Background of the invention

Lenvatinib, 4-[3-Chloro-4-(N'-cyclopropylureido)phenoxy]-7- methoxyquinoline-6-carboxamide methane sulfonate, of formula (I)

is an anti-cancer drug for the treatment of certain kinds of thyroid cancer, and potentially for other cancers as well. It acts as a multiple kinase inhibitor against the VEGFRl , VEGFR2 and VEGFR3 kinases. (Matsui, J. et al., Clinical Cancer Research 14 (17): 5459-65.

Lenvatinib is used for the treatment of differentiated thyroid cancer that is either locally recurrent or metastatic, progressive, and did not respond to treatment with radioactive iodine (radioiodine) - Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Osterreichischer Apothekerverlag; FDA Professional Drug Information for Lenvima.

Lenvatinib is known to have a rather complex polymorphic behavior. Usually the most preferred forms employed in pharmaceutical preparations are the monohydrate or the anhydrous forms. The known crystalline forms, labeled as A, B, C, F, I and DMSO solvate, are described in US 2007/0078159. The amorphous form is described in EP 1 894 918.

There is a strong interest in making available new crystalline forms of Lenvatinib easy to obtain and having the required chemical and physical characteristics.

Description of the invention

The invention concerns novel polymorphs of Lenvatinib mesylate, namely to crystal forms characterized by XP D data and designated as DMSO- 1 , DMSO-2, ACA- 1 , ACA- 1 HT dry, CHF- 1 , FOA- 1 and H ₂ O- 1

The invention is also directed to processes for the preparation of said forms comprising crystallization or re-crystallization from appropriate solvents.

The invention is further directed to pharmaceutical compositions comprising the novel Lenvatinib mesylate crystalline forms.

The new crystal forms were prepared by:

extended stirring (slurry) at room temperature of Lenvatinib mesylate suspensions in different antisolvents or solvent/antisolvent mixtures (CHF-1 form);

thermal treatment at high temperature of powdered solvate forms (ACA-l-HT form);

evaporation of solution or viscous suspension in different temperature/pressure conditions (ACA- 1 , H2O-I forms).

The X-ray powder diffractogram (XRPD) has been obtained using the instrument X'Pert PRO PANalytical with single scan, using Kal radiation. The diffractogram is measured in reflection mode in the range 3-40°2θ.

The FT-Raman spectrum (Fourier transform Raman spectroscopy) was recorded with the Nicolet iS50. The excitation source was a Nd-YAG laser (1064 nm) in the backscattering (180°) configuration. The focused laser beam diameter was approx. 50 um and the spectral resolution 4 cm ^"1 . The spectra were recorded with a laser power at the sample of approx. 100 mW. DSC analyses were carried out using a differential scanning calorimeter DSC 1 Mettler Toledo. The samples were heated at a heating rate of 10 K/min in the temperature range from -25 to 320°C. The thermograms were obtained using the TGA/DSC 1 Mettler Toledo thermo-balance. The samples were heated from 25°C to 450°C at 10 K/min.

The crystal forms of Lenvatinib mesylate of the invention have surprisingly interesting chemical-physical characteristics. They are in particular characterized by high level of chemical purity as well as by good handling characteristics for the preparation of pharmaceutical compositions.

Description of the figures

Figure 1 : X PD spectrum of Lenvatinib, form DMSO-1

Figure 2: FT-Raman spectrum of Lenvatinib, form DMSO- 1

Figure 3 : DSC analysis of Lenvatinib, form DMSO-1

Figure 4: TGA analysis of Lenvatinib, form DMSO-1

Figure 5 : EGA analysis of Lenvatinib, form DMSO-1

Figure 6: XRPD spectrum of Lenvatinib, form DMSO-2

Figure 7: FT-Raman spectrum of Lenvatinib, form DMSO-2

Figure 8: DSC analysis of Lenvatinib, form DMSO-2

Figure 9: TGA analysis of Lenvatinib, form DMSO-2

Figure 10: EGA analysis of Lenvatinib, form DMSO-2

Figure 1 1 : DVS analysis of Lenvatinib, form DMSO-2

Figure 12: XRPD spectrum of Lenvatinib, form ACA-1

Figure 13 : FT-Raman spectrum of Lenvatinib, form ACA- 1.

