulite growing in the GC mode is constant for 1 2 h but can vary for different samples and, in some cases, for different areas of the same spherulite, resulting in acicular, wavy growth fronts.
’ DISCUSSION The fast growth of TP crystals is consistent with the main GC growth features reported in the literature. GC growth can exist below and is inactive above a certain temperature (TGC = 6 7 °C). This threshold temperature is just 7 8 °C higher than the glass
Figure 11. Maximum growth rate in the GC growth mode plotted against TGC/Tg for TP and other compounds exhibiting GC growth.3,8,9
Figure 10. Growth rates of testosterone propionate. (a) TPs spherulites (red circles), TPms spherulites (blue downward triangles), TPmf spherulites (open upward triangles), and TPm loose fibers (black squares). (b) TPmf spherulites. Different symbols correspond to different growth runs. 4461
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Crystal Growth & Design transition temperature. (The difference TGC Tg ranges from 2 to 11 °C for all known compounds exhibiting the GC growth mode.3,4,8,9) However, up to ∼35 °C (∼1.12Tg, close to 1.15Tg for ROY3 and 1.16Tg for o-terphenyl4), it can exist in the form of loose fibers. In addition, TP shows the highest growth rate yet detected for GC growth (Figure 11). GC growth of TP presents three new features: (1) Unlike all other known compounds exhibiting GC growth, TP contains no aromatic rings. (2) Below TGC, both TPmf and TPms spherulites were observed to grow simultaneously, whereas for other compounds, only the fast growth mode was detected. (3) TP is the only example of a compound growing in the GC growth mode in the form of helically twisted fibers. Three mechanisms have been proposed to explain GC growth.3 The homogeneous nucleation-based (HNB) model envisions that homogeneous crystal nuclei are attached to crystal surfaces by the secondary relaxation in glasses.2,8,15 The tensioninduced interfacial mobility model postulates that diffusion is enhanced at crystal/glass interfaces by tensions created by the volume shrinkage upon crystallization.6,16 The solid-state transformation by local mobility model assumes that the formation of certain crystal structures requires relatively minor molecular rearrangement of the liquid’s structure and can occur through local molecular motions.3 In 2008, Sun et al. evaluated these models against features of GC growth known at the time, reaching the conclusion that the solid-state transformation by local mobility model gives a better (though by no means perfect) account of GC growth. The present study of TP now confronts these models with additional observations, in particular, points 2 and 3 in the previous paragraph. The possibility of simultaneously observing the growth of TPms and TPmf presumably reflects the faster crystal growth in liquid TP than in other liquids known to develop GC growth. Because TPms grows sufficiently fast, its growth rate can be measured before the liquid is consumed by the faster-growing TPmf spherulites. This property of the TP system does not discredit or support the existing models of GC growth, because none of them rules out the possibility of simultaneously observing GC growth and “normal” growth, despite the obvious difficulty of measuring the latter while the former is occurring at a much higher rate. The twisting of crystals during GC growth seems more compatible with the notion that GC growth proceeds by attachment of molecules rather than of large pre-existing clusters (the HNB model), as the latter would be less able to place themselves in appropriate places to attach to the imminent corkscrew. This feature seems to present no immediate challenges to the other models because they are concerned with molecular dynamics at crystal/liquid interfaces, not assembly of mesoscale clusters.
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Chemistry Research Instrumentation and Facilities Program (CHE-0840277) for the GADDS diffractometer. L.Y. thanks the NSF (DMR-0804786 and DMR-0907031) for support of this research.
’ REFERENCES (1) Jackson, K. A. Kinetic Processes; VCH: Weinheim, Germany, 2004. Kirkpatrick, R. J. Am. Mineral. 1975, 60, 798. (2) Hikima, T.; Adachi, Y.; Hanaya, M.; Oguni, M. Phys. Rev. B 1995, 52, 3900. (3) Sun, Y.; Xi, H.; Chen, S.; Ediger, M. D.; Yu, L. J. Phys. Chem. B 2008, 112, 5594. (4) Xi, H.; Sun, Y.; Yu, L. J. Phys. Chem. 2009, 130, 094508. (5) Greet, R. J.; Turnbull, D. J. Chem. Phys. 1967, 46, 1243. (6) Konishi, T.; Tanaka, H. Phys. Rev. B 2007, 76, 220201. (7) Hatase, M.; Hanaya, M.; Hikima, T.; Oguni, M. J. Non-Cryst. Solids 2002, 307 310, 257. (8) Hatase, M.; Hanaya, M.; Oguni, M. J. Non-Cryst. Solids 2004, 333, 129. (9) Ishida, H.; Wu, T.; Yu, L. J. Pharm. Sci. 2007, 96, 1131. (10) Sun, Y.; Xi, H.; Ediger, M. D.; Richert, R.; Yu, L. J. Phys. Chem. 2009, 131, 074506. (11) Reisch, J.; Ekin-G€ucer, N.; Takacs, M.; Henkel, G. Liebigs Ann. Chem. 1989, 595. (12) Bechhoefer, J. Int. J. Nanotechnol. 2008, 5, 1121. (13) Shtukenberg, A.; Gunn, E. G.; Gazzano, M.; Freudenthal, J.; Camp, E.; Sours, R.; Rosseeva, E.; Kahr, B. ChemPhysChem 2011, 12, 1558. (14) Shtukenberg, A. G.; Freudenthal, J.; Kahr, B. J. Am. Chem. Soc. 2010, 132, 9341 and references therein. Ryschenkow, G.; Faivre, G. J. Cryst. Growth 1988, 87, 221. (15) Hikima, T.; Hanaya, M.; Oguni, M. J. Non-Cryst. Solids 1998, 235 237, 539. (16) Tanaka, H. Phys. Rev. E 2003, 68, 011505.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. Tel.: +1 (212) 9929815. Fax: +1 (212) 9953884.
’ ACKNOWLEDGMENT B.K. thanks the NSF (CHE-0845526) for support of this research. The authors acknowledge Dr. Chunhua Hu, NYU Department of Chemistry X-ray Diffraction Facility, and the NSF 4462
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