NZ789257A - Solid state forms of spiro-oxindole compounds - Google Patents

Abstract

The present invention provides solid state forms of certain spiro-oxindole compounds, such as funapide and the racemic mixture of funapide and its corresponding (R)enantiomer, pharmaceutical compositions comprising the solid state forms and processes for preparing the solid state forms and the pharmaceutical compositions. aceutical compositions.

Description

Solid State Forms of Spiro-Oxindole Compounds This application is a divisional of New d patent application 749352, which is the national phase entry in New Zealand of PCT international application (published as are incorporated herein by reference.

Field of the Invention The present invention encompasses solid state forms of certain spiro-oxindole compounds, pharmaceutical compositions comprising the solid state forms and pharmaceutically acceptable excipients, and ses for preparing the solid state forms and the pharmaceutical compositions.

Background of the ion PCT Published Patent Application No. WO 10917, PCT Published Patent Application No. 2010/045197, PCT Published Patent Application No.

Patent Application No. 2011/106729 and PCT Published Patent Application No. certain spiro-oxindole compounds, methods of preparing the spiro-oxindole compounds, pharmaceutical itions comprising the oxindole compounds and/or methods of using the spiro-oxindole nds.

One of these spiro-oxindole compounds is de, which is also known as TV-45070 or XEN402. Funapide has the following formula (I-S): and has the chemical name of (S)-1'-{[5-(trifluoromethyl)furan yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one.

In particular, PCT Published Patent Application No. WO 02708 specifically discloses funapide and its ponding (R)-enantiomer; PCT Published Patent Application No. resolving its racemate by either SMB chromatography or by chiral HPLC; and PCT Published Patent Application No. funapide by asymmetric synthesis.

Funapide is the (S)-enantiomer of the racemic compound previously sed in PCT Published Patent Application No.

Compound #428 is also known as XEN401.

Funapide and pharmaceutical compositions comprising funapide are useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as sy, anxiety, depression and bipolar disease; cardiovascular conditions such as arrhythmias, atrial fibrillation and cular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection t stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

The relevant disclosures of the above published patent ations are orated in full by reference herein.

Polymorphism, the occurrence of different crystalline forms of the same le, is a property of some molecules and molecular xes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and al properties such as melting point, thermal behaviors (e.g., ed by differential scanning calorimetry – "DSC" or thermogravimetric analysis – "TGA"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish ent polymorphic forms of a compound.

Different solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or ng characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorphic as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve ilability. Different solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess ions in the properties and characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having ble processing ties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable ediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful nd can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has ble for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for solid state forms ding solvated forms) of funapide.

Summary of the Invention The present invention provides solid state forms of certain spiro-oxindole nds, preferably funapide or the racemic mixture, as sed herein, and pharmaceutical compositions thereof.

The present invention also encompasses the use of any one of solid state forms of certain spiro-oxindole nds, preferably funapide or the racemic mixture, as disclosed herein, for the preparation of pharmaceutical compositions of the spirooxindole compounds.

The present ion also provides methods of preparing the solid state forms of certain spiro-oxindole compounds, preferably funapide or the racemic mixture, as disclosed herein.

The present invention also provides a process for preparing the abovementioned pharmaceutical compositions. The s comprises combining any one of the solid state forms of certain spiro-oxindole compounds, preferably de or the racemic e, as disclosed herein, with at least one pharmaceutically acceptable excipient.

The solid state forms and the pharmaceutical compositions of certain spiro- oxindole compounds, preferably funapide or the racemic mixture, can be used as medicaments, particularly for the ent of sodium channel-mediated diseases and conditions, such as pain.

The present invention also provides a method of treating sodium channelmediated diseases and conditions, such as pain, comprising administering a therapeutically effective amount of any one of the solid state forms of certain spirooxindole compounds, preferably funapide or the racemic mixture, as disclosed herein, or at least one of the above pharmaceutical compositions, to a subject suffering from sodium channel-mediated diseases and conditions, such as pain, or otherwise in need of the treatment.

Brief ption of the Drawings Figure 1 shows a characteristic X-ray powder diffractogram of Form A0 of funapide (TV-45070).

