Conformational Polymorphs of a Muscle Relaxant, Metaxalone

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Conformational Polymorphs of a Muscle Relaxant, Metaxalone Srinivasulu Aitipamula,*,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †

Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833 ‡ Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576

bS Supporting Information ABSTRACT: Metaxalone (MTX) is a muscle relaxant which is used to relieve pain caused by strains and sprains. MTX has been in the market under the brand name of Skelaxin since 1962, and two polymorphs of MTX were first mentioned in a patent published in 2007. However, their crystal structures, stability relationship, and dissolution profiles have not yet been analyzed. We herein report two conformational polymorphs of racemic MTX with an objective to unravel the structural origin of polymorphism and study their phase transformations, stability, solubility, and dissolution properties. Both forms were obtained concomitantly by cooling crystallization experiments from ethyl acetate. Crystal structure analysis revealed that the MTX molecule adopts different conformations in the polymorphs. Interestingly, the imide group of the MTX forms an imideimide catemer synthon in Form A and an imideimide dimer synthon in Form B. Thermal analysis and solubility measurements suggest an enantiotropic relationship between the polymorphs with Form B being the thermodynamically stable form at ambient conditions. The metastable Form A converts to stable Form B in slurry and solid-state grinding experiments and dissolves faster than the stable Form B at 37 °C.

’ INTRODUCTION A thorough characterization of pharmaceutical solids, such as polymorphs, salts, hydrates, solvates, cocrystals, etc., is of fundamental importance in pharmaceutical applications to devise a robust and reliable process.1 Among the various solid forms, polymorphs, which represent alternative arrangements of the same molecular entity in the crystal lattice, draw a special attention because they may exhibit different pharmaceutically relevant properties and also because of the economic significance that they may have in terms of intellectual property.24 Metaxalone (5-[(3,5-dimethylphenoxy)methyl]-1,3-oxazolidin-2-one, hereafter MTX, Figure 1) is a muscle relaxant used to relieve pain caused by strains and sprains.5 It is used as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. It is considered to be a moderately strong muscle relaxant, with relatively low incidence of side effects.6 New therapeutic applications of MTX have been recently reported for the treatment of diabetic neuropathy7 and chronic daily headache.8,9 MTX was approved for therapeutic use in 196210 and has been produced by Elan Pharmaceuticals, Inc. under the brand name of Skelaxin and distributed by King Pharmaceuticals. Although MTX has not yet been classified according to biopharmaceutics classification system (BCS), it has been suggested that it belongs to Class II drugs having low solubility and high permeability.11 The commercially available MTX tablets contain 400 and 800 mg of MTX along r 2011 American Chemical Society

Figure 1. Chemical diagram of MTX with atom numbering (τ1, τ2, and τ3 are torsion angles representing C9O1C1C2, C1O1C9 C10, and O1C9C10O2, respectively).

with inert compression tableting excipients.12 MTX also features in the top 200 U.S. oral drug products list.13 The existence of polymorphism in MTX has been reported in the patent literature,12 which revealed two forms (A and B) that are characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR) spectroscopy. More recently, the unit cell parameters for one of the polymorphs has been reported in a patent.14 In spite of MTX being in therapeutic use for the last 50 years, it is surprising that crystal structures of its polymorphs, their stability and polymorphic phase transformations, and their dissolution properties Received: May 29, 2011 Revised: July 14, 2011 Published: August 04, 2011 4101

dx.doi.org/10.1021/cg200678e | Cryst. Growth Des. 2011, 11, 4101–4109

Crystal Growth & Design

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Table 1. Crystal Data for MTX Polymorphs MTX

Figure 2. A microscopic image of crystals of MTX Form A (plates) and B (needles) that were obtained concomitantly from ethyl acetate.

