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Summary of the Invention

The present invention relates to the amorphous form of macitentan and new crystalline forms thereof. The invention also relates to processes for the preparation of the new compounds, the pharmaceutical compositions comprising them and the use thereof in the therapy.

Technical Field

Macitentan is the International Common Denomination (ICD) of the compound N-[5- (4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-p yrimidinyl]-N'- propyl-sulfamide of formula (I)

Macitentan is an endothelin receptor antagonist compound active in the oral form and has been recently introduced in the therapy for the treatment of pulmonary arterial hypertension, alone or in combination with other active ingredients.

J. Med. Chem. 2012, 55, 7849-7861 describes two crystalline forms of macitentan, obtained by re-crystallizing macitentan from ethyl acetate/hexane mixture and methanol, respectively. In particular, one of the two polymorphs, defined as form I, is pure whereas the polymorph, defined as form II, is a methanol solvate.

It is known that crystalline forms of active pharmaceutical ingredients can show different physico-chemical properties and can offer advantages, for example in terms of solubility, stability and bioavailability. As a consequence, the research and discovery of new crystalline forms of active pharmaceutical ingredients can result in more reliable and effective therapies. For this reason, it is considered a contribution to the art the preparation of new crystalline forms of active pharmaceutical ingredients, because such new forms can allow to improve the stability, the bioavailability and the pharmacokinetics, to limit the hygroscopicity, and/or to aid the galenic and industrial manufacturing of the active pharmaceutical ingredients.

However, the preparation of such new crystalline forms is absolutely not evident, it is not predictable and not always possible.

Also for macitentan, there is an interest in looking for new crystalline forms showing physico-chemical properties suitable for a safe and effective therapeutic use.

It is also of significant interest the research of the amorphous forms of the pharmaceutical compounds, i.e. the non-crystalline forms, because it is known that an amorphous form of an active ingredient could be more bioavailable with respect to a crystalline form.

Objects of the Invention

It is an object of the invention to provide an amorphous (non-crystalline) form of macitentan.

It is another object of the invention to provide new crystalline forms of macitentan. Another object of the invention is to provide processes for the preparation of said new compounds, of the pharmaceutical compositions comprising them and for the use thereof in the therapy.

Brief description of the drawings

Figure 1 shows XRPD of the amorphous form of macitentan

Figure 2 shows FT-IR spectrum of the amorphous form of macitentan

Figure 3 shows DSC spectrum of the amorphous form of macitentan

Figure 4 shows TGA spectrum of the amorphous form of macitentan

Figure 5 shows XRPD of crystalline form III of macitentan

Figure 6 shows FT-IR spectrum of crystalline form III of macitentan

Figure 7 shows DSC spectrum of crystalline form III of macitentan

Figure 8 shows TGA spectrum of crystalline form III of macitentan

Figure 9 shows EGA spectrum of crystalline form III of macitentan

Figure 10 shows XRPD of crystalline form IV of macitentan Figure 11 shows FT-IR spectrum of crystalline form IV of macitentan

Figure 12 shows DSC spectrum of crystalline form IV of macitentan

Figure 13 shows TGA spectrum of form IV of macitentan

Figure 14 shows EGA spectrum of form IV of macitentan

Figure 15 shows XRPD of crystalline form V of macitentan

Figure 16 shows FT-IR spectrum of crystalline form V of macitentan

Figure 17 shows DSC spectrum of crystalline form V of macitentan

Figure 18 shows TGA spectrum of form V of macitentan

Figure 19 shows EGA spectrum of form V of macitentan

Description of the Invention

It has now been found that it is possible to obtain the amorphous form and new crystalline forms of macitentan.

The amorphous form and the new crystalline forms of macitentan of the invention have never been disclosed in the current literature and represent a subject-matter of the present invention.

As a consequence, a subject-matter of the invention, according to one of the aspects thereof, is an amorphous form, i.e. non-crystalline, of macitentan.

Another subject-matter of the invention, according to another of the aspects thereof, is a process for the preparation of the amorphous form of macitentan which comprises dissolving macitentan in dimethyl sulfoxide (DMSO) and then evaporating the solvent, preferably at a temperature between 30°C and 80°C, advantageously around 60°C. The amorphous form of macitentan obtained and/or obtainable with the process described above, represents a further subject-matter of the present invention.

