EP4713324A1

EP4713324A1 - Crystalline form of 3-(1,4-dimethyl-1h-1,2,3-triazol-5-yl)-a,a-dimethyl-5-[(s)- phenyl(tetrahydro-2h-pyran-4-yl)methyl]-5h- pyrido[3,2-2beta]indole-7-methanol

Info

Publication number: EP4713324A1
Application number: EP24734241.3A
Authority: EP
Inventors: Derek J. Norris
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2023-05-16
Filing date: 2024-05-15
Publication date: 2026-03-25
Also published as: KR20260010388A; CN121194972A; WO2024238590A1

Abstract

Disclosed are crystalline forms of 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-α,α-dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-5H-Pyrido[3,2-b]indole-7-methanol. Characterization data for the crystalline forms are disclosed.

Description

CRYSTALLINE FORM OF 3-(l,4-DIMETHYL-l/7-l,2,3-TRIAZOL-5-YL)-A,A- DIMETHYL-5-[CS')-PHENYL(TETR.AHYDR.O-27/-PYR.AN-4-YL)METHYL]-57/- PYRIDO[3,2-_JB]INDOLE-7-METHANOL

FIELD OF THE INVENTION

The present invention generally relates to crystalline forms of 3-(l,4-dimethyl-UT- l,2,3-triazol-5-yl)-a,a-dimethyl-5-[(5)-phenyl(tetrahydro-2J/-pyran-4-yl)methyl]-5JT- Pyrido[3,2-Z>]indole-7-methanol.

BACKGROUND OF THE INVENTION

The compound, 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-a,a-dimethyl-5-[(S)- phenyl(tetrahydro-2H-pyran-4-yl)methyl]-5H-Pyrido[3,2-b]indole-7-methanol, has the structure of Formula (I): and is referred to herein as “Compound (I)”. Compound (I) is disclosed as Example 54 in U.S. Patent 9,458,156 B2, which is assigned to the present assignee.

Compound (I) is a BET inhibitor currently in clinical trials for the treatment of solid tumors and myelofibrosis.

In the synthesis of a chemical compound intended for pharmaceutical use, it is necessary to isolate and purify the compound at the completion of the synthetic process and prior to further processing to provide the compound in a pharmaceutical formulation. The isolation and the purification steps, which can be combined or separate consecutive steps, provide the compound as a purified solid with minimal loss of yield during isolation from other components of the reaction mixture and/or during purification to remove impurities from the isolated compound sample.

It is desirable to provide a solid form that can be reproducibly produced from the isolation and/or purification steps.

Further, it is desirable to isolate the purified compound in a solid form that is physically and chemically stable at a range of storage conditions, such as at different conditions of temperature and humidity.

The Applicants have found a crystalline form of Compound (I) that allows the isolation and purification of Compound (I).

The present invention is also directed to other important aspects.

SUMMARY OF THE INVENTION

The present invention provides crystalline forms of Compound (I) as a free base. The present invention also provides Compound (I) as crystalline Form A. The name used herein to characterize a specific form, e.g. “Form A” etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that this designation is a mere identifier that should be interpreted according to the characterization information also presented herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the observed powder x-ray diffraction pattern (CuKa, = 1.54178 A at T = 25 °C) of crystalline Form A of Compound (I).

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form A of Compound (I).

FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of the Form A of Compound (I).

FIG. 4 shows the observed powder x-ray diffraction pattern (CuKa, = 1.54178 A at T = 25 °C) of amorphous Compound (I).

FIG. 5 shows a differential scanning calorimetry (TMDSC) thermogram of amorphous of Compound (I).

DETAILED DESCRIPTION OF THE INVENTION

The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to Form A single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof.

The names used herein to characterize a specific form, e.g., “Form A” etc., are merely identifiers that are to be interpreted in accordance with the characterization information presented herein and are not to be limited so as to exclude any other substance possessing similar or identical physical and chemical characteristics.

The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.

All numbers expressing quantities of ingredients, weight percentages, temperatures, and so forth that are preceded by the word “about” are to be understood as only approximations so that slight variations above and below the stated number may be used to achieve substantially the same results as the stated number. Accordingly, unless indicated to the contrary, numerical parameters preceded by the word “about” are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

All measurements are subject to experimental error and are within the spirit of the invention.

As used herein, “polymorphs” refer to crystalline forms having the same chemical structure but different spatial arrangements of the molecules and/or ions forming the crystals.

As used herein, “amorphous” refers to a solid form of a molecule and/or ion that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern with sharp maxima.