Figure 14: DSC analysis of Lenvatinib, form ACA-1.

Figure 15: TGA analysis of Lenvatinib, form ACA-1.

Figure 16: EGA analysis of Lenvatinib, form ACA-1

Figure 17: XRPD spectrum of Lenvatinib, form ACA-1 HT DRY

Figure 18: FT-Raman spectrum of Lenvatinib, form ACA- 1 HT DRY.

Figure 19: DSC analysis of Lenvatinib, form ACA-1 HT DRY.

Figure 20: TGA analysis of Lenvatinib, form ACA-1 HT DRY

Figure 21 : EGA analysis of Lenvatinib, form ACA-1 HT DRY Figure 22: DVS analysis of Lenvatinib, form ACA-1 HT DRY

Figure 23: XRPD spectrum of Lenvatinib, form CHF-1

Figure 24: FT-Raman spectrum of Lenvatinib, form CHF- 1

Figure 25: DSC analysis of Lenvatinib, form CHF-1

Figure 26: TGA analysis of Lenvatinib, form CHF-1

Figure 27: EGA analysis of Lenvatinib, form CHF-1

Figure 28: XRPD spectrum of Lenvatinib, form FOA-1

Figure 29: FT-Raman spectrum of Lenvatinib, form FOA- 1

Figure 30: TGA analysis of Lenvatinib, form FOA-1

Figure 31 : EGA analysis of Lenvatinib, form FOA-1

Figure 32: XRPD spectrum of Lenvatinib, form H2O-I

Figure 33 : FT-Raman spectrum of Lenvatinib, form H2O- I

Figure 34: DSC analysis of Lenvatinib, form H2O-I

Figure 35: TGA analysis of Lenvatinib, form H2O-I

Figure 36: EGA analysis of Lenvatinib, form H2O-I

Figure 37: DVS analysis of Lenvatinib, form H2O-I

Details of the preparation and of the characterization of the forms of the invention are reported in the following examples.

Example 1 : DMSO- 1 form

Lenvatinib Mesylate (10-50 mg) was dissolved/suspended in DMSO

(100-200 L), at a temperature ranging from room temperature to the boiling point of the solvent, to give a solution or suspension. The solution/suspension was left under stirring (1- 16 hours) and then filtered to obtain a clear solution.

An anti-solvent (0.5-4.0 mL) was added dropwise to the DMSO solution under stirring at a temperature ranging from 20 to 40°C. The anti-solvents used were esters (preferably ethyl formate, ethyl acetate and isopropyl acetate), ethers (preferably THF and 1 ,2-dimethoxyethane), alcohols (preferably ethanol and 2-propanol), chlorinated solvents (preferably chloroform and dichloromethane), and polar aprotic solvents (preferably acetonitrile).

After 30- 180 minutes the precipitate was recovered under vacuum.

The DMSO-1 form of the invention is a hydrate crystal form.

The solid was recovered in a yield -96% and high level of chemical purity (>99.5%).

The new crystal form DMSO-1 is characterized by the X PD spectrum shown in figure 1. Main peaks at 2theta ± 0.3 degrees are: 4.5, 9.0, 22.8, 25.2.

Table 1 below shows the significant peaks of the spectrum.

Table 1 : XRPD peak list

FT-Raman analysis returns the spectrum shown in figure 2 showing the characteristic bands of form DMSO-1.

DSC analysis, shown in figure 3, does not evidence important endothermic events.

The TGA analysis, shown in figure 4, highlights two weight losses: the first of 1 1.3% and the second of 12.8%. EGA analysis, shown in figure 5, highlights the evolution of water. Above 220°C the melting/degradation of the sample occur. Example 2: DMSO-2 form

Lenvatinib Mesylate (10-50 mg) was dissolved/suspended in DMSO (100-200 L), at a temperature ranging from room temperature to the boiling point of the solvent, to give a solution or suspension. The solution/suspension was left under stirring (1- 16 hours) and then filtered to obtain a clear solution.

