Synthesis, Conformational Polymorphism, and Construction of a G-T Diagram of 2-[(2-Nitrophenyl)amino]-3-thiophenecarbonitrile Hui
Li,*,†
Joseph G. Stowell, Thomas B.
Borchardt,‡
and Stephen R. Byrn
Department of Industrial and Physical Pharmacy, Purdue UniVersity, 575 Stadium Mall DriVe, West Lafayette, Indiana 47907-2051
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 11 2469-2474
ReceiVed NoVember 15, 2005
ABSTRACT: 5-Nor-Me was prepared by a two-step synthesis. A disappearing polymorph, the yellow form (Y), was observed during synthesis, but pure Y could not be obtained with further purification by crystallization. The other two forms, red (R) and orange (O), were prepared by crystallization from tetrohydrofuran (THF) and absolute ethanol, respectively. Single-crystal structure data show that the 5-Nor-Me molecules in R and O have significantly different conformations; the thiophene ring and phenyl ring in 5-Nor-Me R are more planar than those in 5-Nor-Me O. The physical stabilities of 5-Nor-Me O and R were determined using X-ray powder diffraction (XRPD), thermal analysis, hot-stage microscopy, solubility determination, and calculation of lattice energy. DSC shows no difference for the R and O forms. The equilibrium melting point of R is shown to be 0.6 °C higher than O, and the lattice energy of R is lower than O. Slurry conversion studies indicate that R is more stable than O in the investigated temperature range (25-80 °C). Solubility data fit the van’t Hoff equation for both forms; the transition temperature from O to R was determined to be above both melting points, indicating that O and R are monotropically related, with R being more stable in the solid state. The free-energy difference was small (∼200 J/mol) according to the normalized G-T diagram. Transformation from 5-Nor-Me O to R occurred only when R seeds (0.2%) were added, accompanied by grinding in Wig-L-Bug. Therefore, seeding could play a very important role in the crystallization process; the Y form could not be obtained once the more stable R or O seeds appeared in the lab. Introduction A polymorph is a solid crystalline phase of a given compound with at least two different arrangements of the molecules of that compound in the solid state.1 The crystal structure adopted by a given compound when it is crystallized normally exerts a profound effect on the solid-state properties of that system. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal hardness, crystal shape and color, refractive index, electrolytic conductivity, melting or sublimation properties, latent heat of fusion, heat of solution, solubility, dissolution rate, enthalpy of transitions, phase diagrams, stability, hygroscopicity, and rates of reactions are all determined primarily by the nature of the crystal structure.2 Regulatory authorities have become extremely interested in questions pertaining to polymorphism. A strategic approach to the evaluation of polymorphic behavior has been advanced that contains a number of decision trees designed to guide workers at the preformulation stage.3,4 The pharmaceutical industry recognizes the importance of investigating the polymorphism phenomenon.1, 5-7 Conformational polymorphism is a subset of polymorphism in which molecules are folded into different three-dimensional conformations, which then can then be packed into alternative crystal structures. Conformational polymorphism may lead to color and other spectral differences between polymorphs. One excellent example is 5-methyl-2-[(2-nitrophenyl)-amino]-3thiophenecarbonitrile, nickednamed “ROY”, for being initially crystallized as three color polymorphs, red (R), orange (O), and Yellow (Y). Now there are at least eight solvent-free poly* To whom correspondence should be addressed. E-mail:
[email protected]. Phone: 425-489-4799. Fax: 425-486-0300. † Current address: ICOS Corporation, 22021 20th Ave. SE, Bothell, WA 98021. ‡ Current address: Abbott Laboratories, 1401 Sheridan Rd., North Chicago, IL 60064.