Figure 3. Comparison of experimental PXRD patterns of MTX polymorphs.

have not yet been studied. In this contribution, we report the X-ray crystal structures and characterization of both forms by various analytical techniques, such as PXRD, DSC, thermogravimetric analysis (TGA), hot-stage microscopy (HSM), FT-IR and Raman spectroscopy. In addition, stability attributes of the polymorphs are evaluated by solubility and dissolution experiments. The naming of MTX polymorphs is not consistent in the patent literature; Form A of one patent is named as Form B in the other.12,14 We follow the naming system that was followed in the first patent on MTX polymorphs.12

’ RESULTS AND DISCUSSION When the crystallization was conducted in ethyl acetate, crystals of different morphologies (plate and needle) were obtained concomitantly (Figure 2). The crystals were manually separated, and a PXRD analysis on these samples confirmed that the plate-like crystals belong to Form A, and the needle-shaped crystals belong to Form B. The PXRD patterns of the polymorphs are significantly different and are used as reference throughout this study (Figure 3). Interestingly, concomitant crystallization15 was observed only when the crystallization was conducted in ethyl acetate. Crystallization of MTX from various other common organic solvents resulted in the formation of Form A. However, Form B can be selectively prepared by mechanical

Form A

Form B C12H15NO3

chemical formula

C12H15NO3

formula mass

221.25

221.25

crystal system

triclinic

monoclinic

a/Å

5.556(1)

10.101(2)

b/Å

10.321(2)

15.505(3)

c/Å

19.819(4)

7.110(1)

R/°

82.82(3)

90.00

β/° γ/°

88.63(3) 82.49(3)

91.23(3) 90.00

unit cell volume/Å3

1117.9(4)

1113.3(4)

temperature/K

110(2)

110(2)

space group

P1

P21/c

no. of formula units per unit cell, Z

4

4

Dcalculated /g cm3

1.315

1.320

no. of reflections measured

15992

8448

no. of independent reflections Rint

5500 0.0251

2690 0.0441

final R1 values (I > 2σ(I))

0.0709

0.0843

final wR(F2) values (I > 2σ(I))

0.1939

0.2315

final R1 values (all data)

0.0755

0.0955

final wR(F2) values (all data)

0.1997

0.2421

grinding of Form A powder with a few drops of an added solvent prior to the grinding (discussed later). Crystal Structure Analysis. Crystal structure of Form A was solved and refined in the triclinic space group P1 with two molecules of MTX in the asymmetric unit (Z0 = 2) (Table 1) and both the molecules have S-configuration. As shown in Figure 4a, the imide group of the symmetry independent MTX molecules of the same configuration forms an imideimide catemer synthon that involves NH 3 3 3 O (2.844 Å, 160°; 2.844 Å, 159°, Table 2) hydrogen bonds and generates one-dimensional (1D) infinite chains along the crystallographic a-axis. The 1D chains of opposite chirality are connected in the crystal structure via various CH 3 3 3 O (2.552.63 Å, 144150°) interactions. Crystal structure of Form B was solved and refined in the monoclinic, P21/c space group with one molecule of MTX in the asymmetric unit (Z0 = 1) and the molecule has S-configuration. The crystal structure is significantly different from the crystal structure of Form A; the molecules of different configuration are now involved in centrosymmetric imideimide dimer synthon formation via NH 3 3 3 O (2.867 Å, 160°) hydrogen bonds (Figure 4b). The resulting dimeric motifs are arranged in herringbone fashion and connected via intermolecular CH 3 3 3 π interactions. The polymorphs of MTX can be best described as synthon polymorphs, which represent two or more polymorphs that differ by their different hydrogen bonded synthons in their crystal structures.16 Some well-known polymorphic compounds such as furosemide,17 isonicotinamide,18 and tetrolic acid19 all show differences in their hydrogen bond synthons that represent synthon polymorphs. In the case of MTX polymorphs, Form A is distinguished by an imideimide catemer synthon, whereas Form B is distinguished by an imideimide dimer synthon (Figure 4). The chemical structure of MTX (Figure 1) indicates that the molecule is conformationally flexible and can exist in different conformations in polymorphic structures.20 Indeed the conformations of 4102

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Figure 4. Hydrogen bonding in the MTX polymorphs (a) an imideimide catemer synthon in Form A (b) an imideimide dimer synthon in Form B. Note the symmetry independent molecules of MTX in Form A are shown as stick and ball-and-stick models, and the hydrogen bonded 1D chains are formed with the molecules of different configuration.