An anti-solvent (0.5-4.0 mL) was added dropwise to the DMSO solution under stirring at a temperature ranging from 20 to 40°C. The anti-solvents used were aromatic hydrocarbons (preferably toluene) and apolar ethers (preferably TBME).

After 30-180 minutes the precipitate was recovered under vacuum and washed with TBME.

The Lenvatinib mesylate DMSO-2 of the invention is a hydrate crystal form.

The solid was recovered in a yield -96% and high level of chemical purity (>99.5%)

The new crystal form DMSO-2 is characterized by the X PD spectrum shown in figure 13. Main peaks at 2theta ± 0.3 degrees are: 4.6, 9.2, 15.6, 18.8, 22.1 , 23.2.

Table 2 below shows the significant peaks of the spectrum.

Table 2: XRPD peak list

(continued) 23.1879 336.03 0.0669 3.83600 54.25

25.8843 136.23 0.2007 3.44219 21.99

26.8671 125.45 0.1673 3.31846 20.25

31.7064 17.83 0.8029 2.82215 2.88

37.5436 24.74 0.6691 2.39570 3.99

FT- aman analysis returns the spectrum shown in figure 7.

DSC analysis of the Lenvatinib mesylate form DMSO-2, shown in figure 8, shows a linear profile with a single event at about 120°C, corresponding to the loss of water and the decomposition occurs without melting.

TGA profile showed a broad weight loss up to above 200°C: The EGA analysis showed the evolution of water (see figure 9 and 10). The significant high weight loss observed suggested the present of other solvents.

DVS analysis, shown in figure 1 1 , reports the percentage change in mass as of the relative humidity change.

The sorption and desorption of water was not reversible. The weight loss of the sample between the start and the end of analysis suggested that water promoted the extrusion of as solvent (the weight loss of 12.34% is compatible with the loss of a 1 mol of DMSO).

Lenvatinib mesylate form DMSO-2 was stored at 60°C and 75% RH for three days.

Example 3: ACA-1 form

Lenvatinib Mesylate (10-100 mg) was dissolved in acetic acid (1- 10 mL), at a temperature ranging from room temperature to the boiling point of the solvent, to give a solution. The solution was filtered and left to evaporate at 40- 80°C at room pressure in a vial. After three or more days the dry powder was recovered from the vial.

The solid was recovered in a yield -99% and high level of chemical purity (>99.5%)

The new form ACA-1 is a solvate crystal form characterized by the XRPD spectrum shown in figure 12. Main peaks at 2theta ± 0.3 degrees are: 5.9, 7.7, 10.9, 1 1.9, 12.6, 19.4, 22.6, 23.6, 24.5, 25.9, 26.7.

Table 3 below shows the significant peaks of the spectrum.

Table 3: X PD peak list

FT-Raman analysis returns the spectrum shown in figure 13.

The spectrum reports the characteristic bands of form ACA-1.

DSC analysis, shown in figure 14, highlights a broad endothermic peak approx. at 1 18 °C (onset= 91.2°C), associated to the loss of acetic acid, and then a second endothermic peak approx. at 185°C (onset= 169.4°C), associated to the melting/decomposition of the sample. The TGA analysis, shown in figure 15, highlights a first weight loss of 5.0%, between approx. 90 and 160°C, associated to the loss of 0.5 mol. of acetic acid (as confirmed by EGA analysis figure 16) and then two weight losses of acetic acid during the melting/decomposition of the sample, potentially associated to the loss of the solvent mechanically trapped in the solid powder.

Example 4: ACA-1 HT DRY form

The Lenvatinib mesylate ACA- 1 HT DRY of the invention is an anhydrous crystal form which is obtained by heating a sample of the ACA-1 form in an oven at a temperature from 80 to 160 °C and a pressure from 1 to 10 ^"2 atm.

The solid was recovered in a yield -99% and high level of chemical purity (>99.5%).The new crystal form ACA- 1 HT DRY is characterized by the XRPD spectrum shown in figure 17. Main peaks at 2theta ± 0.3 degrees are: 6.0, 7.7, 1 1.2, 13.6, 19.4, 20.0, 23.1 , 26.9.