morphs, which can be distinguished by crystal colors and shapes. Their relative thermodynamic stability was determined using melting and eutectic melting data.8,9 Its derivatives are also shown to exhibit conformational color polymorphism.10,11 One of these derivatives, 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (5-Nor-Me), is studied here. 5-Nor-Me has three polymorphs: red (R), orange (O), and yellow (Y). During the synthesis, it was found that Y is an appearing/disappearing polymorph; this phenomenon is addressed by several authors.12-16 Because no pure Y could be obtained by usual crystallization techniques, we do not study Y here. The objective of this study is to determine the relative thermodynamic stability of 5-Nor-Me R and O and to construct a quantitative energy-temperature (G-T) diagram. The importance of seeding on the physical stability was also addressed. Experimental Section Materials. 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was synthesized in two steps, shown in Scheme 1. To synthesize 2-amino-3-thiophenecarbonitrile, we suspended 2 mol of malonitrile (136 g, Aldrich) and 1 mol of 1,4-dithiane-2,5-diol in 1 L of ice-water, with an initial pH of 3 adjusted by concentrated HCl. The pH was then adjusted to 12-13 over 20 min by the addition of aqueous sodium hydroxide solution (25 wt %). Ice was added into the mixture to maintain the temperature at 10 °C. The mixture was allowed to react for 2 h, and the resulting light brown solids were collected by vacuum filtration and dried in the hood overnight. The dried solids were purified by column chromatography using neutral aluminum oxide (150 mesh, 50 Å, Aldrich) as the absorbent and 80% ethyl acetate/ 20% methylene chloride as the eluent. The pale yellow band corresponding to the products was collected and dried on a rotary evaporator. The resulting solids were dissolved in boiling benzene, and pale white crystals were collected after cooling. The crystals were collected by vacuum filtration, dried in the hood overnight, and stored in -20 °C to prevent degradation. Yield: 70.08 g (64%). To synthesize 2-[(2-nitrophenyl)amino]-3-thiophenecarbontrile, we prepared two solutions separately. Solution 1: 1 mol of 2-amino-3thiophenecarbonitrile (124 g) and 1 mol of 2-fluoro-1-nitrobenzene
10.1021/cg050608p CCC: $33.50 © 2006 American Chemical Society Published on Web 10/05/2006
2470 Crystal Growth & Design, Vol. 6, No. 11, 2006 Scheme 1. Synthesis of 2-[(2-Nitrophenyl)amino]-3-thiophenecarbonitrile (5-Nor-Me)
(Aldrich) were dissolved in 300 mL of tetrahydrofuran (THF) in an addition funnel. Solution 2: 80 g of sodium hydride (NaH, 60% dispersion, 2.0 equiv, Aldrich) was suspended in 250 mL of anhydrous THF. Solution l was added to solution 2 dropwise, and the resulting dark purple mixture was allowed to stir overnight. The mixture was poured onto 2 L of icy distilled water and neutralized with 60 mL of concentrated HCL. A total of 6 L of methylene chloride was used to extract the mixture three times, using 2 L each time. The combined organic layer was washed with distilled water twice in a total amount of 6 L. The solution was then charged to silica (around 500 mL, 230400 mesh, 40-60 µm, acid-washed, Aldrich) on a rotary evaporator. Half of the charged silica was applied on top of a silica column, and eluted with a gradient of hexane/methylene chloride solutions. The gradient of hexane/methylene chloride used was 2 L each of each 100% hexanes, 80/20 hexanes/methylene chloride, 60/40 hexanes/methylene chloride, and 12 L of 40/60 hexane/methylene chloride. The band corresponding to 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was collected and dried on a rotary evaporator. The final product was obtained by recrystallization of the above dried solids from absolute ethanol. Yield: 47 g (38.4%). Elemental anal. Calcd: C, 53.9; H, 2.9; N. 17.1. Found: C, 53.69; H, 2.82; N, 16.89. Preparation of Polymorphs. 5-Nor-Me was found to have three anhydrous polymorphs by polymorph screening. A heating and cooling method was used for crystallization. Around 10 g of 5-Nor-Me was dissolved in 50 mL of organic solvent by heating to 60 °C, and the resulting solution was allowed to cool with no seeds added. Precipitate was collected by filtration and dried overnight in vacuo. The red form (R) was crystallized from tetrahydrofuran (THF). The orange form (O) was crystallized from absolute ethanol solution. The yellow (Y) form could not be obtained by crystallization methods, as it was an appearing/ disappearing polymorph during synthesis. Crystal Structure Determination. A Nonius Kappa CCD diffractometer with Mo-KR radiation (λ ) 0.71073 Å) was used to acquire the data. The structures were solved by direct methods using SIR97,17 and refinements were performed using the program SHELX-97.18 X-ray Powder Diffraction (XRPD). The XRPD