Table 2. List of Intermolecular Interactions in the Polymorphs of MTX (Neutron Normalized) MTX

DH 3 3 3 A

Form A

N1H1 3 3 3 O3A N2H1A 3 3 3 O3 C6AH6A 3 3 3 O2 C10H10 3 3 3 O3 C10AH10A 3 3 3 O3 C11H11B 3 3 3 N1 N1H1 3 3 3 O3 C9H9A 3 3 3 O1

Form B

H 3 3 3 A /Å

D 3 3 3 A /Å

DH 3 3 3 A /°

symmetry code

1.88

2.844(2)

160

1 + x, 1 + y, 1 + z

1.88

2.844(2)

159

x, 1 + y, 1 + z

2.63

3.514(2)

139

1 x, 1 y, 1 z

2.59

3.517(2)

144

1 x, 1 y, z x, 1 y, 1 z

2.62

3.556(2)

144

2.55

3.530(2)

150

2 x, 1 y, z

1.90 2.66

2.867(3) 3.505(3)

160 134

2 x, 1 y, 1 z x, 3/2 y, 1/2 + z

Table 3. Torsion Angles (τ, °) of Various Conformers of MTX τ (C9O1C1C2)

MTX Form A

red

Form B

blue green

τ (C1O1C9C10)

2.7(2) 176.5(2) 11.1(3)

MTX molecule in the crystal structures are significantly different. The torsion angles for various MTX conformers are tabulated in Table 3 and the extent of conformational diversity of MTX molecule was highlighted with an overlay of conformers in

τ (O1C9C10O2)

179.1(1)

179.6(1)

167.6(1) 169.4(2)

69.9(2) 179.0(2)

Figure 5. The torsion angles in Table 3 suggest that the conformational difference arises because of the free rotation of the oxazolone ring along the adjacent CC and CO bonds. The two conformers of Form A (red and blue) have distinct 4103



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Table 4. FT-IR and Raman Vibrational Frequencies of MTX Polymorphs NH stretch (cm1)

MTX Form A

FT-IR

Form B

Raman FT-IR Raman

CdO stretch (cm1)

3283

1728, 1738

3239

1714, 1743 1755 1723

Figure 5. An overlay diagram of the conformers found in the polymorphs of MTX, Form A (red and blue) and Form B (green).

Figure 7. Comparison of FT-Raman spectra of MTX polymorphs in the range of 4001800 cm1 (inset shows close up of the Raman spectra in the region 17501700 cm1).

Figure 6. Comparison of FT-IR spectra of MTX polymorphs (inset shows close up of the FT-IR spectra in the region 17801700 cm1).

torsion angles which are also different from the conformer in Form B. Spectroscopic Analysis. FT-IR spectroscopy is often used to obtain information pertaining to the differences in molecular conformation and hydrogen bonding in the solid state. Polymorphic structures containing strong hydrogen bonds, such as NH 3 3 3 O and OH 3 3 3 O hydrogen bonds, can be easily differentiated by IR spectroscopy.21 Comparison of FT-IR spectra of MTX polymorphs is shown in Figure 6. The carbonyl stretching vibration of Form A is observed at two different values, 1728 and 1738 cm1; this could be because of the presence of two symmetry independent molecules in the crystal structure. The same is observed as a single vibration at 1755 cm1 for Form B (Table 4). The NH stretching vibration is observed at 3283 cm1 (Form A) and 3239 cm1 (Form B). These significant differences in the vibrational modes in Forms A and B are due to the differences in the hydrogen bonding in the polymorphs, that is, the imide group of MTX forms a catemer synthon in Form A, but it is involved in imideimide dimer synthon in Form B. In line with the FT-IR data, significant differences are also observed in the Raman spectra for the carbonyl stretching vibration that involved in hydrogen bonding (Figure 7 and Table 4). The NH stretching vibration is not observed in the Raman spectra of both forms. Thermal Analysis. Different thermal behavior has been reported for the same polymorph in different patents on MTX

Figure 8. DSC thermograms of MTX polymorphs A and B recorded at 5 °C min1.

polymorphs (Figures S3S7 of the Supporting Information).12,14 While Form A was found to show a single endotherm in both the patents, Form B showed two endothermic peaks at the melting temperature in one of the patents (Figure S4 of the Supporting Information).12 In the present study, DSC thermograms of Form A and B were recorded using a heating rate of 5 °C min1, and it was found that both forms show a single sharp endotherm in the temperature range of 121123 °C (Figure 8). While the melting endotherm of Form A was observed at 121.9 ( 0.1 °C (ΔHfus = 137.1 J g1), the corresponding endotherm was observed at 4104



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Figure 9. Photomicrographs of Forms A and B at various temperatures in the HSM experiment. Notice that there is no visual change in the crystal morphology of both forms before melting.