Figure 2 shows a DSC graph of Form A0 of funapide (XEN-402).

Figure 3 shows an FTIR spectrum by ATR of Form A0 of funapide.

Figure 4 shows a Raman shift spectrum for Form A0 of funapide.

Figure 5 shows a characteristic X-ray powder diffractogram of Form B0 of funapide 070).

Figure 6 shows a DSC thermograph of Form B0 of funapide (TV-45070).

Figure 7 shows an FTIR um by ATR of Form B0 of funapide.

Figure 8 shows a Raman shift spectrum for Form B0 of funapide.

Figure 9 shows a characteristic X-ray powder ctogram of amorphous funapide (TV-45070).

Figure 10 shows a DSC thermograph of the amorphous form of funapide (TV­45070).

Figure 11 shows a characteristic X-ray powder diffractogram of the racemic mixture of funapide and its corresponding (R)-enantiomer.

Figure 12 shows a Raman shift spectrum for the racemic mixture of funapide and its corresponding (R)-enantiomer.

Figure 13 shows an overlay of the X-ray powder ctograms of the racemic mixture, Form A0 of de and Form B0 of funapide.

Figure 14 shows an overlay of the Raman shift spectrums of the c mixture, Form A0 and Form B0.

Detailed Description of the Invention The present invention encompasses solid state forms of certain spiro-oxindole compounds, preferably funapide or a racemic mixture of funapide and its corresponding (R)-enantiomer. Solid state properties of de or the racemic mixture can be nced by controlling the conditions under which funapide or the racemic mixture is obtained in solid form.

As used herein, "solid state forms of certain spiro-oxindole compounds" is intended to include the lline forms of funapide, the amorphous form of funapide, and the crystalline form of the racemic mixture comprising funapide and its corresponding (R)-enantiomer, as described herein.

In some embodiments, the crystalline forms of funapide of the ion are substantially free of any other forms of funapide, or of specified polymorphic forms of funapide, respectively.

As used herein, "substantially free" when referring to a solid state form of the funapide is intended to mean that the solid state form of the present invention contains % (w/w) or less of any other polymorphs, or of ied polymorph of funapide, or the amorphous form of funapide. According to some ments, a solid state form of funapide contains 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, 1% (w/w) or less, 0.5% (w/w) or less, or 0.2% (w/w) or less of any other rphs, or of specified polymorph of funapide or the amorphous form of funapide. In other embodiments, a solid state form of funapide of the present invention contains from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of any other solid state form or of a specified polymorph of funapide or of the amorphous form of funapide.

Depending on with which other solid state form a comparison is made, the crystalline forms of funapide of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or l habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low t of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density. ularly, it has been found that the lline forms of funapide of the present invention are highly soluble in numerous solvents such as acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, ydrofuran and toluene.

The lline forms of funapide of the present invention also demonstrate good physical stability.

As used herein, the term "highly soluble" in reference to solid state forms of funapide of the present invention corresponds to a solid state form of funapide having a solubility of above 100 mg/mL at room temperature.

A solid state form, such as a crystalline form or an amorphous form, may be referred to herein as being characterized by graphical data "as depicted in" or "as ntially depicted in" a Figure. Such data include, for example, powder X-ray diffractograms, DSC thermographs, FTIR ums by ATR and Raman shift spectrums. As is well-known in the art, the cal data potentially provides additional technical information to r define the respective solid state form (a socalled "fingerprint") which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in ment response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would y be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown lline form and confirm whether the two sets of graphical data are terizing the same crystal form or two different crystal forms.

A crystalline form of funapide or the racemic mixture referred to herein as being characterized by graphical data "as depicted in" or "as substantially depicted in" a Figure will thus be understood to include any crystalline forms of funapide or the racemic mixture terized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

As used herein, the term "isolated" in nce to solid state forms of funapide or the racemic mixture of the present invention corresponds to a solid state form of funapide or the racemic mixture that is physically separated from the on mixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are taken using copper Kα radiation at 45 kV and 40 mA.

As used herein, unless stated otherwise, the DSC measurements were measured with a heat ramp of 10 °C/ min.