patterns of the samples were obtained using a Siemens D500 Crystalloflex diffractometer equipped with a Kevex psi peltier cooled silicon (Si(Li)) detector. Cu KR radiation (20 mA, 40 kV), scan range 5-40° and scan rate 0.6°/min with step size 0.02°, was used. Powdered samples were packed into the well of the aluminum holders, which were made in house. Fourier Transform Infrared Spectroscopy (FT-IR). A KBr disk was pressed after mixing 2 mg of 5-Nor-Me R or O with 300 mg of dry KBr powder. The experiments were run on a Nicolet Magna IR spectrometer 550. Differential Scanning Calorimetry. The DSC instrument (model 2920, TA Instruments) was calibrated with indium for the baseline, cell constant, and temperature. Samples (2-5 mg) were loaded onto an aluminum pan and hermetically sealed. The heating rate was 5 °C/ min. Dry nitrogen was used to purge the system (25 mL/min). The average heat of fusion was reported from three independent measurements. Hot-Stage Microscopy. A Zeiss microscope (Germany) with a Mettler hot-stage chamber was used to observe the thermal events
Li et al. (transformation and melting) of samples placed on a glass slide covered with cover glass. Calculation of Lattice Energy. Lattice energy of the R and O forms were calculated using Cerius2 version 4.0. The total charge of an individual molecule in the crystal lattice was assigned to zero, and a Dreiding (DREIDING 2.21) force field was loaded to perform the calculation. The heat of transformation at absolute-zero temperature was the difference of the lattice energy between these two forms. Solubility Studies. The solubility of R and O in anhydrous ethanol was measured at six investigated temperatures: 22.5, 27.8, 32, 40, 45, and 49.8 °C. Three 15 mL scintillation vials used for holding 5-NorMe ethanol solutions were put in a jacketed beaker water bath, and the temperature was controlled by a programmable circulator (Fischer Scientific). Ten milliliters of anhydrous ethanol was put into each of the three vials and equilibrated at the investigated temperatures for 30 min. An excess amount of the O or R form was put into the first two vials, respectively, and a thermometer was put inside the third vial to get an accurate temperature reading. The solutions were stirred all along and settled for 5 min before sampling. The supernatant was withdrawn with a needled syringe and filtered through a 0.45 µm membrane (Nylon, Alltech). No absorption was observed for the membrane. The filtered samples were quickly diluted 10-40 times using the HPLC mobile phase in order to be in the accurate range of the UV detector. The concentrations were determined using an HPLC method. Aliquots were withdrawn at various time intervals and it showed that solution reached equilibrium solubility in 1 h (data not shown). Here, the solubility values at 5 h were used in the calculation. The remaining solids were collected afterward and tested using X-ray powder diffraction. No phase transformation was observed during the course of the study. High-Performance Liquid Chromatography (HPLC). A Rainin HPLC system was used that consisted of a HPXL solvent delivery system, a Dynamax model UV-D II UV detector, and a Dynamax autosampler. A Beckmann ultrafine 5 µ C18 reverse-phase HPLC column (4.6 × 250 mm) was used together with a guard column (Alltech, C18, 4.6 × 7.5 mm). The flow rate used was 1 mL/min with an injection of 10 µL and a wavelength of 215 nm. The mobile phase used was 60/40 (v/v) acetonitrile/water. A linear standard curve of peak area versus concentration of the standard samples was constructed. The concentration of an unknown sample was then calculated. Slurry Conversion. Slurry conversion studies were carried out in the range of 20-80 °C. For 20 and 60 °C, anhydrous ethanol was used as the solvent, whereas for 80 °C, a 50/50 water/ethanol mixture was used. Ten milliliters of solutions with a slightly visible amount of solids was equilibrated at the investigated temperatures, and 2 g of an O/R mixture in a 50/50 ratio was added. The suspensions were allowed to stir until there were no more visual color changes. The solutions were allowed to settle for 20 min. The solids on the bottom were withdrawn using glass tubing and filtered by vacuum. The solids remaining on the top of the filter were packed into an aluminum holder for XRPD. Grinding of 5-Nor-Me Form O. Form O with 0.2% R was ground using Wig-L-Bug model 3100A (Cresent Dental) for 8 min. Transformation was investigated using XRPD.
Results and Discussions O and R under the Microscope. Figure 1 shows the morphology of O and R forms under the microscope. By slow evaporation from methyl tert-butyl ether, both R and O crystals are produced with different morphologies: R crystals are plates, whereas O crystals are needles.
Figure 1. 5-Nor-Me R (left) and O (right) crystals under the microscope.