122.2 ( 0.1 °C (ΔHfus = 119.3 J g1) for Form B. The heat of fusion values suggest that the polymorphs of MTX are related enantiotropically based on the Burger and Ramberger’s heat of fusion rule of polymorphs, according to which if the higher melting polymorph has a lower heat of fusion to that of the lower melting polymorph then the polymorphs are enantiotropically related.22 The melting of the polymorphs of MTX was also visualized under a HSM. There was no visual change in the crystals before they melt in the temperature range of 124125 °C (Figure 9). The higher melting point values in the HSM experiments compared to DSC experiments were consistently observed (Figure S8 and S9 of the Supporting Information); this could be attributed to the physical nature of the samples used. Whereas the DSC experiments were conducted on powder samples, the HSM experiments were performed on single crystals of the polymorphs. The TGA plots for both the polymorphs show no weight loss before they decompose after 130 °C, indicating that the polymorph samples are free from residual solvent (Figure S10 of the Supporting Information). Even though Form B melts at a slightly higher temperature, a small difference between the melting points of the polymorphs and the absence of an endotherm for polymorphic phase transition in the DSC thermograms make it difficult to judge the exact stability order of polymorphs with respect to the temperature. This prompted us to investigate the possible phase transformations between the polymorphs (discussed next). Stability and Phase Transformations upon Grinding and Slurry Experiments. It is important to determine whether a polymorphic system is enantiotropic or monotropic so as to understand the stability relationship and phase transformations that are possible between the polymorphs. In the case of MTX polymorphs, inconclusive observations from the thermal analysis prompted us to further study the stability relationships. One of the most reliable methods to investigate the stability relationships between polymorphs is to measure their solubility in a solvent at different temperatures and construct a solubility curve.23 In general, the solubility curves for enantiotropic polymorphs intersect at a temperature lower than the melting points

of both the polymorphs. The point of intersection is considered as the thermodynamic transition point. If the solubility curves do not intersect, then the polymorphs are related monotropically. The solubility of MTX polymorphs in the temperature range of 1550 °C was measured in deionized (DI) water, and Figure 10 shows the solubility curve and van’t Hoff plot (log solubility vs the reciprocal of absolute temperature) constructed from these data. It is clear from the van’t Hoff’s plot that the slopes of the solubility curves are different and suggest a cross over point where the solubility of both forms is the same. Extrapolation of the van’t Hoff plots lends a transition point of 272 K (0.69 °C) and confirms that Form A and B are related enantiotropically. Furthermore, Form B is less soluble than Form A above this temperature, and hence it should be the thermodynamically stable form at RT (up to its melting point). Conversely, Form A is less soluble than Form B below the transition temperature, and hence it should be the stable form at lower temperatures. Effect of solid-state grinding during the pharmaceutical formulations and drug development has been well documented. Metastable polymorphs often transform to the more stable polymorph upon grinding. For example, many pharmaceutical compounds have been shown to undergo polymorphic phase transformations upon grinding/milling, some selected examples include, indomethacin,24 cimetidine,25 sulfamerazine.26 In the case of MTX, neat grinding (NG) and solvent-drop grinding (SDG) experiments were conducted on both forms. SDG experiments were conducted by adding two drops of ethyl acetate or methanol to the samples prior to the grinding. Resulting powder samples were analyzed by PXRD for phase identification. Grinding Form A for 30 min results in the complete conversion to Form B; however, under identical experimental conditions Form B remained unchanged (Figure 11). These experiments suggest that it is possible to prepare Form B in a pure form in an environmentally friendly manner using the solvent free/solvent-less techniques such as NG and SDG. The phase transformation from Form A to Form B was also verified by slurry experiments at RT. Excess solids of Form B and a mixture of both the forms were stirred in water for 2 days at RT, 4105



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Figure 10. Solubility curves of MTX polymorphs, (a) solubility vs temperature curve, and (b) van’t Hoff’s plot. Notice the difference between the slopes of the solubility curves in the plots.