When an object or a mixture, such as a solid state form of funapide or the racemic e or a on mixture or on, is characterized herein as being at or allowed to come to "room temperature" or "ambient temperature" (often abbreviated as "RT"), it is intended to mean that the ature of the object or e is close to, or the same as, that of the space, e.g., the room or fume hood, in which the object or mixture is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

The amount of solvent employed in a chemical process, e.g., a reaction or a crystallization, may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this t, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the t per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

A process or step may be referred to herein as being d out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, lly about 16 hours.

As used herein, the term "reduced pressure" refers to a pressure that is less than heric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

As used herein "crystalline form A0 of funapide" or "Form A0" or "Form A0 of funapide" refers to a crystalline form of funapide which may be characterized by X-ray powder diffraction pattern as ed in Figure 1.

As used herein "crystalline form B0 of funapide" or "Form B0" or "Form B0 of funapide" refers to a crystalline form of funapide which may be characterized by X-ray powder diffraction pattern as depicted in Figure 5.

As used herein "amorphous form of funapide" refers to an amorphous form of funapide which may be characterized by X-ray powder diffraction n as depicted in Figure 9 and further by a DSC thermograph as depicted in Figure 10 showing a glass transition at 42 °C and crystallization at 72 °C.

As used herein "the racemic mixture" refers to the crystalline form of the racemic mixture of funapide and its corresponding (R)-enantiomer which may be characterized by an X-ray powder diffraction pattern as depicted in Figure 11.

In one embodiment, the present invention comprises a crystalline form of funapide, designated herein as crystalline form A0 of funapide, characterized by data selected from one or more of the following: X-ray powder ction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ ± 0.2° θ; an X-ray powder diffraction pattern as ed in Figure 1; and combinations of these data. lline form A0 of funapide may be further characterized by the X-ray powder ction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ ± 0.2° θ and also having one, two, three or four additional peaks selected from: 15.94°, 17.77°, 20.26°, 23.79°, and 30.84° θ ± 0.2° θ; a DSC thermogram as depicted in Figure 2; a 110 -116 °C melting point, preferably a 114 -116 °C g point; an FTIR spectrum as depicted in Figure 3, and a Raman shift spectrum as depicted in Figure 4.

Crystalline form A0 of funapide may be terized by each of the above characteristics alone and/or by all possible combinations, e.g., by X-ray powder diffraction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ ± 0.2° θ and by an X-ray powder diffraction pattern as depicted in Figure 1.

In another embodiment, crystalline form A0 of funapide is characterized by one or more of the following Raman shift peaks listed in Table 1: Table 1 Peak No. Raman shift (cm-1) 1 3137.83 2 3110.35 3 3088.66 4 3075.64 3062.62 6 3012 7 2973.91 8 3 9 2890.5 5 11 2846.14 12 2773.34 13 1718.42 14 1632.6 1608.98 16 1601.75 17 1554.5 18 1502.43 19 1489.89 1468.19 21 1451.8 22 2 23 1394.43 24 1379.96 1374.66 26 1345.25 27 1338.02 28 1302.34 29 1280.64 1260.88 31 1234.36 32 4 33 1203.98 Peak No. Raman shift (cm-1) 34 1169.27 1162.04 36 1104.18 37 1018.36 38 968.7 39 937.84 40 823.1 41 776.81 42 761.86 43 751.26 44 740.17 45 706.9 46 679.9 47 646.15 48 626.38 49 567.08 50 494.76 51 490.9 52 453.78 53 428.71 54 406.53 55 386.76 56 375.19 57 312.03 58 300.94 59 276.84 60 228.62 61 189.09 62 142.32 63 116.28 64 81.57 65 60.84 In another embodiment, the present invention comprises crystalline form of funapide, designated herein as lline form B0 of funapide, terized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at 9.61°, 10.03°, 14.95°, 19.28°, and 21.30° θ ± 0.2° θ; an X-ray powder diffraction pattern as depicted in Figure 5; and combinations of these data.

Crystalline form B0 of funapide may be further characterized by the X-ray powder diffraction pattern having peaks at 9.61°, 10.03°, , 19.28°, and 21.30° θ ± 0.2° θ and also having one, two, three or four additional peaks selected from: 12.51°, 16.14°, 18.03°, 18.72°, and 25.50° θ ± 0.2° θ; a DSC thermogram as depicted in Figure 6 g a 104 -107 °C melting point; an FTIR spectrum as depicted in Figure 7 and a Raman shift spectrum as depicted in Figure 8.