Synthesis, Polymorphism, and G-T Diagram of 5-Nor-Me
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Table 1. Crystallographic Data and Selected Bond Lengths and Bond Angles for R and O Polymorphs of 5-Nor-Me
space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) Z dcalcd (g cm-3) V (Å3) C11-N1-C21-S (deg) C11-N1-C21-C22 (deg) C21-N1-C11-C16 (deg) C21-N1-C11-C12 (deg) C24-S-C21-N1 (deg) C23-C22-C21-N1 (deg) C11-N1-C21 (deg) angle between rings (deg) N1-C21 (Å) intramolecular H-bond N‚‚‚O (Å) N‚‚‚H (Å)
5-Nor-Me R
5-Nor-Me O
C2/c 13.8617 8.7921 17.511 90.0 96.1 90.0 8 1.535 2121 4.0 175.7 0.8 -179.7 179.8 -179.9 132.8 5.01 1.362
P1 3.9331 7.1080 10.154 75.949 78.08 87.372 1 1.510 269.43 52.5 -134.6 4.9 -174.7 173.9 -173.6 125.1 53.8 1.412
2.60 1.97
2.61 1.63
Crystal Structure of R and O Forms. Table 1 shows the cell parameters and selected bond angles and bond lengths of these two forms. R belongs to the monoclinic system, whereas O belongs to the triclinic system. According to the density rule, the more tightly packed crystal with higher density is more stable.19,20 The density of R is higher than that of O, indicating that R is probably more stable. The crystal packing of the two forms is shown in Figure 2. The molecular conformations in R and O crystals are distinct when torsion angles between the thiophene and phenyl rings are compared, with O’s (53.8°) being much higher than R’s (5.01°) (refer to Figure 3 and Table 1). Furthermore, the planarity of the nitrogen in amino group and the thiophene ring also differ significantly. The nitrogen in the amino group is 52.5° out of the plane of the thiophene ring in 5-Nor-Me O, compared to 4.0° in 5-Nor-Me R. Because the molecule becomes more planar in 5-Nor-Me R, the increased overlap of the nitrogen in the amino group and the thiophene π-orbital shortens the N1-C21 bond from 1.412 to 1.362 Å. The FT-IR spectra are shown in Figure 4. The increase in planarity in 5-Nor-Me R can also be revealed by the shift of the N-H to lower frequency than 5-Nor-Me O, 3292 to 3206 and 3267 cm-1 (Table 2). No inter- or intramolecular hydrogen bonding is observed for either R or O in the crystal structure. X-ray Powder Diffraction. Figure 5 shows the calculated and experimental XRPD of R and O, indicating that experimental XRPD are consistent with the XRPD calculated from the crystal structures although experimental XRPD have background noise. At the same time, they also show that these two forms have very distinct XRPD, which can be used to monitor the phase transformation. Measurement of Equilibrium Melting Temperature of 5-Nor-Me R and O by Hot-Stage Microscopy. The meltng
Figure 2. Stereoview of crystal packing of 5-Nor-Me R (top) and O (bottom) forms.
Figure 3. Stereoview of molecular conformations of 5-Nor-Me R (top) and O (bottom) forms.
points of R and O were initially tested on DSC with the heating rate of 5 °C/min but showed no difference (Table 4). An alternative method, hot-stage microscopy, was used. Its versatility in temperature setting and heating rate adjustment fits better for this case, and equilibrium melting points, which are independent of heating rate, can be measured. The equilibrium temperature is the temperature at which the solid crystal and liquid phases are in equilibrium, i.e., when the temperature is increased a little, the crystal will “dissolve” in the already-melted droplets, whereas if it is decreased a little, the crystal will grow. The particically melted R and O crystals are shown in Figure 6, showing that there is no polymorphic conversion during melting, which affects measurement accuracy. The melting points were determined to be 132.3 ( 0.1 °C and 131.7 ( 0.1 °C for R and O, respectively. Thus, the melting point of R is 0.6 °C higher than that of O, indicating that the R crystal lattice is more stable than the O crystal lattice. Slurry Conversion Studies. Slurry mixtures of R and O transform into R completely in 12 h, indicating that at the studied temperature range 20-80 °C, R is always more stable than O thermodynamically (Figure 7). Solubility Studies of 5-Nor-Me R and O. Table 3 shows the equilibrium solubility data of both forms at the six investigated temperatures. The remaining solids were collected
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Figure 4. FT-IR of 5-Nor-Me O and R.