Figure 11. Comparison of the PXRD patterns of (a) Form A, (b) Form B, and the solids obtained from (c) NG on Form A, (d) SDG on Form A, (e) NG on Form B, and (f) SDG on Form B.

and the resulting solids were filtered and air-dried. Analysis of the solids by PXRD revealed that Form B remained the same, but the mixture of both forms was completely converted to Form B (Figure 12). These observations indicate that the transformation from the metastable Form A to the stable Form B is mediated by the solvent, and it is reasonable to speculate that such a transformation follows the dissolution of Form A and subsequent growth of the Form B. These observations suggest that the thermodynamic transition point is below RT. The observations made in the grinding and slurry experiments are in good agreement with the van’t Hoff’s plot that Form B is the stable form at RT and the thermodynamic transition point for the phase transformation of Form A to Form B lies below RT. In light of the above definite evidence on the metastable nature of Form A at RT, the absence of an endothermic transition in the DSC of Form A could be due to kinetic reasons. Therefore, we surmise that either the solid-to-solid phase transition is so slow that it cannot be detected by DSC at the scan rate employed or it may not occur. Absence of an endothermic transition in the DSC of a pair of enantiotropic polymorphs is uncommon, but a similar observation has been reported for an anticonvulsant drug,

Figure 12. Comparison of the PXRD patterns of (a) Form A, (b) Form B and the solids obtained in the slurry experiments on a 1:1 mixture of Form A and B (c), and Form B (d).

carbamazepine.27 It was found that solid-to-solid phase transition could be kinetically inhibited when carbamazepine was subjected to high heating rate during DSC analysis.27 Another possible explanation for the uncommon thermal behavior of MTX polymorphs is that the phase transition can occur concomitantly with the melting, and it may not be easily distinguished by the DSC. The inability to detect the transition endotherm in the DSC analysis of the enantiotropic polymorphs of MTX emphasizes the importance of using multiple analytical techniques for the comprehensive characterization of the thermodynamic behavior of polymorphs. Solubility and Intrinsic Dissolution Rate (IDR). The solubility of MTX polymorphs was measured in three different media, DI water, 0.1 N HCl (pH 1.2), and potassium dihydrogen phosphate buffer (pH 7.4), at 37 °C. The equilibrium solubility values are provided in Table 5. In line with the stability order at RT, the equilibrium solubility of Form B is lower than that of the solubility of Form A in all the media. The solubility ratio between the forms of MTX is 1.14 (in DI water), 1.32 (in 0.1 N HCl), and 1.11 (in pH 7.4 buffer). These values are consistent with the general solubility trend of polymorphs which suggest that the ratio of polymorph solubility is typically less than 2.28 The intrinsic dissolution experiments were conducted at 37 °C in 4106



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Table 5. Equilibrium Solubility (mg mL1) and IDR (μg cm2 min1) of MTX Polymorphs equilibrium solubility

IDR

polymorph

water

0.1 N HCl (pH 1.2)

pH 7.4 buffer

0.1 N HCl (pH 1.2)

pH 7.4 buffer

Form A

0.33

0.29

0.30

1.13

1.17

Form B

0.29

0.22

0.27

0.87

0.92

Figure 13. Intrinsic dissolution profiles of MTX polymorphs in 0.1 N HCl (pH 1.2) (left) and pH 7.4 buffer (right). Dissolution profiles up to 4 h were provided in the Supporting Information (Figures S13 and S14).

the 0.1 N HCl (pH 1.2) and pH 7.4 buffer solutions. Figure 13 shows the corresponding dissolution profiles. The intrinsic dissolution rates (IDRs) calculated from 0 to 40 min of the dissolution curve or up to a linear regression of 0.997 are tabulated in Table 5. These values indicate that Form A which is the metastable polymorph at RT dissolves faster than the stable Form B in both the media. Notably, the dissolution of MTX polymorphs is slower at a low pH. The difference in the IDR values in different dissolution media clearly indicates that the dissolution of MTX polymorphs is pH dependent. The samples remained after the dissolution experiments did not show any signs of phase transformation; this was confirmed by analysis of the samples by PXRD and finding that they match with the parent polymorphs (Figures S11 and S12 of the Supporting Information).