Table 4 below shows the significant peaks of the spectrum.

Table 4: XRPD peak list

(continued) 24.9569 219.93 0.1673 3.56795 33.56

25.2778 155.38 0.1338 3.52338 23.71

26.9899 293.07 0.2007 3.30364 44.72

28.8555 174.53 0.1 171 3.09416 26.63

31.6848 30.62 0.2007 2.82403 4.67

33.5104 33.25 0.4015 2.67424 5.07

35.6614 40.96 0.2007 2.51771 6.25

37.5763 27.1 1 0.4015 2.39370 4.14

FT- aman analysis returns the spectrum shown in figure

spectrum reports the characteristic bands of form ACA- 1 HT DRY.

DSC analysis, shown in figure 19, highlights a first endothermic event (peak approx. at 47°C) associated to the evaporation of water, and an endothermic peak at 185°C (onset = 167.6°C) associated to the melting/decomposition of the sample.

The TGA analysis, shown in figure 20, highlights an initial weight loss of 4.8%, between approx. 25 and 1 15°C, reasonably associated to the evaporation of adsorbed water (confirmed by EGA analysis figure 21).

The DVS analysis, shown in figure 22, reports the percentage change in mass as function of the relative humidity change.

The sorption and desorption of water was not very reversible and the analysis evidenced a small event (probably associated to molecular rearrangements of the API).

The sample recovered at the end of DVS analysis was analyzed by XRPD: its diffractogram was quite amorphous but its crystal structure did not change.

Example 5: CHF-1 form

A) Lenvatinib Mesylate (100-1000 mg) in an anhydrous form was suspended in chloroform (2-10 mL) and stirred for 1 -30 days at a temperature from room temperature to the boiling point of chloroform.

The suspension was recovered under vacuum.

B) Lenvatinib Mesylate (50-100 mg) was dissolved/suspended in acetic acid (100-200 L), at a temperature ranging from room temperature to the boiling point of the solvent, to give a solution/suspension. The solution/suspension was left under stirring (1-16 hours) and then filtered to obtain a clear solution.

Chloroform (0.5-4.0 mL) was added dropwise to the formic acid solution under stirring at a temperature ranging from 10 to 40°C.

After 1-5 days the precipitate was recovered under vacuum and washed with chloroform.

The new crystal form CHF- 1 is characterized by the X PD spectrum shown in figure 23.

Main peaks at 2theta ± 0.3 degrees are: 4.5, 9.1 , 15.7, 16.9, 17.3, 18.2,

18.9, 19.9, 20.5, 21.1 , 21.8, 22.4, 22.8, 25.1 , 25.6.

Table 5 below shows the significant peaks of the spectrum.

Table 5: XRPD peak list

(continued) 26.7025 84.65 0.2007 3.33855 8.99

27.4179 191.40 0.1673 3.25304 20.33

28.1352 64.50 0.2007 3.17171 6.85

29.3075 216.21 0.1673 3.04746 22.97

31.6745 59.36 0.3346 2.82492 6.31

32.0849 96.81 0.2007 2.78972 10.28

32.7288 94.40 0.2007 2.73629 10.03

33.2522 47.13 0.2007 2.69441 5.01

34.1278 72.77 0.2342 2.62726 7.73

35.9972 164.31 0.1673 2.49499 17.45

36.9065 41.47 0.1673 2.43558 4.41

38.4582 59.55 0.2007 2.34081 6.33

39.2658 45.51 0.2007 2.29451 4.83

FT- aman analysis returns the spectrum shown in figure 24. The spectrum reports the characteristic bands of form CHF- 1.

DSC analysis, shown in figure 25, highlights an endothermic peak during the weight loss at approx. 120°C and the melting at approx. 240°C.

The TGA analysis, shown in figure 26, highlights a weight loss approx. of 12%, between approx. 90 and 150°C, and then the decomposition of the sample after 230 °C. The EG analysis demonstrates that the weight loss was due to the simultaneously loss of acetic acid and chloroform (see figure 27).

