Evaluation of the Crystal Growth Rate of Felodipine Polymorphs in the

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Evaluation of the crystal growth rate of felodipine polymorphs in the presence and absence of additives as a function of temperature Umesh Kestur, and Lynne S. Taylor Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg400708p • Publication Date (Web): 06 Aug 2013 Downloaded from http://pubs.acs.org on August 9, 2013

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Crystal Growth & Design

Evaluation of the crystal growth rate of felodipine polymorphs in the presence and absence of additives as a function of temperature Umesh S. Kestur1,2 and Lynne S. Taylor1* 1

Department of Industrial and Physical Pharmacy, College of Pharmacy Purdue University, West Lafayette, IN, 47907, USA

*Corresponding Author E-mail address: [email protected] Phone: 765-496-6614 2

Current address- Drug Product Science & Technology, Bristol Myers Squibb, 1 Squibb Dr, New Brunswick, NJ, 08903, USA

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Abstract The purpose of the present study was to compare the effect of temperature and a polymeric additive, poly(vinyl pyrrolidone) (PVP), on the crystal growth rate of two polymorphs of felodipine from amorphous samples. Comparing the growth rates of the two polymorphs in the presence of PVP should provide mechanistic information on whether PVP inhibits crystal growth of felodipine by interacting at the crystal surface of felodipine or in the amorphous regions. Optical microscopy was used to measure the growth rates at various temperatures in the range of 18-100°C for the form I polymorph and 40-100°C for the form II polymorph. Both surface and bulk growth rates for the form I polymorph were evaluated, while for the form II polymorph, only the bulk growth rate could be studied. No difference in the growth rate between surface and bulk crystals of form I was observed at higher temperatures (>70°C). However, below 65°C the surface crystal growth rate was faster than the bulk crystal growth rate. Another mode of growth rate was activated for the form I polymorph near the glass transition temperature of felodipine. In the absence of any polymer, the bulk growth rate of felodipine form I polymorph was faster than that of form II by 1-2 orders of magnitude. PVP was found to reduce the crystal growth rate of both polymorphs at all temperatures. The ratio of the growth rate of felodipine in the absence of any polymer to that in the presence of PVP for both polymorphs appear to be similar in the temperature range 60-100°C indicating that the inhibitory effect of PVP on felodipine crystal growth most likely arises from an effect on the amorphous material rather than at the crystal surface.


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Introduction The low dissolution rate, solubility and bioavailability of some poorly water soluble crystalline drugs can be overcome with the use of amorphous form of a solid1,2. However the physical instability of the amorphous solid can result in a loss of these advantages. Therefore, understanding the crystallization behavior of pharmaceutically relevant amorphous systems is important for developing successful strategies to utilize the advantages conferred by the amorphous form, as well as being of fundamental interest. Crystal growth kinetics can be used to provide insight into the crystallization behavior of pharmaceutical compounds. The experiments typically involve studying crystal growth rates from the supercooled liquid and/or glass as a function of temperature. In some cases the crystallization is slow at experimentally convenient temperatures. Therefore crystallization experiments may be performed at higher temperature and the results extrapolated to near or below glass transition temperature (Tg). This approach assumes that crystal growth decreases in a predictable manner with temperature below the peak growth rate, and is mainly controlled by bulk properties such as viscosity. However, it has been shown for certain small organic molecules of pharmaceutical relevance, such as indomethacin and nifedipine, that the material shows a sudden jump in crystal growth rate at temperatures close to and below Tg, in addition to having surface enhanced growth 3-5. If these modes of growth are activated in pharmaceutical materials then the growth rate observed at higher temperatures may not be predictive of crystallization rates at lower temperatures, leading to overestimates of the stability of amorphous formulations. It is therefore important to study the crystallization over a range of temperatures including normal storage conditions to develop better prediction capabilities.



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Stabilization of amorphous compounds against crystallization using polymeric inhibitors is a well known strategy 6,7. In this regard, the crystallization kinetics of the calcium channel blocker, felodipine, in the presence of poly(vinyl pyrrolidone) (PVP) has been studied extensively in our lab, and it has been observed that PVP delays the crystal growth of felodipine; this effect is mainly attributed to specific interaction between PVP and felodipine 8,9. However it is not clear whether the interaction happens at the crystal surface or in the amorphous region. Therefore the purpose of the present study was to compare the effect of temperature and a polymeric additive, PVP, on the crystal growth rate of two polymorphs of felodipine to better understand how PVP inhibits the growth of felodipine, with the secondary goal of understanding if felodipine polymorphs exhibit additional modes of growth at temperatures close to Tg.