The amorphous form of macitentan has been characterized and the X-ray diffraction (XRPD), infrared (FT-IR), differential scanning calorimetry (DSC) spectra are provided in Figures 1 to 3 appended to the present description. Figure 4 reports the thermogravimetric (TGA) analysis plot of the amorphous form.

New crystalline forms of the invention have been also synthesized and have been characterized by means of X-ray diffraction (XRPD), infrared (FT-IR), differential scanning calorimetry (DSC) spectra thereof, and have shown to be different from the known forms I and II above. Characterization data of the crystalline compounds of the invention are provided in the Experimental Section of the present description and in the appended figures.

Therefore another subject-matter of the invention, according to another of the aspects thereof, is a new crystalline form of macitentan, herein defined as form III, which shows the X-ray diffraction spectrum of Figure 5 and the IR spectrum of Figure 6 and the DSC plot of Figure 7. Figures 8 and 9 report the plots of the thermogravimetric analysis (TGA) and of the evolved gas analysis (EGA).

It has been observed that crystalline form III is a crystalline form of macitentan 1,4- dioxane solvate.

Another subject-matter of the invention, according to another of the aspects thereof, is a process for the preparation of crystalline form III, which comprises dissolving macitentan in 1,4-dioxane or in a solvent mixture comprising 1,4-dioxane and then evaporating the solvent. Advantageously, form III can be obtained from dioxane in a mixture with a solvent selected from acetonitrile, acetone, methyl ethyl ketone, chloroform and ethyl acetate. Solvent evaporation can be carried out at room temperature: 17-25°C/1 arm, at low temperature: 4-10°C/l arm; at high temperature: 60°C/1 arm; at low pressure 17-25°C/10 ^"2 arm or at high temperature and low pressure: 40°C/10 ^"2 atm.

According to a preferred embodiment, evaporation is carried out at low temperature and at room pressure (4-10°C/l atm) or at 40°C and at a pressure of 10 ^"2 atm.

DSC profile of the crystalline form III presents a first endothermic peak at 76°C (probably related to solvent loss) and, following an exothermic signal, a melting peak at about 113°C.

TGA and EGA analyses confirmed the presence of the solvent in the crystal.

The crystalline form III of macitentan obtained and/or obtainable with the process described above, represents a further subject-matter of the present invention.

Another subject-matter of the invention, according to another of the aspects thereof, is a new crystalline form of macitentan, herein defined as form IV, which exhibits the X- ray diffraction spectrum of Figure 10 and the FT-IR spectrum of Figure 11 and the DSC plot of Figure 12. Figures 13 and 14 report the plots of the thermogravimetric analysis (TGA) and of the evolved gas analysis (EGA). Another subject-matter of the invention, according to another of the aspects thereof, is a process for the preparation of crystalline form IV, which comprises dissolving macitentan in a solvent mixture comprising at least 2-methoxyethanol and acetonitrile, advantageously from a mixture of 2-methoxyethanol and acetonitrile, and then evaporating the solvents.

According to a preferred embodiment, evaporation is carried out at room temperature and pressure (17-25°C/1 atm).

It has been observed that crystalline form IV is a crystalline form of macitentan 2- methoxyethanol solvate.

DSC profile of crystalline form IV has a first endothermic peak at 96°C (probably related to solvent loss) and a melting peak at about 125°C.

TGA and EGA analyses confirmed the presence of the solvent in the crystal.

Crystalline form IV of macitentan obtained and/or obtainable with the process described above, represents a further subject-matter of the present invention.

The terms "solvate" or "solvate form" are used herein to denote that the crystalline compound comprises stoichiometric or non-stoichiometric quantities of one or more solvents.

A subject-matter of the invention, according to another of the aspects thereof, is a new crystalline form of macitentan, herein defined as form V, which exhibits the X-ray diffraction spectrum of Figure 15 and the IR spectrum of Figure 16 and the DSC plot of Figure 17. Figures 18 and 19 report the plots of the thermogravimetric analysis (TGA) and of the evolved gas analysis (EGA).

It has been observed that the crystalline form V is a crystalline form of macitentan chloroform solvate.

A subject-matter of the invention, according to another of the aspects thereof, is a process for the preparation of the crystalline form V, which comprises evaporating a solution of macitentan from a mixture of chloroform and acetone.

According to a preferred embodiment, evaporation is carried out at low temperature and room pressure. DSC profile of crystalline form V has a first endothermic peak at 76°C (probably related to solvent loss) and, following an exothermic signal, a melting peak at about 132°C.