Crystalline form B0 of funapide may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by X-ray powder diffraction pattern as having peaks at 9.61°, , 14.95°, 19.28°, and 21.30° θ ± 0.2° θ and by an X-ray powder diffraction pattern as depicted in Figure 5.

In r embodiment, crystalline form B0 of funapide is characterized by one or more of the following Raman shift peaks listed in Table 2: Table 2 Peak No. Raman shift (cm-1) 1 9 2 3121.92 3 3108.9 4 3090.1 3069.37 6 3029.35 7 3010.07 8 2981.14 9 2966.19 2957.51 11 2932.92 12 2905.93 13 2891.46 14 2849.03 2785.39 16 1727.1 17 1715.05 18 1635.98 19 5 1601.75 21 1569.44 22 1501.46 23 1490.37 Peak No. Raman shift (cm-1) 24 1467.71 1433 26 1390.09 27 1376.11 28 1346.21 29 1339.46 1321.14 31 1303.3 32 1278.23 33 1247.86 34 6 1178.43 36 1157.7 37 1100.32 38 1043.91 39 1018.36 40 957.61 41 937.36 42 825.51 43 799.95 44 758.01 45 744.99 46 734.86 47 726.19 48 718.95 49 704.01 50 685.69 51 674.12 52 634.58 53 581.55 54 569.49 55 493.8 56 488.01 57 432.08 58 394.96 59 372.78 60 327.94 61 322.16 62 300.46 63 282.14 64 257.55 Peak No. Raman shift (cm-1) 65 224.28 66 210.3 67 202.1 68 164.98 69 124.96 70 112.43 71 90.73 72 61.8 In one embodiment, the present invention ses a crystalline form of the racemic mixture of funapide and its corresponding (R)-enantiomer, designated herein as the crystalline form of the racemic mixture, characterized by data selected from one or more of the following: X-ray powder diffraction pattern having peaks at , 14.83°, .17°, 25.49° and 29.80° θ ± 0.2° θ; an X-ray powder diffraction pattern as depicted in Figure 11; and combinations of these data.

The lline form of the racemic e may be further characterized by the X-ray powder diffraction pattern having peaks at 13.68°, 14.83°, 20.17°, 25.49° and 29.80° θ ± 0.2° θ and also having one, two, three or four additional peaks selected from: 15.94°, 22.24°, 27.21°, and 31.91° θ ± 0.2° θ; and a Raman shift spectrum as depicted in Figure 12.

In another embodiment, the racemic mixture is characterized by one or more of the XRPD peaks listed in Table 3: Table 3 Pos. [°2θ] d-spacing [Å] Rel. Int. [%] 12.38 7.15 3 13.68 6.47 17 14.83 5.97 100 .94 5.56 5 17.74 5.00 3 18.98 4.67 2 .17 4.40 6 21.78 4.08 4 22.24 3.99 4 .07 3.55 3 .11 3.54 3 Pos. [°2θ] d-spacing [Å] Rel. Int. [%] .49 3.49 6 27.21 3.27 5 27.45 3.25 3 29.13 3.06 2 29.58 3.02 1 29.80 3.00 8 31.54 2.83 2 31.91 2.80 4 39.12 2.30 3 In another embodiment, the crystalline form of the c mixture is characterized by one or more of the ing Raman shift peaks listed in Table 4: Table 4 Peak No. Raman shift (cm-1) 1 3147.48 2 3113.73 3 8 4 3075.64 3060.69 6 3013.92 7 2984.03 8 2955.1 9 2931.48 2909.3 11 2848.07 12 2715.96 13 1717.94 14 1611.87 1602.71 16 1569.93 17 1505.32 18 1487 19 1469.64 1430.11 21 1375.14 22 1350.55 23 1308.61 24 1279.68 1259.91 Peak No. Raman shift (cm-1) 26 6 27 1197.72 28 1159.14 29 1105.63 1012.09 31 969.18 32 938.33 33 822.13 34 778.74 759.45 36 749.33 37 741.61 38 720.4 39 714.61 40 695.33 41 684.24 42 619.63 43 604.69 44 495.73 45 488.01 46 454.74 47 431.12 48 422.92 49 413.76 50 393.03 51 369.41 52 350.12 53 323.12 54 299.01 55 270.57 56 240.19 57 205.96 58 160.16 59 133.64 60 114.84 61 82.53 62 78.68 63 70.48 64 54.57 The present invention comprises pharmaceutical compositions and formulations comprising any one of the crystalline forms of funapide, the amorphous form of funapide or the crystalline form of the racemic mixture of the present invention and one or more pharmaceutically able excipients. Typically, the pharmaceutical ition is a solid composition and the funapide s its solid state form therein.