Materials and Methods Felodipine (3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate, form I polymorph ) was a generous gift from AstraZeneca, Södertälje, Sweden. Crystal growth rate measurements were performed using a polarized light microscope (Nikon Eclipse E600 POL microscope, Nikon Corp, Tokyo, Japan).Pure amorphous felodipine samples for microscopy experiments were prepared by melting crystalline form I felodipine onto a clean 18X18 mm microscopic coverglass for 3 min, covered with an 18mm round coverglass and then placed into contact with a cold surface. The thickness of the film was 5-10 µm and thickness did not impact the growth rate. The top coverslip was then removed to expose the top surface in order to study the growth of crystals nucleated at the surface. To study the bulk crystallization of form I, the top coverglass remained in place, and samples were seeded from the side by placing felodipine form I crystals in contact with the supercooled liquid. Additional bulk growth experiments were also performed by partial melting of felodipine between two microscopic


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coverglasses so that the partially melted crystals acted as seeds. No difference in the crystal growth rates were observed with the two methods. Samples were also prepared by cooling of the melted material on a hot stage at 10 and 20K/min. Growth rates of the crystals formed from these samples were similar to crystals which were spontaneously cooled by placing on a cold surface indicating cooling rates did not impact the crystal growth rates of felodipine. Seeding of crystals was performed for bulk crystal growth rate measurements to control the polymorph that grew during the experiments. In the absence of seeding, developing crystals from amorphous films sandwiched between two coverglasses resulted in the formation of form II polymorph 9. A two-step process was used to prepare a PVP dispersion in felodipine. A 10wt% PVP (PVP K29/32, Sigma Aldrich Co, St Louis, MO) dispersion in felodipine was prepared by rotary evaporation from a PVP/felodipine solution in a 1:1 (by weight) mixture of ethanol and dichloromethane. (Dichloromethane and ethanol were obtained from Mallinckrodt Baker Inc., Paris, KY and Aaper alcohol and chemical Co., Shelbyville, KY respectively. Afterwards, the sample was further dried in a vacuum oven for 48 hours to remove any residual solvent. The 10% PVP dispersion in felodipine was diluted by mechanically blending with an appropriate amount of additional pure crystalline felodipine in a cryogenic mill (6750 freezer mill, Spex Sampleprep, Metuchen, New Jeresey) to yield a PVP-in-felodipine mixture at the required concentration. Samples suitable for microscopy experiments were prepared by melt quenching of the PVP:felodipine mixture in a similar manner to that described above for the pure drug. Samples were stored at jars containing phosphorous pentoxide to maintain a low humidity environment. The growth rate for form I was monitored in the temperature range 18°C to 100°C for samples with and without a top coverslip. Growth rate data for the form II polymorph was obtained over the temperature range 40-60°C and at 60°C for the PVP felodipine system; growth



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rate data for pure form II polymorph and PVP felodipine system in the temperature range 70110°C has been reported in an earlier study8. The temperature for growth rate measurements was maintained either using a hot-stage (Linkham THMS 600, Surrey, UK) or by using temperature controlled ovens. The hot stage was calibrated for temperature using the melting points of naphthalene and adipic acid (Mettler Thermometric Standards, Mettler Instrument Corporation, Princeton, NJ). The temperature at which the crystals melted was also noted on the hotstage to confirm the polymorph grown on the microscopic slides. For the samples placed in the ovens, the growth rate was monitored by taking out samples at appropriate time intervals to measure the extent of crystal growth. In the case of felodipine crystals seeded from the side, growth of the crystals into the bulk of the sample was monitored. A separate sample preparation was undertaken at each temperature point and experiments were performed in triplicate to determine the growth rate. In addition, for crystal growth measurements made over a period of hours to days, the growth of at least three different crystals were followed for each sample. In all other studies, the crystals grew as spherulites. A plot of size vs time was found to be linear and the slope of the line taken as the growth rate. The average of three different readings and their standard deviations are reported. Raman microscopy measurements were performed using a Renishaw Ramascope Raman Microscope system (Renishaw Plc.,New Mills, Gloucestershire, UK) attached to a Leica microscope equipped with a 783-nm diode-laser source. Spectra were acquired using a 30-60s exposure time over a wavenumber range of 2000-200 cm-1, a 50X objective lens, and a laser power of about 21 mW.