’ CONCLUSIONS From a pharmaceutical perspective, knowledge of the relative thermodynamic stability of polymorphs is very important, and if the polymorphs are related enantiotropically the determination of thermodynamic transition point is vital for successful development of a consistent and reliable production for drug development. In this study, we have disclosed the structural origin of polymorphism in racemic metaxalone. The two polymorphs are obtained concomitantly from ethyl acetate, and the conformation of the metaxalone molecule in the crystal structures is different. The hydrogen bonding is significantly different in the polymorphs. The thermal behavior of the polymorphs is investigated with DSC and HSM, but both techniques failed to detect the expected phase transformation from the metastable to the stable polymorph. However, slurry, grinding, and solubility experiments helped to make definite conclusions on the stability relationship and the polymorphic phase transformations. Form B is found to be the thermodynamically stable polymorph at

ambient conditions, and the transition point from metastable Form A to the stable Form B lies below room temperature. Dissolution experiments in different dissolution media indicate that the metastable Form A dissolves faster than the stable Form B at 37 °C.

’ EXPERIMENTAL SECTION Metaxalone was purchased from Junda Pharmaceutical Co., Ltd., China, and used without any further purification. PXRD analysis of the commercial sample revealed that it belongs to Form A. Analytical grade solvents were used for the crystallization experiments. Preparation of Polymorphs by Crystallization. The commercial material that belonged to Form A is in crystalline form, and thus it was directly used for further experiments without any treatment. Crystals suitable for single crystal X-ray analysis were obtained from slow evaporation of an acetonitrile or methanol solution at RT. Form B could be obtained only concomitantly with Form A when the crystallization experiments were conducted in ethyl acetate. In a typical experiment, 15 g of Form A was dissolved in 50 mL of ethyl acetate and resulting solution was refluxed for 30 min. The solution was left at RT for slow evaporation. Plate and needle-shape crystals were obtained concomitantly in 2 days (Figure 2). Microscopic and X-ray diffraction analysis revealed that plate-like crystals belong to Form A and the needles belong to Form B. Form B can also be prepared by solid-state grinding of Form A for 30 min in a ball-mill. Grinding Experiments. Grinding was performed using a Retsch Mixer Mill model MM301 with 10 mL stainless steel grinding jars with one 7 mm stainless steel grinding ball at a rate of 20 Hz for 30 min. Experiments were carried out with 200 mg of material. Liquid-assisted grinding or solvent-drop grinding experiments were carried out by adding ca. 0.05 mL (2 drops from a pipet) of ethyl acetate or methanol to the solids prior to the grinding. The external temperature of the grinding jar after completion of the experiments did not exceed ca. 30 °C. 4107


Crystal Growth & Design Single Crystal X-ray Diffraction. A good quality single crystal grown from the solution crystallization was chosen under a Leica microscope and placed on a fiber needle which was then mounted on the goniometer of the X-ray diffractometer. X-ray reflections were collected on a Rigaku Saturn CCD area detector with graphite monochromated MoKR radiation (λ = 0.71073 Å). Data were collected and processed using CrystalClear (Rigaku) software. Structures were solved by direct methods, and SHELX-TL29 was used for structure solution and least-squares refinement. The non-hydrogen atoms were refined anisotropically. All hydrogen atoms were fixed at idealized positions except for the NH hydrogen which was located from the difference Fourier map and allowed to ride on their parent atoms in the refinement cycles. All NH and CH distances are neutron normalized to 1.009 and 1.083 Å, respectively. X-Seed was used to prepare the packing diagrams. CCDC 827459 and CCDC 827460 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac. uk/conts/retrieving.html and are deposited as Supporting Information. Crystallographic data for the structures described in this paper are listed in Table 1. Details of hydrogen bond distances in the crystal structures are provided in Table 2. Powder X-ray Diffraction (PXRD). The powder materials were identified by D8 Advance powder X-ray diffractometer (Bruker AXS GmbH, Germany) with CuKR radiation (λ = 1.54056 Å). The voltage and current applied were 35 kV and 40 mA, respectively. Samples were placed on the sample holder which has 1 mm thickness and 1.5 cm diameter. The sample was scanned within the scan range of 2θ = 5° to 50° continuous scan, with a scan rate of 2 deg min1. The PXRD patterns were plotted using OriginPro 7.5. Thermal Analysis. DSC was performed with a Perkin-Elmer Diamond DSC with an Autosampler. Crystals taken from the mother liquor were blotted dry on a filter paper and manually powdered. The samples were placed in crimped but vented aluminum sample pans. The sample size was 25 mg and the temperature range was typically 25150 °C at a heating rate of 5 °C min1. The samples were purged with a stream of flowing nitrogen (20 mL min1). The calculated enthalpy values are the averages of three independent experiments. The instrument was calibrated using indium as the reference material. TGA was performed on a TA Instruments TGA Q500 thermogravimetric analyzer. Approximately 15 mg of the sample was added to an alumina crucible. The samples were heated over the temperature range of 25300 °C at a constant heating rate of 5 °C min1. The samples were purged with a stream of flowing nitrogen throughout the experiment at 40 mL min1. Thermomicroscopic investigations were performed with an optical polarizing microscope (Olympus, BX51) equipped with a Linkam hotstage THMS 600 connected to a TMS 94 temperature controller and a LNP 94/2 liquid nitrogen pump (Linkam Scientific Instruments Ltd., Tadworth, Surrey, UK). The microscopic images were recorded with a CCD camera attached to the Olympus BX-51 microscope (Olympus Optical GmbH, Vienna, A) at every 12 s time intervals using Soft Imaging System’s Analysis image capture software. Samples were heated over the temperature range of 30150 °C at a constant heating rate of 5 °C min1. The hot-stage was calibrated using USP melting point standards. Vibrational Spectroscopic Analysis. Transmission infrared spectra of the solids were obtained using a FT-IR spectrometer (BioRad, FTS 3000MX IR spectrometer). Typically, ∼25 mg of the sample was ground with KBr in an agate mortar and pressed with a steel die into a pellet. The FT-IR spectra were collected for 64 scans at 4 cm1 resolution. The dispersive Raman microscope employed in this study was a JY Horiba LabRAM HR equipped with a confocal microscope, liquidnitrogen-cooled charge coupled device (CCD), and a multichannel