The pharmaceutical compositions of the invention can be prepared by methods similar to those disclosed in PCT hed Patent Application WO 47174 or by methods similar to those disclosed in PCT Published Patent Application No.

Application No.

The above crystalline forms of funapide and the racemic mixture and the amorphous form of funapide of the present invention can also be used as a medicament.

The present invention further encompasses 1) the use of the above-described crystalline forms or amorphous form of funapide or the crystalline form of the racemic mixture in the manufacture of a pharmaceutical composition, and 2) a method of treating a subject suffering from sodium channel-mediated diseases and conditions, such as pain, or otherwise in need of the treatment, sing administration of an effective amount of a pharmaceutical composition comprising any one of the above crystalline forms or ous form of funapide described herein.

The use of the above crystalline forms or amorphous form of funapide or the crystalline form of the racemic mixture and pharmaceutical compositions sing same can be used in treating the es and conditions as described in PCT Published Patent Application No.

Having thus bed the invention with reference to particular red embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way.

The funapide used herein to prepare the crystalline forms of funapide sed herein was prepared according to the methods disclosed in PCT Published Patent Application No.

Patent Application No.

Analysis Methods XRPD - X-Ray Powder Diffraction X-ray powder diffraction (XRPD, also known as powder X-ray ction or powder XRD) patterns were recorded on a PANalytical X’Pert Pro diffractometer equipped with an X'celerator detector using Cu Kα radiation at 45 kV and 40 mA. The diffractometer was controlled with PANalytical Data Collector1. All s were analyzed using algorithms in orePlus2.

Standard Reflection Mode Kα1 radiation was ed with a highly oriented crystal (Ge111) incident beam monochromator. A 10mm beam mask, and fixed (1/4°) divergence and antiscatter (1/8°) slits were inserted on the incident beam side. A 0.04 radian Soller slits and a fixed 5 mm receiving slit were ed on the diffracted beam side. The X-ray powder pattern scan was collected from ca. 2 to 40° 2θ with a 0.0080° step size and 96.06 sec counting time which resulted in a scan rate of approximately 0.5°/min. The sample was spread on a silicon zero background (ZBG) plate for the measurement. The sample was rotated at 15 revolutions/min on a PANalytical PW3065/12 Spinner.

Measurement of the Si reference standard before the data collection resulted in values for 2θ and intensity that were well within the tolerances of 28.0° < 2θ < 28.5° and significantly greater than the minimum peak height of 150 cps.

Capillary Transmission Mode Powder XRD patterns were recorded on a PANalytical X Pert Pro diffractometer equipped with an X celerator detector using Cu Kα radiation at 45 kV and 40 mA. An incident beam (Cu W/Si) focusing MPD mirror was used in the incident beam path. Fixed (1/20) ence and anti-scatter (1/40) slits and 0.01 Sollers were inserted on the incident beam side. A fixed 5.0 mm antiscatter slit and 0.01 Sollers were inserted on the diffracted beam side. If the antiscatter device (PW3094/10) is employed, an additional 2.0 mm slit is oned 197 mm from the detector. The X-ray powder n scan was collected from ca. 2.75 to 40° 2θ with a 0.0080° step size and 101 second counting time which ed in a scan rate of approximately 0.5°/min. The sample was loaded into a thin walled Kapton capillary and place in a modified transmission holder. The holder is a standard transmission sample ring with added mechanical features that allow for measurement of a spinning capillary.