Results


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The polymorphic form obtained in the bulk of the sample during the unseeded crystal growth rate experiments was confirmed to be form II polymorph by Raman spectroscopy and melting point measurements using hot stage similar to the results from earlier studies at other temperatures reported 8,9. For unseeded pure amorphous felodipine samples in the form of films sandwiched between two coverglasses, crystallization was seen along the edges within 2 days however no nuclei were seen at the center of the amorphous samples. Nuclei in the center of samples were typically seen within 5 days. Samples without a coverslip on top crystallized to the form I polymorph, and always crystallized faster than unseeded samples with a top coverslip. The time taken for the uncovered samples to show signs of crystallinity depended on the temperature at which the top coverglass was removed. When the top coverslip was removed below the glass transition temperature (Tg), the samples appeared to crystallize faster than when the top coverslip was removed above the Tg. Figure 1 shows felodipine form I crystals grown at the free surface and the bulk at different temperatures. Felodipine form I grows in the form of spherulitic structures in the absence of a top coverslip over the temperature range used for this study (Figure 1). The spherulitic crystals are compact, dense and have a smooth interface with the amorphous matrix at lower temperatures (< 40°C, Fig. 1a), with less dense crystals having a rougher interface with the amorphous matrix being observed at slightly higher temperatures (45-65°C, Fig. 1b) and crystals with a zigzag shaped interface growing at higher temperatures (> 70°C, Fig. 1c ). In the presence of a top coverslip, form I showed different morphologies depending on the temperature. At temperatures less than 40°C, the crystals formed dense compacts with a smooth surface at the interface between the amorphous matrix and the growing crystal (Fig. 1d). In the temperature regime of 50- 70 °C, the crystals had fiber like features (Fig. 1e). In addition to a layer of fibers 7 ACS Paragon Plus Environment


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that thickened with time and had a more definite boundary, individual fiber-like structures were seen growing from the thickened layer. The individual fibers grew faster than the thickened fiber layer and showed different rates of growth depending on the fibers observed. In certain cases fibers were seen growing from compact crystals. The growth rates reported here are for the increase in the size of thickened fiber growth front into the amorphous matrix. At even higher temperatures the crystals are faceted (Fig. 1f). Form II polymorphs always grew in the form of spherulites. Similar features were seen for felodipine form I growing in the presence of PVP in this study. The surface and bulk growth rate kinetics of the felodipine form I polymorph as a function of temperature are shown in Figure 2. Overall, decreasing the temperature from 100°C (Tg +56.5°C) to 18°C (Tg -25.5°C), produces approximately 3-4 orders of magnitude decrease in surface and bulk growth rates. There are no differences in the growth rates between the surface and bulk grown crystals for form I at higher temperatures (>70°C). However, below 65°C the surface crystal growth rate is faster than the bulk crystal growth rate. The surface crystal growth is approximately 6 times faster than bulk growth rate at 18°C. This shows that felodipine growth rate is enhanced at the free surface compared to that of bulk. Surface enhanced growth rate has also been observed for other pharmaceutical systems including indomethacin, nifedipine and griseofulvin 5,10-12. In addition to the surface enhanced growth rate, below 50°C, a jump in the growth rate is seen for both bulk and surface growth crystals and is seen to continue below Tg. This mode of crystal growth has been labeled as glass-crystal (GC) or a diffusionless mode of growth 13,14 . The transition between the GC mode of growth and the thickened fiber like crystals grown at a temperature just above Tg is abrupt. Going from 50°C to 45°C the growth rate increases 2-3 times for crystals growing on both the surface and the bulk. In contrast, the growth 8 ACS Paragon Plus Environment

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rate of the form II polymorph decreases smoothly with decreasing temperature (Figure 2). The form II polymorph growth rate decreases 5 orders of magnitude on going from 105°C to 40°C. The surface growth rate of crystals of felodipine form II could not be determined as the crystals always nucleated as form I. In the presence of PVP, the peak growth rate is seen at 100 and 105°C for form I and form II respectively (Figure 3). At this temperature, the growth rate of felodipine in the presence of PVP was similar to pure felodpine. As the temperature is decreased to 50°C, form I shows a 3-4 orders of magnitude decrease in growth rate. The uncovered surface crystals grow 1-1.5 orders of magnitude faster than the crystals growing in the bulk. Similar to pure felodipine, surface enhanced growth rate is also seen in the presence of PVP. In addition, below 50°C and in the region of the glass transition temperature of felodipine (40-45°C), a sudden jump in growth rate is also seen for both surface and bulk grown crystals of form I when PVP is present in the matrix, as seen in the absence of the polymer. In the case of form II, the growth rate in the presence of PVP shows a smooth decline with temperature (Figure 3). Below 60°C, the growth rates were too slow to be measured in a reasonable time frame. However based on the growth rate data for pure form II felodipine, a jump in growth rate is not expected for samples containing the polymer in the case of form II. The ratio of the growth rate of felodipine in the absence of any polymer and in the presence of PVP is shown in Figure 4. Within statistical error, there appears to be little difference in the growth rate ratios for the different polymorphs.