As used herein, “substantially pure,” when used in reference to a crystalline form, means a compound having a purity greater than 90 weight %, including greater than 90, 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of Compound (I), based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of Compound (I) may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises amorphous and/or other form(s) of Compound (I) and/or reaction impurities and/or processing impurities.

As used herein, a powder x-ray diffraction (PXRD) pattern “comprising” a number of peaks selected from a specified group of peaks, is intended to include PXRD patterns having additional peaks that are not included in the specified group of peaks. For example, a PXRD pattern comprising four or more, preferably five or more, 29 values selected from: A, B, C, D, E, F, G, and H, is intended to include a PXRD pattern having: (a) four or more, preferably five or more, 29 values selected from: A, B, C, D, E, F, G, and H; and (b) zero or more peaks that are not one of peaks A, B, C, D, E, F, G, and H.

The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy.

As used herein, the unit cell parameter “molecules per unit cell” refers to the number of molecules of Compound (I) in the unit cell.

Table 1

Crystalline Form of Compound (I), Free Base

Form A of Compound (I)

In one embodiment, Form A of Compound (I) is provided as a crystalline material comprising Form A. The crystalline Form A of Compound (I) is a neat crystalline form.

In one embodiment, crystalline Form A of Compound (I) is characterized by unit cell parameters approximately equal to the following: a = 28.74 ± 9.19 A b = 8.81 ± 0.10 A c = 11.25 ± 9.19 A a = 90.0 ± 1.0°

P = 102.7 ± 1.0° y = 90.0 ± 1.0°

Space group: C2

Molecules per unit cell (Z): 4

Unit cell volume = 2778 ± 20 A³

Calculated density 1.188 g/cm³ wherein the unit cell parameters of Form A of Compound (I) are measured at a temperature of about 296 K.

Table 2

Form A of Compound (I)

Selected PXRD 29 values (CuKa X= 1.5418 A) measured at 25 °C

In one embodiment, crystalline Form A of Compound (I) is characterized by a powder x-ray diffraction pattern comprising five or more 29 values (CuKa ±=1 .5418 A) selected from: 6.4 ± 0.2; 8.0 ± 0.2; 9.1 ± 0.2; 12.9 ± 0.2; 16.1 ± 0.2; 18.7 ± 0.2 and 24.2 ± 0.2, wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C.

In one embodiment, crystalline Form A of Compound (I) is characterized by a powder x-ray diffraction pattern comprising six or more 29 values (CuKa =1.5418 A) selected from: 6.4 ± 0.2; 8.0 ± 0.2; 9.1 ± 0.2; 12.9 ± 0.2; 16.1 ± 0.2; 18.7 ± 0.2 and 24.2 ± 0.2, wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C.

In one embodiment, crystalline Form A of Compound (I) is characterized by a powder x-ray diffraction pattern comprising seven or more 29 values (CuKa =1.5418 A) selected from: 6.4 ± 0.2; 8.0 ± 0.2; 9.1 ± 0.2; 12.9 ± 0.2; 16.1 ± 0.2; 18.7 ± 0.2 and 24.2 ± 0.2, wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C.

In one embodiment, crystalline Form A of Compound (I) is characterized by an observed powder x-ray diffraction pattern substantially as shown in Figure 1.

In one embodiment, crystalline Form A of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2. In one embodiment, crystalline Form A of Compound (I) is characterized by an endotherm with onset temperature in the range of from 232 °C to 236 °C.

In one embodiment, crystalline Form A of Compound (I) is characterized by an endotherm with onset temperature in the range of from 233 °C to 235 °C.

In one embodiment, crystalline Form A of Compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3.

In still yet an even further embodiment, crystalline Form A of Compound (I) is substantially pure.

In another embodiment, the crystalline form of Compound (I) consists essentially of Form A. The crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the crystalline form, Form A of Compound (I).

One embodiment provides a composition comprising 3-(l,4-dimethyl-lH-l,2,3- triazol-5-yl)-a,a-dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-5H- Pyrido[3,2-b]indole-7-methanol, wherein at least 95 wt. %, preferably at least 97 wt. %, and more preferably at least 99 wt. % of said 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-a,a- dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-5H-Pyrido[3,2-b]indole-7- methanol is in crystalline Form A.

Amorphous form of Compound I

In one embodiment, an amorphous form of Compound (I) is provided.

In one embodiment, an amorphous form of Compound (I) is characterized by an observed powder x-ray diffraction pattern substantially as shown in Figure 4.

In another embodiment, an amorphous form of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 5.

Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (counter solvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2^nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term “slurry”, as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in “Programmed Cooling of Batch Crystallizers,” J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph). A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, powder x-ray diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be co milled or passed through a mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium of the final process for preparing Compound (I). This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which Compound (I) may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.

The presence of more than one polymorph in a sample may be determined by techniques such as powder x-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data. Smith, D.K., “d FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

The forms of Compound (I) may be characterized using various techniques, the operation of which are well known to those of ordinary skill in the art. The forms may be characterized and distinguished using single crystal x-ray diffraction, which is based on unit cell measurements of a single crystal at a fixed analytical temperature. A detailed description of unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is herein incorporated by reference. Alternatively, another means of characterizing the crystalline structure is by powder x-ray diffraction analysis in which the diffraction profile is compared to a simulated profile representing pure powder material, both run at the same analytical temperature, and measurements for the subject Form characterized as a series of 20 values (usually four or more).

Other means of characterizing the form may be used, such as solid-state nuclear magnetic resonance (ssNMR), differential scanning calorimetry, thermal analysis, and vibrational spectroscopy. These parameters may also be used in combination to characterize the subject form.

UTILITY

Crystalline Form A of Compound (I) can be used to isolate Compound (I) from other components at the completion of the synthesis process; and/or to purify Compound (I) by one or a series of crystallization steps. The isolation and the purification steps can be combined or practiced as separate process steps.

EXAMPLES

The invention will now be further described by the following working example(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise indicated. These examples are illustrative rather than limiting and it is to be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the claims appended hereto.

The synthesis of Compound (I) is disclosed in U.S. Patent 9,458,156 B2.

The following procedures are included to show various methods of preparing Crystalline Form A of Compound I.

Form A Procedures:

Example 1 Preparation of Crystalline Form A of Compound (I) lOOmg of Compound 1 was dissolved in 4.75 mL THF (tetrahydrofuran) and 0.25 mL water and subjected to heat for complete dissolution. 50 pl of the solution was added to each well of a 96 well quartz plate and evaporated to dryness. Acetonitrile/water was dispensed on the dried material in one of the wells and the plate was sealed. The plate was subjected to temperature cycling in an oven by keeping it isothermal at 50°C for 2 hours then linearly cooling to 20°C over 8 hours, and repeating this procedure 9 times. The plate was removed from the oven to allow evaporation of residual solvent. The solids matched Form A.

Example 2 Preparation of Crystalline Form A of Compound (I)

Approximately 50mg of Compound 1 was dissolved in 5 mL of DMF (Dimethylformamide) at 45 °C and then cooled to room temperature. 15 mL of water was added. Slurry was stirred overnight at room temperature. Slurry was isolated and washed with water. The material was dried at 50°C under vacuum overnight, which resulted in Form A.

Example 3 Preparation of Crystalline Form A of Compound (I)

50mg of Compound 1 was dissolved in 0.50 mL of DMF at 60°C. 0.50 mL of water was added over 10 minutes. The resulting slurry was isolated and dried at 60 °C under 150 torr and slow N2 purge for 16 hours, which resulted in Form A.

Example 4 Preparation of Crystalline Form A of Compound (I)

50mg of Compound 1 was dissolved in 0.25 mL of DMF at 60°C. 0.75 mL of water was added over 10 minutes. The resulting slurry was isolated dried at 60 °C under 150 torr, and slow N2 purge for 16 hours, which resulted in Form A.

Example 5 Preparation of Crystalline Form A of Compound (I)

50mg of Compound 1 was dissolved in 1 mL of acetone at 60°C. 1 mL of water was added over 10 minutes. The resulting slurry was isolated and dried at 60 °C under 150 torr and slow N2 purge for 16 hours, which resulted in Form A.

Amorphous Procedures:

Example 1

Compound 1 was melted at 275°C, then rapidly cooled to 0°C. The solids were amorphous. Example 2

Compound 1 was melted at 275°C, then rapidly cooled to room temperature under nitrogen. The material was exposed to water vapor at room temperature for 5 days. The solids were amorphous.

Example 3

Compound 1 was melted at 275°C, then rapidly cooled to room temperature under nitrogen. The material was exposed to heptane vapor at room temperature for 5 days. The solids were amorphous.

SINGLE CRYSTAL DATA

Single crystal X-ray data were collected using a Bruker X8-Proteum diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator of monochromatic Cu Ka radiation. The single crystal was at room temperature during data collection.

Indexing and processing of the measured intensity data were carried out with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA).