Variable Temperature (VT) Mode Variable temperature s were preformed with an Anton Paar CHC temperature/humidity r under computer control. The temperatures were set with Data Collector using an Anton Paar TCU110 temperature control unit.

Kα ion was obtained with a Nickel filter. A fixed (1/40) divergence and anti-scatter (1/20) slits were inserted on the incident beam side. A fixed 0.10mm receiving slit was inserted on the diffracted beam side. Soller slits (0.04 radians) were inserted in both the incident and diffracted beam sides. The X-ray powder pattern scan was collected from ca. 2 to 40° 2θ with a 0.0080° step size and 96.06 sec counting time which resulted in a scan rate of approximately 0.5°/min.

For temperature studies, measurements were made with N2 gas flow. The temperatures chosen for study were based on DSC results. Measurements were started after the CHC chamber reached requested temperature. After the requested temperature was reached, the sample was cooled at 35 °C/minute and a slow scan was measured at 25 °C. This technique avoids "cooking" the sample at higher temperatures. Scans were collected from ca. 3° to 30° or 40° 2θ with a 0.008° step size and 100 sec counting time which resulted in a scan rate of approximately in.

DSC - Differential Scanning Calorimetry l curves were acquired using a Perkin-Elmer Sapphire DSC unit equipped with an autosampler g Pyris software version 6.0 calibrated with Indium prior to analysis. Solid samples of 1-10 mg were d into 20 μL aluminum pin hole sample pans. The DSC cell was then purged with nitrogen and the temperature heated from 0 to 270 °C at 10 °C / min. Indium (Tm = 156.6 °C; ΔHFus = 28.45 J/g) was used for calibration.

FTIR Spectroscopy Spectra were ed using a Bruker Tensor 27 with ATR attachment containing a diamond crystal window. The OPUS data collection program (Version 7.0, Bruker) was used to obtain the IR spectrum from 4000 to 400 cm-1. A background scan was collected before spectral resolution and averaged.

Raman Spectroscopy Raman a were collected on a Vertex 70 FTIR (Bruker) optical bench equipped with a 1064nm NdYAG laser and liquid-nitrogen cooled Ge or with either the RAMII module or the RamanScope. Thirty-two scans were collected in a double-sided acquisition mode at 5KHz scan velocity with a 5mm aperture. Data was sed with a phase resolution of 32cm-1, 8x illing and a weak Norton-Beer apodization function. Sample spectra were collected through the glass vial using the RAMII whenever possible. Irregularly shaped samples were analyzed on the RamanScope using a10x. In that situation, 64 scans were ted with an 1197mW laser power. ing Methods Slurry Equilibration in Different Solvents Equilibration at 25 °C Approximately 20 mg of funapide was equilibrated with ~0.2 mL solvents for at least 48 h at 25±3 °C in 4 mL vials. The resulting mixtures were ed and the solids air-dried for at least 10 min.

Equilibration at 50 °C Approximately 40 mg of funapide was equilibrated with ~0.4 mL solvents for at least 24 h at 50 °C in 4 mL vials. The solutions were then filtered and air-dried for at least 10 min.

Cooling Crystallization at 5 °C Approximately 20 mg of funapide was completely dissolved in 200 μL of solvents at 22-25 °C in 4 mL vials. Care was taken to ensure that there were no visible crystals remaining. The ons were cooled to 5 °C at a rate of 2 °C/min. The precipitates (if present) were collected on a filter and dried.

Evaporation Slow ation at 5 °C Approximately 20 mg of funapide were completely dissolved in 200 μL of solvents at 22-25 °C in 4 mL vials. The solutions were cooled to 5 °C at a rate of 2 °C/min. Care was taken to ensure there were no visible crystals remaining. While temperature and agitation were maintained, the cover of each vial was loosened to allow slow evaporation of the solvent for at least one day.

Fast Evaporation at 50 °C Approximately 40 mg of funapide were mixed with 200 μL of solvents at 22-25 °C in 4 mL vials. The solutions were heated to 50 °C as fast as the instrument allowed.

Care was taken to ensure there were no visible crystals remaining at this point. With temperature and agitation ined, each vial was red to allow fast evaporation of the solvent until dryness.