Discussion The results in the study clearly show that the felodipine form I polymorph grows faster from the free surface than from the bulk at lower temperatures, with the surface growth rate approximately 5-6 times faster closer to and below Tg. However, the growth rate between the



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free surface and the bulk mode is indistinguishable in the temperature region 70-90°C. In other pharmaceutical systems including indomethacin, nifedipine and griseofulvin, the surface enhanced growth has been shown to be one to two orders of magnitude faster than the bulk growth3,5,11. For organic glasses like indomethacin it has been observed that the surface crystals grow upward and laterally without penetrating deep into the bulk and that the surface growth is a different mode of growth than bulk growth.15 Felodipine thus represents another pharmaceutical system which shows surface enhanced growth behavior at temperatures close to and below Tg. A faster surface growth may be attributed to the presence of mobile molecules at the surface with the surface behaving in a more liquid-like manner and the interior behaving more solid-like in terms of their mobility10,12. Zhu et al have shown that for indomethacin glasses, surface diffusion is a million times faster than bulk diffusion, thus demonstrating the greater mobility of the surface molecules over those in the bulk

16

. Additional studies have shown that coating of the

surface crystals with an ultrathin layer of gold can change the growth rate of these surface crystals to be more like the growth rate of bulk crystals 5,10. The faster surface growth rate has implications for the stability of amorphous systems to crystallization. Previous studies with amorphous felodipine powders, both with and without PVP, have shown a biphasic pattern of crystallization, with the initial fast crystallization rate attributed to surface crystallization, followed by slow crystallization attributed to bulk crystallization 17. The temperature regime where surface growth is faster than bulk growth is very relevant for pharmaceutical amorphous solids in terms of using elevated temperatures to predict crystallization rates at lower temperatures. If the surface enhanced growth mode is not considered during such stability studies, an over prediction of the stability of the amorphous solid may result.


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The form I polymorph also shows a jump in the growth rate near Tg. This is most likely due to a mode of growth which is activated near Tg, termed glass-crystal or GC growth by Yu and coworkers 14, which occurs for some crystals in addition to diffusion controlled growth and surface enhanced growth. This mode of growth has been shown to be activated in the supercooled liquid region as the sample temperature is reduced to temperatures close to Tg and continues into the glass. It is manifested by an abrupt increase in volume growth rate at a certain temperature close to Tg, termed the transition temperature 13,14. From Figure 2, it apparent that the transition temperature for felodipine, based on the growth rates of the volume filling spherulites, is between 45-50°C, for both the bulk and surface growth. The jump in growth rate is also seen in the presence of PVP at around the same temperature (Figure 3). In addition, Sun and others have observed fast growing fibers at temperatures higher than the transition temperature, and these were also seen for felodipine form I polymorph as shown in Figure 1e which shows the crystals growing at 60°C; due to their curvature, it was not possible to measure the growth rate of these fibers. Other systems for which GC growth has been reported include O-terphenyl, indomethacin , nifedipine and ROY3,4,13,14,18. In these systems the GC mode of growth is thought to persist in the form of fast growing fibers above the glass transition temperature .i.e. when the growth rate of these fibers and the GC mode of growth are plotted as a function of temperature they fall on a smooth continuous line. Therefore the jump in growth rate is only for the growth rate of the front (spherulites) and not for individual fibers. Yu and co-workers explain GC growth as a diffusionless mode of growth based on data that show that the GC growth rate is much faster than would be predicted based on the diffusion rates of the substance. In diffusion controlled growth, addition of a new molecular layer during the growth of crystals is controlled by the diffusion rate of the molecules towards the growth front 19. Under this regimen, it has