TGA and EGA analyses confirmed the presence of the solvent in the crystal.

The crystalline form V of macitentan obtained and/or obtainable with the process described above, represents a further subject-matter of the present invention.

Details about the process described above are provided in the Experimental Section of the present description.

The new amorphous form of the invention showed excellent physico-chemical properties and is, therefore, a valuable alternative to the currently available macitentan forms for the administration in humans and/or animals.

A subject-matter of the invention, according to another of the aspects thereof, is a pharmaceutical composition which comprises the amorphous (non-crystalline) form of macitentan according to the invention, in combination with one or more pharmaceutically acceptable vehicles or excipients. Advantageously, the compositions of the invention comprise the amorphous form as defined in the present description and in the appended figures.

The pharmaceutical compositions of the invention are particularly suited for the oral administration.

For the oral administration, said compositions can be in the form of tablets, capsules or granules and are prepared according to conventional methods with pharmaceutically acceptable excipients such as binders, fillers, lubricants, disintegrants, wetting agents, flavors, etc. Tablets can in addition be coated by means of methods well known in the art.

The compositions of the invention are advantageously in the form of unit dose. Preferably, each unit dose according to the invention comprises 1 to 100 mg, e.g. 5 to 50 mg, advantageously 8 to 20 mg, e.g. about 10 mg, of the new crystalline forms or the amorphous form according to the invention, advantageously in combination with standard excipients and additives well known to one skilled in the field. Other dosages can be obviously provided, depending on diseases and on conditions of the subject to be treated. According to a preferred embodiment, the compositions of the invention comprise as active ingredient, the amorphous form of macitentan, advantageously the amorphous form as defined in the present description and in the appended figures.

A subject-matter of the invention, according to another of the aspects thereof, is the amorphous form of macitentan, and/or the pharmaceutical compositions of the invention for the use thereof in the therapy, in particular in the therapy of pulmonary arterial hypertension.

The invention also comprises a method for the treatment of the pulmonary arterial hypertension which comprises administering, to a subject in need of it, an effective amount of the amorphous form of macitentan, advantageously in the form of a pharmaceutical composition as defined above.

The amorphous form and the new crystalline forms of macitentan can be also converted in other polymorphs of macitentan.

Therefore a subject-matter of the invention, according to another of the aspects thereof, is the use of the amorphous form of macitentan for the preparation of macitentan crystalline forms.

A subject-matter of the invention, according to another of the aspects thereof, is the use of a crystalline form of macitentan selected from forms (III), (IV), (V) and mixtures thereof, for the preparation of the amorphous form of macitentan or of another crystalline form of macitentan.

Experimental Section

XRPD

The samples underwent X-ray powder diffraction on the untreated samples.

Instrument: X'Pert PRO

Scan Axis

Start Position [°2Th.]

End Position [°2Th.]

Step Size [°2Th.]

Scan Step Time [s]

Scan Type

PSD Mode PSD Length [°2Th.] 2.12

Offset [°2Th.] 0.0000

Divergence Slit Type Fixed

Divergence Slit Size [°] 0.4354

Specimen Length [mm] 10.00

Measurement Temperature [°C] 25.00

Anode Material Cu

K-Alphal [A] 1.54060

K-Alpha2 [A] 1.54443

K-Beta [A] 1.39225

K-A2 / -Al Ratio 0.50000

Generator Settings 40 mA, 40 kV

Diffractometer Type 0000000011019590

Diffractometer Number 0

Goniometer Radius [mm] 240.00

Dist. Focus-Diverg. Slit [mm] 100.00

Incident Beam Monochromator No

Spinning Yes

FT-IR

The analysis has been carried out using a Thermo Nicolet 6700 FT-IT spectrometer equipped with Smart performer ZnSe; DTGS Kbr Detector; IR Source; KBr Beam Splitter.

DSC

The analysis has been carried out by using a DSC 200 F3 Maia ^®

Temperature range -170°C. .. 600°C

Heating rate 0.001 K/min .. lOOK/min

Cooling rate 0.001K/min..00K/min (depending

temperature)

Sensor "heat flux system"

Measurement interval 0 mW .. ± 600 mW

Temperature accuracy 0.1 K Enthalpy accuracy < 1%

TGA

The analysis has been carried out with a Mettler Toledo Star ⁶ System.