Figure 5. Cerius2 calculated and experimental XRPD patterns for 5-Nor-Me O and R. Table 2. Selected Vibrational Frequencies (cm-1) for the 5-Nor-Me O and R
nitro-symmetric aromatic amine nitro-asymmetric thiophene benzene ring benzene νCN νNH
5-Nor-Me O
5-Nor-Me R
1250.5,1280.5 1338.2 1499.1,1521.3 1549.3 1577.3 1617.1 2221.2 3292.0
1238.8,1278.0 1345.1 1518.2,1502.0 1551.0 1590.2 1616.5 2211.6 3205.5,3167.4
Table 3. Solubility Data for 5-Nor-Me R and O T (°C)
R, Cs (mg/mL)
O, Cs (mg/mL)
22.5 27.8 32.0 40.0 45.0 49.8
2.335 ( 0.005 2.834 ( 0.045 3.510 ( 0.059 5.191 ( 0.166 6.579 ( 0.093 8.129 ( 0.137
2.595 ( 0.007 3.062 ( 0.042 3.818 ( 0.059 5.631 ( 0.055 7.061 ( 0.121 8.705 ( 0.124
afterward and tested using X-ray powder diffraction. Results showed that no polymorphic transformation occurred during the course of study (data not shown). From the experimental data, O always has a higher solubility than R, indicating that R is a
Figure 6. Hot-stage microscopy: partially melted 5-Nor-Me R (left) and O (right).
thermodynamically more stable phase than O. The small standard deviations imply that the developed HPLC method is suitable for measuring the concentration of 5-Nor-Me in ethanol solution. The obtained solubility data were fitted into the van’t Hoff equation (ln Cs ) a + bT-1) to calculate the heat of fusion, transition temperature, heat of transformation, etc. (see Figure 8).21 A linear relationship, shown in Figure 6, was obtained for both forms, with good correlation coefficients (0.9972 for R and 0.9954 for O). The transition temperature is determined to be 139.1 °C, which is above both of the melting points.
Synthesis, Polymorphism, and G-T Diagram of 5-Nor-Me
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Figure 7. XRPD patterns of slurry conversion studies of 5-Nor-Me R/O pair. From bottom to top: O, R, R/O 50:50 mixture, slurry at 20 °C, slurry at 60 °C, and slurry at 80 °C.
Figure 8. van’t Hoff plot of 5-Nor-Me R (bottom) and O (top).
Figure 9. Energy-temperature (G-T) diagram of 5-Nor-Me O and R, normalized to R.
Table 4. Summary of Physical Parameters of 5-Nor-Me R and O 5-Nor-Me R lattice energy (kcal/mol) Htr (lattice energy, kcal/mol) melting point (hot-stage) melting point (DSC) Hf (DSC, kJ/mol) Hsolu (solubility, kJ/mol) Htr (solubility, kJ/mol) Ttr (solubility, °C)
-2.2139 132.3 ( 0.1 134.57 ( 0.29 30.35 ( 0.36 36.265 -
5-Nor-Me O -0.7696 1.4443 131.7 ( 0.1 134.56 ( 0.14 30.39 ( 0.38 37.105 0.84 139.1
Therefore, R and O are monotropically related, with R being the stable form. According to the equation ∆G ) RT ln(Cs(O)/Cs(R)),22 the free-energy difference can be calculated and a normalized energy-temperature (G-T) diagram can be constructed (see Figure 9). O always has higher free energy than R. The G-T diagram gives a quantitative view to the stability of these two forms. Thermodynamic data of both forms are summarized in Table 4. In summary, O and R are monotropically related, with R being the stable form. The heat of transformation is positive
from both lattice energy data and solubility data; heat is given off during transformation, which is quite typical for monotropic systems. There is no difference in heat of fusion and melting temperature on DSC for O and R, probably because the normal heating rate of 5 °C/min cannot distinguish O from R. Measurement of equilibrium temperature using a hotstage is a better technique than DSC, because a very slow heating rate (0.1 °C/min) can be used, during which one can see the crystal growth and melting under the microscope during temperature decrease/increase. And at the same time, the solubility and slurry conversion studies gave us enough information to analyze the physical stability of these two forms. Seeding To Initiate the Transformation. According to the above data, it was shown that the free energy difference of R and O is very small (∼0.2 kJ/mol). Thus, it might be assumed that the transformation from O to R may be very fast. However, it was found that the transformation is virtually impossible for the pure O sample, either by vigorous grinding by Wig-L-Bug (30 min) or at 105 °C. To initiate this transformation, we mixed 0.2% R seeds, which is below the detection limit of XRPD, with O before grinding or heating. The transformation from O
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Figure 10. Seeding effect on transformation of 5-Nor-Me O to R.