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been observed that the number of molecular layers that are added to the crystalline phase in one structural relaxation time is 0.1-1 13.For the GC growth mode, the number of molecular layers added is much higher than this, 1700-2400 for different ROY polymorphs14. Thus substantial diffusion or structural relaxation is not possible during this timeframe of addition of molecules to the growth front 13,14. For materials which show this fast mode of growth, the addition of a new layer has been related to oscillatory motions available in the glasses and the bulk liquid 5,13,14. In the case of felodipine form I polymorph, at 45°C (Tg is 43.5) the crystal growth rate in the bulk is 2.6x10-9 m/s. At this rate, approximately 500 molecular layers are added in one structural relaxation time (taken as 100s) assuming a radius of 9Å for the felodipine molecule supporting the supposition that the form I polymorph of felodipine also exhibits the diffusionless mode of growth seen for other compounds. In contrast, the form II polymorph does not show this fast mode of growth and the growth kinetics decrease smoothly with temperature and less than one molecular layer is added at 45°C. The presence or absence of this fast mode of growth among polymorphs is thought to be related to the crystal density and anisotropy of molecular packing based on behavior observed for ROY polymorphs 13. For ROY, polymorphs which show this fast mode of growth, measured densities were higher and molecules were more isotropically packed in the crystal lattice based on radial distribution function calculations. The form I polymorph of felodipine does have a higher density than the form II polymorph, 1.45 vs 1.42 g/cm19. The much faster growth rate of the form I polymorph relative to the form II polymorph, both at the surface and in particular below Tg, combined with its tendency to nucleate at the surface, most likely explains why in powdered amorphous samples, only this polymorph is observed following crystallization 17,21.


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The growth rate of form I polymorph is one to two orders of magnitude faster than that of the form II polymorph over the temperature range studied. In order to compare the relative effectiveness of PVP in retarding the crystal growth of both the polymorphs, the ratio of bulk growth rates of felodipine in the absence of PVP to that of in the presence of PVP was calculated. In the temperature range of 60-100°C, there appears to be little or no difference in the ratio of growth rates for both the polymorphs. Thus, PVP reduces the growth rate by approximately the same magnitude for each polymorph. This result has important potential implications in that if a crystal phase has a fast growth rate, relatively more polymer will be required to reduce the growth rate to a sufficiently low value to retard crystallization over the desired timeframe. It is also important to understand the impact of the polymer on different polymorphs, since amorphous systems frequently crystallize to either a mixture of polymorphs, or to a metastable form. Furthermore, the results suggest that for this temperature range, the interacting environment between PVP and felodipine is similar for both polymorphs. Polymorphs have different crystal interfacial structures but grow from the same liquid phase suggesting that the impact of the polymer on the crystal growth rate has its origins on its impact on the properties of the liquid phase. This is in contrast to crystal growth from solutions where polymer adsorption to the crystal surface is the generally accepted mechanism of crystal growth modification when only trace quantities of the additives are present 22-25. The results for this system are complicated by the fact that form I starts showing an enhanced growth rate closer to Tg therefore a jump in growth rate is seen for this system, in addition to the slow growth rate of the form II polymorph which precludes measurement of the growth rate in the presence of PVP at lower temperatures due to the time involved for the experiment. It would thus be of interest to study the impact of a



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polymer on a different and faster growing polymorphic system where the fast growth mode is not observed.

Conclusions The felodipine form I polymorph shows both surface enhanced crystal growth and an enhanced bulk growth rate as Tg is approached. In contrast, the form II polymorph could not be grown at the surface, and showed a smooth decrease in growth rate with a reduction in temperature to temperatures lower than Tg. The growth rate of the stable form I polymorph was substantially higher than that of the metastable form II polymorph. PVP reduces the bulk growth rate of each polymorph by approximately the same extent suggesting that faster growing crystals will require more polymer to inhibit crystal growth to negligible values than for more slowly growing crystals. Thus when studying crystallization from amorphous systems, it is important to evaluate which polymorphic form is produced and the subsequent impact of additives on crystal growth.

Acknowledgements We are grateful to AstraZeneca for funding this work.


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Figure 1: Photomicrographs of felodipine form I crystals grown on the free surface at (a) 18°C, (b) 60°C, (c) 90°C and in the bulk between two microscopic coverglasses at (d) 18°C, (e) 60°C and (f) 90°C.