Temperature interval from room temperature to 1100 °C

Temperature accuracy ±1 K

Temperature precision ±0.4 K

Heating rate 0.02 ... 250 K/min

Cooling time 20 min (H00 ... 100 °C)

Sample volume <100 μ1_,

EGA

The analysis has been carried out on gases produced by the TGA.

Automation 34 samples positions

TGA-FTIR coupled with a Thermo Nicolet 6700 spectrometer "Balance data" XP5

Measurement range <5 g

Resolution 1.0 μ _§

Weight accuracy 0.005%

Weight precision 0.0025%

Loads of the inner ring 2

Reproducibility of background curve: greater than ±10 μg over the whole temperature range

Example 1

Preparation of the amorphous form of macitentan

A solution of 50 mg of macitentan in 5 ml of dimethyl sulfoxide (DMSO) is prepared by heating up to about 100°C under stirring. It is then left to cool down to room temperature, filtered with a Whatman 0.45 micron filter and the solvent is evaporated at a temperature of about 60°C and at room pressure.

The IR spectrum of the amorphous form exhibits the following absorption bands:

Position Intensity

502 34,602 543 26,189

557 28,557

574 32,026

614 44,842

630 44,953

657 49,751

690 42,717

721 56,458

740 58,837

790 37,198

802 54,341

826 39,547

857 53,983

935 52,056

998 29,590

1013 39,744

1054 31,840

1083 35,824

1139 51,162

1167 41,863

1212 61,073

1305 33,299

1331 49,726

1389 54,374

1420 24,181

1452 51,858

1548 48,338

1567 39,023

1618 73,819

1652 76,412 2876 78,496

2930 75,954

2963 75,165

3048 79,450

Example 2

Preparation of the crystalline form III of macitentan

50 mg of macitentan are dissolved in 5 ml of 1,4-dioxane. The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is left to evaporate. The crystalline form III of macitentan is then obtained. The X-ray diffraction spectrum showed the following characteristic peaks

Pos. [°2Th.] Intensity [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]

8.0493 435.45 0.1171 10.98421 15.71

11.4367 1661.68 0.1338 7.73737 59.95

13.0675 500.42 0.1171 6.77516 18.05

13.3493 317.58 0.1338 6.63278 11.46

13.9920 438.57 0.0836 6.32954 15.82

14.3374 428.42 0.1171 6.17780 15.46

16.1004 2771.76 0.1338 5.50509 100.00

17.1908 439.05 0.1338 5.15830 15.84

17.6316 27.22 0.2007 5.03030 0.98

18.1851 1438.57 0.1338 4.87843 51.90

18.5730 1869.92 0.1673 4.77742 67.46

19.6098 79.22 0.1004 4.52709 2.86

20.0937 705.31 0.1171 4.41915 25.45

20.3594 216.08 0.0836 4.36207 7.80

21.3017 719.95 0.1004 4.17120 25.97

21.4241 810.37 0.1171 4.14765 29.24

22.0501 809.63 0.1004 4.03129 29.21

22.7109 436.44 0.1004 3.91547 15.75 22.9603 576.61 0.1171 3.87351 20.80

23.4471 1522.65 0.1338 3.79417 54.93

24.5808 223.07 0.0836 3.62169 8.05

25.3961 1850.34 0.1171 3.50724 66.76

25.6632 252.05 0.1004 3.47134 9.09

26.0670 390.93 0.1004 3.41847 14.10

26.5784 714.24 0.1020 3.35108 25.77

26.6859 967.33 0.0836 3.34059 34.90

27.7052 328.44 0.0669 3.21996 11.85

28.2708 1010.83 0.1338 3.15681 36.47

28.5287 725.92 0.0836 3.12886 26.19

29.0698 221.25 0.1171 3.07183 7.98

29.4389 89.23 0.1338 3.03416 3.22

29.7298 134.30 0.1004 3.00512 4.85

30.0408 185.13 0.1171 2.97472 6.68

31.2096 930.92 0.1338 2.86593 33.59

31.7284 138.41 0.1338 2.82024 4.99

32.4998 215.26 0.0502 2.75505 7.77

32.9927 131.76 0.1338 2.71500 4.75

33.5837 131.91 0.1338 2.66857 4.76

34.3216 201.07 0.1338 2.61286 7.25

35.5495 164.39 0.2342 2.52538 5.93

36.5207 84.65 0.1338 2.46042 3.05

36.8522 155.73 0.1004 2.43905 5.62

37.3291 88.66 0.1004 2.40898 3.20

37.6369 238.57 0.1171 2.38998 8.61

38.4727 115.95 0.1338 2.33996 4.18

38.9075 53.88 0.1004 2.31481 1.94

39.6135 98.87 0.1004 2.27517 3.57

The IR spectrum the form III exhibits the following absorption bands: Position Intensity