Precipitation by Addition of Anti-solvent In 4 mL vials, imately 20 mg of funapide were completely dissolved in solvents where funapide solubility is high, and then a second solvent, in which de is highly insoluble, was added. Samples were withdrawn from the resulting slurry. The samples were filtered to obtain solids.

Examples 1-66 The following Examples 1-66 are the solid state forms of funapide resulting from ing with the different methods described above in varying solvents.

Table 5: Equilibration at 25 °C (Examples 1-18) Example Solvent XRPD 1 Chloroform/2-propanol (1:3) A0 2 1,4-dioxane/water (1:3) A0 3 Ethyl acetate/2-propanol (1:3) A0 e Solvent XRPD 4 2-propanol B0 Acetone/water (1:1 v:v) B0 6 Acetic Acid/water (1:1) B0 7 Chloroform/heptanes (1:3) B0 8 Dichloromethane/heptanes (1:3) B0 9 Dichloromethane/2-propanol (1:3) B0 Ethyl acetate/heptanes (1:3) B0 11 Isobutyl alcohol/heptanes (1:3) B0 12 Isopropyl acetate/heptanes (1:3) B0 13 Methyl tert-butyl heptanes (1:3) B0 14 ydrofuran/heptanes (1:3) B0 Toluene/heptanes (1:3) B0 16 N-butyl acetate/heptanes (1:1) A0+ B0 17 N-butyl acetate/2-propanol (1:3) A0+ B0 18 Heptane A0+ B0 Table 6: Equilibration at 50 °C (Examples 19-30) Example Solvent XRPD 19 Heptanes A0 Water A0 21 Acetic Acid/water (1:1) A0 22 Acetone/water (1:1) A0 23 n-Butyl acetate/heptanes (1:3) A0 24 Chloroform/heptanes (1:3) A0 Chloroform/2-propanol (1:3) A0 26 Ethyl acetate/heptanes (1:3) A0 27 Isobutyl alcohol/heptanes (1:3) A0 28 Isopropyl acetate/heptanes (1:3) A0 29 Methyl tert-butyl ether/heptanes (1:3) A0 Toluene/heptanes (1:3) A0 Table 7: Cooling Crystallization at 5 °C (Example 31) Example t XRPD 31 Methyl tert-butyl ether A0 Table 8: Slow Evaporation at 5 °C (Examples 32-39) Example t XRPD 32 Acetone A0 33 N-butyl acetate A0 34 Ethyl acetate A0 Isobutyl alcohol A0 36 Isopropyl acetate A0 37 Methyl tert-butyl ether A0 38 Tetrahydrofuran A0 39 Ethyl acetate/heptanes (4:1) A0 Table 9: Fast Evaporation at 50 °C (Examples 40-45) Example Solvent XRPD 40 Acetone A0 41 Dichloromethane A0 42 Isopropyl acetate A0 43 Methyl tert-butyl ether A0 44 Tetrahydrofuran A0 45 e A0 Table 10: Anti-Solvent Addition at Room Temperature (Examples 46-66) Example Solvent 1 and solvent 2 XRPD 46 Acetic Acid/water (1:1) A0 47 Acetone/water (1:1) A0 48 n-Butyl acetate/heptanes (1:3) B0 49 n-Butyl acetate/2-propanol (1:3) A0 50 Chloroform/heptanes (1:3) B0 51 Chloroform/2-propanol (1:3) A0 52 Dichloromethane/heptanes (1:3) B0 53 romethane/2-propanol (1:3) A0 54 1,4-dioxane/water (1:3) B0 55 Ethyl acetate/heptanes (1:3) B0 56 Isobutyl l/heptanes (1:3) B0 57 Isopropyl acetate/heptanes (1:3) B0 e Solvent 1 and solvent 2 XRPD 58 Tetrahydrofuran/heptanes (1:3) B0 59 Toluene/heptanes (1:3) A0 60 Acetic Acid/water (1:1) A0 61 Acetone/water (1:1) A0 62 l acetate/heptanes (1:3) B0 63 n-Butyl acetate/2-propanol (1:3) A0 64 Chloroform/heptanes (1:3) B0 65 Chloroform/2-propanol (1:3) A0 66 Dichloromethane/heptanes (1:3) B0 Example 67 Crystallization Process for Form B0 of Funapide Funapide (1.952 Kg) was dissolved in 7070 mL methanol (3.62 volumes). Full dissolution in the 10L reactor was obtained at 56 °C (in r). When the reactor temperature reached 64 °C, 742 mL of water were added dropwise over a period of 65 minutes. At the end of the water addition period a clear solution was still obtained (reactor temperature reached 68 °C). The solution was mixed for 30 minutes. The jacket temperature was cooled from 85 °C to 40 °C over a period of 40 minutes. At the end of this g period, temperature in r reached 59 °C (jacket temperature was 40 °C) and a white slurry was obtained. The slurry was cooled according to reactor jacket temperature from 40 °C to -5 °C over a period of 5 hours and mixed for additional 11.5 hours. The solid obtained was collected by filtration and washed with cold mixture of methanol and water (908 mL water and 1160 mL ol). The white solid was dried in a vacuum oven at 50 °C for 43 hours to obtain a dry solid. Yield: 1831 g (93.8% of theory).