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Figure 2: Crystal growth kinetics of felodipine form I at the free surface (■) and in the bulk (□). The bulk growth rate of form II polymorph (▲) from 40-60°C is newly reported. Above 60°C the bulk growth rate has been reported previously 9


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Figure 3: Crystal growth kinetics of felodipine form I from 3% PVP felodipine solid dispersion at the free surface (■) and in the bulk (□). The bulk growth rate of form II polymorph (▲) at 60°C is newly reported. Above 60°C the bulk growth rate has been reported previously.8



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Figure 4: Ratio of the growth rates of felodipine in the absence of any polymer to felodipine in the presence of 3% PVP for form I (■) and form II ( ) as a function of temperature.


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References (1) Law, D.; Schmitt, E. A.; Marsh, K. C.; Everitt, E. A.; Wang, W. L.; Fort, J. J.; Krill, S. L.; Qiu, Y. H. J. Pharm. Sci. 2004, 93, 563. (2) Kennedy, M.; Hu, J.; Gao, P.; Li, L.; Ali-Reynolds, A.; Chal, B.; Gupta, V.; Ma, C.; Mahajan, N.; Akrami, A.; Surapaneni, S. 2008, 5, 981. (3) Wu, T.; Yu, L. J. Phys. Chem. B. 2006, 110, 15694. (4) Ishida, H.; Wu, T. A.; Yu, L. A. J. Pharm. Sci. 2007, 96, 1131. (5) Zhu, L.; Wong, L.; Yu, L. Mol Pharm 2008, 5, 921. (6) Ford, J. L. Pharm .Acta. Helv. 1986, 61, 69. (7) Serajuddin, A. T. M. J. Pharm. Sci. 1999, 88, 1058. (8) Kestur, U. S.; Lee, H.; Santiago, D.; Rinaldi, C.; Won, Y.-Y.; Taylor, L. S. Cryst Growth Des 2010, 10, 3585. (9) Kestur, U. S.; Taylor, L. S. Crystengcomm 2010, 12, 2390. (10) Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L. Langmuir 2007, 23, 5148. (11) Zhu, L.; Jona, J.; Nagapudi, K.; Wu, T. Pharm Res 2010, 27, 1558. (12) Wu, T.; Yu, L. Pharm Res 2006, 23, 2350. (13) Sun, Y.; Xi, H. M.; Chen, S.; Ediger, M. D.; Yu, L. J. Phys. Chem. B. 2008, 112, 5594. (14) Sun, Y.; Xi, H.; Ediger, M. D.; Yu, L. J. Phys. Chem B 2008, 112, 661. (15) Sun, Y.; Zhu,L.; Kearn, K.L.; Ediger, M.D, Yu,L.; PNAS 2011, 108(15): p. 5990-5995. (16) Zhu, L.; Brian, C.; Swallen, S.; Straus, P.; Ediger, M.; Yu, L. Phys Rev Lett 2011, 106, 256103. (17) Kestur, U. S.; Ivanesivic, I.; Alonzo, D. E.; Taylor, L. S. Powder Technol 2013, 236, 197. (18) Hikima, T.; Adachi, Y.; Hanaya, M.; Oguni, M. Phys Rev B 1995, 52, 3900. (19) Ediger, M. D.; Harrowell, P.; Yu, L. J Chem Phys 2008, 128, 034709. (20) Surov, A. O.; Solanko, K. A.; Bond, A. D.; Perlovich, G. L.; Bauer-Brandl, A. Cryst Growth Des 2012, 12, 4022. (21) Rumondor, A. C. F.; Stanford, L. A.; Taylor, L. S. Pharm Res 2009, 26, 2599. (22) Mullin, J. W. Crystallization; 4th ed.; Butterwoth, Heinemann: Oxford, UK, 2001; (23) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Crystengcomm 2012, 14, 6503. (24) Kubota, N.; Yokota, M.; Mullin, J. W. J. Crystal Growth 1997, 182, 86. (25) Kubota, N.; Yokota, M.; Mullin, J. W. J. Crystal Growth 2000, 212, 480.



For Table of Contents Use Only

1E-6

Tg 1E-7

1E-8

Growth Rate (m/s)

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

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Polymorph I surface crystal

1E-9

Polymorph I bulk crystal

1E-10

Polymorph II

bulk crystal

1E-11

1E-12

20

40

60

80

100

o

Temperature ( C)

The felodipine form I polymorph shows both surface enhanced crystal growth and an enhanced bulk growth rate as Tg is approached. The form II polymorph showed a smooth decrease in growth rate with a reduction in temperature to temperatures lower than Tg. This behavior is sustained in the presence of a polymeric additive.


Evaluation of the Crystal Growth Rate of Felodipine Polymorphs in the

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