528 29.948

545 26.019

577 22.255

613 53.790

639 49.924

658 42.098

674 56.742

691 42.032

718 57.507

746 61.303

788 37.947

828 38.036

862 37.990

927 55.923

997 33.940

1016 47.790

1029 41.666

1060 15.587

1079 20.682

1118 56.444

1148 52.949

1160 39.150

1255 63.885

1293 31.614

1306 34.240

1326 39.292

1358 66.268

1385 47.109

1411 40.509 1432 33.343

1463 41.508

1553 40.992

1567 29.196

2853 75.535

2921 72.689

3321 81.658

Example 3

Preparation of the crystalline form III of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of 1,4-dioxane and acetonitrile (1/1 ; v/v). The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is left to evaporate. The crystalline form III of macitentan is then obtained.

Example 4

Preparation of the crystalline form III of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of 1,4-dioxane and acetone (1/1 ; v/v). The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is evaporated at low pressure (10 ^"2 atm) and at room temperature. The crystalline form III of macitentan is then obtained.

Example 5

Preparation of the crystalline form III of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of 1,4-dioxane and ethanol (1/1; v/v). The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is evaporated at low pressure (10 ^"2 atm) and at 40°C. The crystalline form III of macitentan is then obtained. Example 6

Preparation of the crystalline form III of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of 1 ,4-dioxane and chloroform (1/1 ; v/v). The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is evaporated at low temperature (about 4-10°C) and at room pressure. The crystalline form III of macitentan is then obtained.

Example 7

Preparation of the crystalline form IV of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of 2- methoxyethanol/acetonitrile (1/1, v/v). The solution is left under stirring at room temperature for about 60 minutes. It is filtered with a Whatman 0.45 micron filter and the solvent is left to evaporate. The crystalline form IV of macitentan is then obtained. The X-ray diffraction spectrum showed the following characteristic peaks

Pos. [°2Th.] Intensity [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]

6.3286 56.94 0.2007 13.96646 3.74

8.5215 87.34 0.2007 . 10.37664 5.73

10.8300 169.10 0.0836 8.16936 11.09

12.2972 159.85 0.2342 7.19779 10.48

13.1878 112.59 0.2342 6.71362 7.38

14.2819 100.58 0.1338 6.20169 6.60

14.6698 105.34 0.1338 6.03859 6.91

15.7754 23.13 0.4015 5.61778 1.52

17.0345 59.62 0.1338 5.20527 3.91

17.8573 180.01 0.0836 4.96723 11.81

18.3238 38.74 0.2007 4.84182 2.54

19.0408 1524.57 0.1673 4.66108 100.00

19.7305 97.67 0.1673 4.49968 6.41

20.4674 49.71 0.1673 4.33932 3.26

21.1624 169.64 0.1673 4.19834 11.13

21.8297 487.97 0.1171 4.07149 32.01

22.6196 266.60 0.1673 3.93106 17.49

22.9343 175.35 0.1004 3.87783 11.50

23.5891 310.37 0.1338 3.77166 20.36

23.7925 413.62 0.1338 3.73987 27.13 24.0965 154.63 0.1004 3.69337 10.14

24.7001 190.17 0.1004 3.60446 12.47

25.1239 710.31 0.1171 3.54461 46.59

25.7126 246.95 0.1338 3.46479 16.20

26.5195 42.99 0.1338 3.36116 2.82

27.2119 123.63 0.2007 3.27719 8.11

27.9508 153.20 0.1673 3.19221 10.05

28.4721 116.55 0.2342 3.13494 7.64

29.6389 60.21 0.2007 3.01413 3.95

30.4165 21.48 0.2007 2.93883 1.41

30.9051 37.21 0.1004 2.89347 2.44

31.3248 55.82 0.2007 2.85565 3.66

31.8986 116.36 0.1338 2.80558 7.63

32.1976 68.55 0.1338 2.78021 4.50

32.6730 59.48 0.1338 2.74083 3.90

33.3799 69.90 0.1338 2.68439 4.58

33.7918 75.05 0.1004 2.65261 4.92

36.0388 36.52 0.2007 2.49220 2.40

37.9547 35.56 0.2007 2.37069 2.33

38.5948 50.19 0.2676 2.33284 3.29

The IR spectrum of form IV exhibits the following absorption bands:

Position Intensity

510 48.153

544 37.405

557 41.826

574 35.789

640 53.714

650 62.535

689 52.228 717 70.262

745 73.945

789 49.109

828 50.064

846 66.218

862 58.906

892 61.223

932 64.630

939 66.541

998 43.031

1016 56.188

1059 30.401

1091 45.573

1102 56.469

1126 72.998

1163 44.592

1217 74.292

1268 69.040

1288 53.639

1308 44.918

1330 45.831

1361 71.053

1384 59.277

1422 36.792

1451 48.707

1566 44.969

1723 89.461

2769 85.194

2855 80.805

2923 77.036 2961 79.513

3284 81.559

Example 8

Preparation of the crystalline form V of macitentan

50 mg of macitentan are dissolved in 5 ml of a mixture of chloroform and acetone (1/1 , v/v) by heating to the boiling point of the mixture, under stirring. The solution is left to cool down to room temperature, it is filtered with a Whatman 0.45 micron filter and the solvent is evaporated at low temperature, about 4-10°C and at room pressure. The crystalline form V of macitentan is then obtained. The X-ray diffraction spectrum showed the following X-ray diffraction features:

Pos. [°2Th.] Intensity [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]

4.5808 43.33 0.8029 19.29049 8,24

6.0557 97.15 0.2007 14.59529 18,47

7.9465 151.36 0.1673 11.12613 28.77

11.3513 452.23 0.0836 7.79535 85.97

11.7196 191.95 0.0836 7.55118 36.49

13.1926 32.90 0.3346 6.71119 6,25

14.1869 44.71 0.4015 6.24301 8,50

15.8233 82.44 0.2007 5.60087 15.67

16.4248 526.03 0.0836 5.39709 100.00

17.0945 94.20 0.1338 5.18714 17.91

17.9948 70.52 0.2007 4.92958 13,41

18.2910 146.63 0.1338 4.85042 27.87

18.7023 252.73 0.1171 4.74468 48.04

20.6271 215.83 0.1004 4.30606 41.03

21.8438 351.49 0.2007 4.06890 66.82

22.8555 118.34 0.2676 3.89103 22,50

23.5836 87.18 0.3346 3.77252 16,57

24.1386 91.96 0.1673 3.68703 17,48

24.7511 89.54 0.1338 3.59715 17,02 25.4151 101.97 0.0669 3.50466 19,38

26.2492 48.54 0.2007 3.39516 9,23

26.7233 107.23 0.1004 3.33600 20,39

27.8562 254.70 0.1004 3.20285 48.42

28.5091 94.58 0.4015 3.13096 17.98

29.1929 45.36 0.1338 3.05916 8.62

29.7448 61.22 0.3346 3.00365 11.64

30.3009 90.57 0.3346 2.94978 17,22

31.3651 61.97 0.2342 2.85208 11.78

31.8773 27.05 0.2007 2.80741 5,14

32.4984 21.68 0.2007 2.75516 4,12

33.7678 31.79 0.2342 2.65444 6,04

35.9834 26.40 0.8029 2.49592 5,02

38.5004 17,34 0.4015 2.33834 3,30

The IR spectrum of form V exhibits the following absorption bands:

Position Intensity

510 40,049

544 21,837

557 31,326

575 28,321

631 50,522

640 42,038

657 43,423

667 51,487

674 51,063

691 39,793

719 54,347

746 45,329

758 47,914 W

20

788 34,182

814 42,221

829 39,866

845 60,569

863 53,684

892 57,744

923 54,208

933 59,048

997 29,749

1016 43,661

1027 49,286

1058 21,741

1084 28,308

1101 55,488

1118 66,997

1126 69,014

1161 41,384

1217 68,125

1260 58,244

1289 44,675

1307 31,685

1326 40,259

1356 64,213

1383 50,641

1412 40,980

1430 41,370

1458 44,458

1553 42,045

1566 32,523

2730 82,580 2767 82,051

2853 77,829

2923 73,054

2961 75,555

3030 83,407

3285 82,871