Example 6 FOA-1

Lenvatinib Mesylate (50- 100 mg) was dissolved in formic acid (100-200 L), at a temperature ranging from room temperature to the boiling point of the solvent, to give a solution. The solution was left under stirring (1- 16 hours) and then filtered to obtain a clear solution.

An anti-solvent (0.5-4.0 mL) was added dropwise to the formic acid solution under stirring at a temperature ranging from 10 to 40°C. The anti- solvents used were esters (preferably ethyl formate, ethyl acetate and isopropyl acetate), ethers (preferably THF and TBME), alcohols (preferably ethanol and 2-propanol), chlorinated solvents (preferably chloroform and dichloromethane), ketones (preferably acetone and MEK), and polar aprotic solvents (preferably acetonitrile). After 30-180 minutes the precipitate was recovered under vacuum and washed with a low-boiling anti-solvent.

The Lenvatinib mesylate FOA-1 of the invention is a solvate crystal form characterized by the X PD spectrum shown in figure 28. Main peaks at 2theta ± 0.3 degrees are: 4.7, 10.5, 1 1.9, 16.1 , 16.8, 17.5, 21.4, 22.4, 22.9, 23.7, 26.1.

Table 6 below shows the significant peaks of the spectrum.

Table 6: XRPD peak list

(continued) 31.9960 61.97 0.1338 2.79726 0.72

34.5173 50.78 0.2676 2.59850 0.59

35.7922 61.68 0.2676 2.50881 0.71

38.2843 42.21 0.4015 2.35104 0.49

39.3257 82.72 0.1338 2.291 15 0.96

FT- aman analysis returns the spectrum shown in figure 29. The spectrum reports the characteristic bands of form FOA- 1.

The TGA analysis, shown in figure 30, highlights a combination of two step weight loss of 12.5% (between approx. 60 and 140°C) and then the melting/degradation of the sample above 220 °C. An endothermic peak in the heat- flow during the loss of weight was present.

The EG analysis shows that the weight loss was due to the loss of formic acid and ethyl acetate (see figure 31).

Example 7:H2O-l Lenvatinib Mesylate (100-1000 mg) in anhydrous or hydrate form was suspended in water (10- 100 mL) and stirred for 1 -7 days at a temperature from room temperature to the boiling point of water. The viscous liquid obtained was dried at a temperature from 30 to 80 °C and at a pressure from 1 to 10 ^"2 atm.

The Lenvatinib mesylate H2O-I of the invention is an anhydrous crystal form, characterized by evaporation in different conditions of the very viscous liquid obtained stirring for several hours the crystal Form A in pure water. This viscous liquid (similar to a gel) was also obtained by kneading and by heating/cooling cycles of the suspension of Form A in pure water.

The preferred evaporation conditions tested were:

- 60°C / approx. 1 atm

40°C / 10- ² atm

30°C7 10 ^"2 atm.

The solid was recovered in a yield -99% and high level of chemical purity (>99.5%).

The new crystal form H2O- I is characterized by the XRPD spectrum shown in figure 32. Main peaks at 2theta ± 0.3 degrees are: 4.5, 5.1 , 9.1 , 10.5, 19.9, 24.1. Table 7 below shows the significant peaks of the spectrum.

Table 7: XRPD peak list

FT-Raman analysis returns the spectrum shown in figure 33. The spectrum reports the characteristic bands of form H2O- I .

DSC analysis, shown in figure 34, highlights two endothermic events: the first peak at approx. 69°C (onset= 34.6°C) is broad and it was associated to the loss of water; the second peak at 154 °C (onset= 140.5°C) can be associated to the melting of the sample.

The TGA analysis, shown in figure 35, highlights a broad weight loss of 6.7%, between approx. 25 and 150°C, associated to the evaporation of water (as confirmed by EG analysis), and then the degradation of the sample after 200 °C (confirmed by EGA analysis figure 36).

In DVS analysis, shown in figure 22, the sorption and desorption of water was reversible and the analysis did not evidence any event.

The sample recovered at the end of DVS analysis was analyzed by XRPD: its diffractogram did not show any important modification.

The data recorded by DVS analysis showed a mass increased percentage of 10.9% between 40% end 80% RH of the absorption cycle: the sample was classified as hygroscopic.