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detector (256 pixels 1024 pixels). The NIR 784.8 nm argon ion laser was selected to excite the Raman scattering. The Raman shift range acquired was in the range of 4001700 cm1 and 31003500 cm1 with spectral resolution of 1.72 cm1. Solubility and Dissolution Experiments. High performance liquid chromatography (HPLC, Agilent 1100 series) equipped with an Agilent Extend-C18 column (3.5 μm, 4.6 mm 150 mm) was used to measure the equilibrium solubility and dissolution rate of MTX polymorphs. The mobile phase used was a mixture of water and acetonitrile (50:50) in a gradient elution at 1 mL min1. An injected volume of 2 μL was used. Detection wavelength in the UVvisible range was set at 273 nm. A linear calibration plot was constructed at a concentration range of 0.22 mg mL1 and with R2 of 0.99 (n = 3). Dissolution experiments were performed using a Varian VK7010 dissolution apparatus equipped with a VK750D heater/circulator. 0.1 N HCl (pH 1.2) and phosphate buffer (pH 7.4) were used as dissolution media at 37 °C. In each experiment, 900 mL of dissolution medium was used, which was stirred at 100 rpm for uniform temperature distribution and control. Approximately 200 mg of powder samples of MTX polymorphs were compressed to a 1.3 cm diameter tablet using SSP10A hydraulic press with 80 KN force for 2 min. The bottom and side surfaces of the tablets were coated with paraffin wax and mounted on a microscopic slide.30 These samples were immersed in the dissolution media, and at a regular time interval 1.2 mL of the samples were withdrawn manually. The collected samples were filtered through 0.2 μm nylon filter and assayed for MTX concentration using HPLC.

’ ASSOCIATED CONTENT

bS

Supporting Information. ORTEP diagrams, DSC thermograms from the patents, TGA plots, photomicrographs from HSM experiments, dissolution profiles, and crystallographic information files (.cif) for MTX polymorphs A and B. This material is available free of charge via the Internet at http://pubs. acs.org.

’ AUTHOR INFORMATION Corresponding Author

*(S.A.) E-mail: [email protected]. Tel: (65) 6796 3858. Fax: (65) 6316 6183. (R.B.H.T.) E-mail: [email protected].

’ ACKNOWLEDGMENT This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore. We thank Miss Grace Lau, Mr. Satyanarayana Thirunahari, and Drs. Alvin Yeoh Chong Yeow and Venu R. Vangala for helpful discussions. ’ REFERENCES

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