The material was analyzed by XRPD, showing a Form B0 pattern. The DSC of the sample had thermal events at 106.6 °C, which is consistent with the typical Form Example 68 Preparation of Amorphous Form of de A. The amorphous form of funapide was generated by melting Form A0 of funapide in a dry N2 atmosphere optionally using the VT stage on the XRPD unit. The sample was heated to 140 °C and then cooled to room temperature and crushed. No decomposition was observed. The sample was confirmed to be the amorphous form of funapide by XRPD.

B. atively, Form B0 of de may be melted in the same manner to produce the amorphous form of funapide. e 69 Solid State Characterization of Racemic Mixture A racemic mixture comprising funapide (as Form A0 of funapide) and its corresponding antiomer was studied to determine if the c mixture was a racemic compound or a racemic conglomerate.

Figure 11 shows a characteristic X-ray powder diffractogram of the c e. Figure 12 shows the Raman shift spectrum for the racemic mixture.

Figure 13 shows an overlay of the X-ray power diffractograms of the racemic mixture, Form A0 of funapide and Form B0 of funapide. Figure 14 shows an overlay of the Raman shift spectrum of the racemic mixture, Form A0 and Form B0.

The XRPD pattern and melting point of the racemic mixture are drastically different from that of Form A0 and Form B0 (140 °C vs. 110 °C of Form A0 and 104 °C of Form B0). Shifts of some Raman peaks of the racemic mixture were also noticeable when compared to those of Form A0 or Form B0.

To identify the nature of the racemic mixture, a binary phase diagram from DSC's of mixtures of the racemic mixture and Form A0 was constructed based on experimental results and theoretical predication. A good agreement was observed between the experimental s and theoretical predications. The typical binary phase diagram of a racemic compound confirmed that the racemic mixture is a c compound (instead of a racemic conglomerate).

An overlay of 6 DSC thermographs of the c e, Form A0 and different mixtures of the c mixture and Form A0 showed that Form A0 and the c mixture both have one sharp peak which corresponds to the melting of Form A0 and the racemic mixture. The mixtures of the racemic mixture and Form A0, two ermic peaks; a eutectic fusion (with its onset defined as TE) and a pure species melting (its max as Tf) were observed.

The crystal ure of the racemic mixture was resolved. There was one molecule in the asymmetric unit and there were four pairs of enantiomers packed in one unit cell. Furthermore, the molecule conformed to the "U-shape" of Form B0 (rotation along the N-CH2 bond in funapide gives either a "Chair-shape", which conforms with Form A0, or a "U-shape", which conforms with Form B0).

The crystal structure determination of the racemic mixture provides definitive evidence that the racemic mixture is a racemic compound rather than a merate.

******* All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference in their entireties.

Although the ing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not ctive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims (1)

What is claimed is:

1. A crystalline form of funapide, designated as Form A0, characterized by one or more of the following: a powder X-ray diffraction pattern having peaks at 10.10°, 10.69°, , 22.69° and 33.12° θ ± 0.2° θ; a powder X-ray diffraction pattern substantially as depicted in