The final unit cell parameters were determined using the full data set. The structures were solved by direct methods and refined by full-matrix least-squares approach using the SHELXTL software package (G. M. Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.). Structure refinements involved minimization of the function defined by ^w(|F_o| - |Fc|)², where w is an appropriate weighting factor based on errors in the observed intensities, F_o is the structure factor based on measured reflections, and F_c is the structure factor based on calculated reflections. Agreement between the refined crystal structure model and the experimental X-ray diffraction data is assessed by using the residual factors R ⁼ ZI -RI/Z ⁼ EH ' )²/ Z^W’E'|]' ²- Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced using idealized geometry with isotropic temperature factors and included in structure factor calculations with fixed parameters. XRPD

XRPD analysis of Form A was performed on a Bruker D8 Advance X-Ray diffractometer with Bragg-Brentano optics configured with a Lynxeye detector was used. The tube was powered to 40kV and 40mA with a fixed detector slit and a scattered radiation slit of 8 mm. The aperture slit was kept at 0.6mm. Sample was loaded on low- background domed sample holders sealed with O-ring and analyzed from 3°-40° 29 with a step size of 0.017° 29 and 0.3 sec/step with sample rotation switched on.

XRPD pattern of amorphous was collected with a PANalytical X'Pert PRO MPD diffractometer in transmission mode using an incident beam of Cu radiation (voltage 45kV and 40mA) produced using a long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector. A specimen of the sample was sandwiched between 3 -pm -thick Kapton films and analyzed in transmission geometry from 1.01-40.00 °29 with a step size of 0.017 °29. The scan speed was 1.2°/min with a fixed diffraction slit of 1/2° and a revolution time of Is. A beam-stop, short anti scatter extension, and anti scatter knife edge were used to minimize the background generated by air. Seller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 5.5.

DSC

DSC of Form A was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter.

The sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, the lid was pierced, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was pierced prior to sample analysis. The samples were analyzed from -30 °C to 250 °C or 350 °C at 10 °C/min.

Temperature Modulated DSC (TMDSC) for the amorphous material was performed using Mettler-Toledo DSC3+ differential scanning calorimeter. TOPEM® overlays the isothermal or ramped temperature with a time series of random temperature pulses of different durations. The sample was placed into a hermetically sealed aluminum DSC pan, and the weight was accurately recorded. The pan lid was pierced then inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was pierced prior to sample analysis. The data was collected from -50 °C to 250 °C at 2 °C/min with a modulation amplitude of ± 0.25 °C and a 15 to 30 second period with an underlying heating rate of 2°C/minute.

TGA TG analysis of Form A was performed using a Mettler-Toledo TGA/DSC3+ analyzer. The sample was placed in an aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. The sample was analyzed from 25 °C to 350 °C at 10 °C/min.

Claims

CLAIMS What is claimed is:

1. Crystalline Form A of Compound (I):

2. The crystalline Form A of Compound (I) according to Claim 1, wherein said crystalline Form A is characterized by a powder x-ray diffraction pattern (PXRD) comprising five or more 29 values (CuKa =1.5418 A) selected from: 6.4 ± 9.2; 8.9 ± 9.2; 9.1 ± 9.2; 12.9 ± 9.2; 16.1 ± 9.2; 18.7 ± 9.2 and 24.2 ± 9.2, wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C.

3. The crystalline Form A of Compound (I) according to Claim 1, wherein said crystalline Form A is characterized by a powder x-ray diffraction pattern (PXRD) comprising six or more 29 values (CuKa =1.5418 A) selected from: 6.4 ± 0.2; 8.0 ± 0.2; 9.1 ± 0.2; 12.9 ± 0.2; 16.1 ± 0.2; 18.7 ± 0.2 and 24.2 ± 0.2, wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C.

4. The crystalline Form A of Compound (I) according to Claim 1, wherein said crystalline Form A is characterized by:

(i) a powder x-ray diffraction pattern (PXRD) comprising four or more 29 values (CuKa =1.5418 A) selected from: 6.4 ± 9.2; 8.0 ± 0.2; 9.1 ± 0.2; 12.9 ± 0.2; 16.1 ± 0.2; 18.7 ± 0.2 and 24.2 ± 0.2; wherein the PXRD pattern of Form A is measured at a temperature of about 25 °C; and

(ii) an endotherm with onset temperature in the range of from 232 °C to 236 °C.

5. The crystalline Form A of Compound (I) according to Claim 1, wherein said crystalline Form A is characterized by an observed powder x-ray diffraction pattern substantially as shown in Figure 1.