to R was observed (see Figure 10), indicating that seeding is necessary to initiate this transformation. During the synthesis of 5-Nor-Me, a third form (yellow, Y) was initially obtained, but it disappeared with further crystallization. Because seeding plays a very important role in the transformation, it is hypothesized that very unstable Y was unable to be produced; existence of R or O seeds in the lab area, even a trace amount, caused rapid transformation of Y to R or O forms. It is believed that the appearance and disappearance of Y is associated with the impurity level during the synthesis; this phenomenon needs further investigation, possibly by controlling its crystallization with a certain level of tailor-made impurity incorporated. In addition, control of crystallization to produce either R or O is out of the scope of this study and remains to be investigated as well. Pure O polymorph does not transform to R in either solution or solid state; thus, the metastable O form may be formulated instead of R because O is “kinetically” stable. The O form has higher solubility and does not transform to R during processing if direct compression or encapsulation is used instead of wet granulation, which may show solution-mediated transformation.
Conclusions The molecular conformations in 5-Nor-Me O and R are different, with the thiophene ring and phenyl ring in R being more coplanar. The physical stability of polymorphs R and O of 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (5-Nor-Me), using X-ray powder diffraction (XRPD), thermal analysis, hotstage microscopy, solubility determination, and calculation of lattice energy, was determined. R and O are monotropically related, with R being the stable form. The third form, Y, could not be obtained at this stage. Transformation from 5-Nor-Me O to R occurred only when R seeds (0.2%) were added, accompanied by grinding in Wig-L-Bug. Therefore, seeding could play a very important role in the crystallization process.
Acknowledgment. H.L. thanks the Purdue/Michigan/ Wisconsin Program for the Study of the Chemical and Physical Stability of Solid Pharmaceuticals and the Purdue Research Foundation for funding. The authors thank Dr. Phil Fanwick in the Chemistry Department at Purdue University for solving the single-crystal structures. References (1) Haleblian, J.; McCrone, W. J. Pharm. Sci. 1969, 58, 911-29. (2) Giron, D. S. T. P. Pharma. 1990, 6, 87-98. (3) Byrn, S.; Pfeiffer, R.; Ganey, M.; Hoiberg, C.; Poochikian, G. Pharm. Res. 1995, 12, 945-954. (4) Yu, L.; Reutzel, S. M.; Stephenson, G. A. Sci. Pharm. 1998, 1, 118127. (5) Haleblian, J. K. J. Pharm. Sci. 1975, 64, 1269-88. (6) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs, 2nd ed.; SSCI, Inc.: West Lafayette, IN, 1999. (7) Pharm. J. 1992, Oct 10, 479. (8) Chen, S.; Guzei, L. A.; Yu, L. J. Am. Chem. Soc. 2005, 127 (27), 9881-9885. (9) Yu, L.; Stephenson, G. A.; Mitchell, C, A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G.; Byrn, S. R. J. Am. Chem. Soc. 2000, 122, 585-591. (10) He, X.; Griesser, U. J.; Stowell, J. G.; Borchardt, T. B.; Byrn, S. R. J. Pharm. Sci. 2001, 90 (3), 371-388. (11) Borchardt, T. B. Ph.D. Thesis, Purdue University, West Lafayette, IN, 1997. (12) Blagden, N. Powder Technol. 2001, 121 (1), 46-52. (13) Henck, J.-O.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123 (9), 1834-1841. (14) Blagden, N.; Davey, R. J.; Rowe, R.; Roberts, R. Int. J. Pharm. 1998, 172 (1-2), 169-177. (15) Bernstein, J.; Henck, J. O. Cryst. Eng. 1998, 1 (2), 119-128. (16) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28 (4), 193-200. (17) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Burla, M. C.; Polidori, G.; Camalli, M.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115-119. (18) Sheldrick, G. M. SHELX-97, A Program for Crystal Structure Refinement; University of Go¨ttingen: Go¨ttingen, Germany, 1997. (19) Kitaigorodsky, A. I. Molecular Crystals and Molecules; Academic Press Inc.: New York, 1973. (20) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 159-271. (21) Alexander, K. S.; Laprade, B.; Mauger, J. W.; Paruta, A. N. J Pharm. Sci. 1978, 67, 624-627. (22) Grant, D. J. W.; Brittian, H. G. Physical Characterization of Pharmaceutical Solids; Marcel Dekker: New York, 1995.
CG050608P
