Crystal forms of lenvatinib

Abstract

The present invention provides novel crystalline forms of 4-[3-Chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate, as well as methods for their preparation.

Description

This application is a U.S. national stage of PCT/EP2017/073354 filed on 15 Sep. 2017, which claims priority to and the benefit of European Application No. 16189825.9 filed on 21 Sep. 2016, the contents of which are incorporated herein by reference in their entireties.)

BACKGROUND OF THE INVENTION

Lenvatinib, 4-[3-Chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate, 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 VEGFR1, 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: Österreichischer 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 XPRD data and designated as DMSO-1, DMSO-2, ACA-1, ACA-1 HT dry, CHF-1, FOA-1 and H₂O-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-1-HT form);
  • evaporation of solution or viscous suspension in different temperature/pressure conditions (ACA-1, H₂O-1 forms).

The X-ray powder diffractogram (XRPD) has been obtained using the instrument X′Pert PRO PANalytical with single scan, using Kα1 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 cm¹. 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 DSC1 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/DSC1 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

FIG. 1: XRPD spectrum of Lenvatinib, form DMSO-1

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

FIG. 3: DSC analysis of Lenvatinib, form DMSO-1

FIG. 4: TGA analysis of Lenvatinib, form DMSO-1

FIG. 5: EGA analysis of Lenvatinib, form DMSO-1

FIG. 6: XRPD spectrum of Lenvatinib, form DMSO-2

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

FIG. 8: DSC analysis of Lenvatinib, form DMSO-2

FIG. 9: TGA analysis of Lenvatinib, form DMSO-2

FIG. 10: EGA analysis of Lenvatinib, form DMSO-2

FIG. 11: DVS analysis of Lenvatinib, form DMSO-2

FIG. 12: XRPD spectrum of Lenvatinib, form ACA-1

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

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

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

FIG. 16: EGA analysis of Lenvatinib, form ACA-1

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

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

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

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

FIG. 21: EGA analysis of Lenvatinib, form ACA-1 HT DRY

FIG. 22: DVS analysis of Lenvatinib, form ACA-1 HT DRY

FIG. 23: XRPD spectrum of Lenvatinib, form CHF-1

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

FIG. 25: DSC analysis of Lenvatinib, form CHF-1

FIG. 26: TGA analysis of Lenvatinib, form CHF-1

FIG. 27: EGA analysis of Lenvatinib, form CHF-1

FIG. 28: XRPD spectrum of Lenvatinib, form FOA-1

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

FIG. 30: TGA analysis of Lenvatinib, form FOA-1

FIG. 31: EGA analysis of Lenvatinib, form FOA-1

FIG. 32: XRPD spectrum of Lenvatinib, form H₂O-1

FIG. 33: FT-Raman spectrum of Lenvatinib, form H₂O-1

FIG. 34: DSC analysis of Lenvatinib, form H₂O-1

FIG. 35: TGA analysis of Lenvatinib, form H₂O-1

FIG. 36: EGA analysis of Lenvatinib, form H₂O-1

FIG. 37: DVS analysis of Lenvatinib, form H₂O-1

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 μL), 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 XRPD spectrum shown in FIG. 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
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5429	248.09	0.2007	19.45152	52.51
9.0235	472.43	0.0836	9.80039	100.00
15.4862	92.07	0.5353	5.72203	19.49
17.2633	100.86	0.1004	5.13680	21.35
18.2150	108.87	0.2007	4.87049	23.05
18.7118	35.46	0.4015	4.74229	7.51
19.9001	76.88	0.2676	4.46170	16.27
20.5089	128.13	0.1004	4.33062	27.12
22.8334	334.74	0.0836	3.89474	70.86
25.2097	155.03	0.1338	3.53275	32.82
27.3991	86.96	0.2676	3.25523	18.41
29.4589	56.68	0.3346	3.03214	12.00
32.2925	47.61	0.2676	2.77226	10.08
36.2486	25.73	0.3346	2.47826	5.45
38.6625	47.57	0.1338	2.32891	10.07

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

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

The TGA analysis, shown in FIG. 4, highlights two weight losses: the first of 11.3% and the second of 12.8%. EGA analysis, shown in FIG. 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 μL), 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 XRPD spectrum shown in FIG. 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
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5837	606.74	0.0669	19.27843	97.96
9.2097	619.40	0.0502	9.60272	100.00
12.5481	69.54	0.1004	7.05441	11.23
13.8887	109.17	0.5353	6.37637	17.63
15.6527	139.24	0.4015	5.66152	22.48
18.5731	161.14	0.1673	4.77739	26.02
19.2159	114.87	0.1338	4.61900	18.54
21.0908	114.94	0.3346	4.21244	18.56
22.1037	189.44	0.1338	4.02164	30.58
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-Raman analysis returns the spectrum shown in FIG. 7.

DSC analysis of the Lenvatinib mesylate form DMSO-2, shown in FIG. 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 FIGS. 9 and 10). The significant high weight loss observed suggested the present of other solvents.

DVS analysis, shown in FIG. 11, 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 FIG. 12. Main peaks at 2theta±0.3 degrees are: 5.9, 7.7, 10.9, 11.9, 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
XRPD peak list
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
5.9675	678.70	0.1171	14.81073	97.27
7.7192	355.59	0.1171	11.45318	50.96
10.0603	45.24	0.2676	8.79263	6.48
10.9027	509.55	0.0502	8.11507	73.03
11.9794	287.64	0.0836	7.38802	41.22
12.5944	188.77	0.2342	7.02859	27.05
13.7300	135.54	0.2007	6.44974	19.43
15.6097	223.70	0.1338	5.67702	32.06
16.1897	78.19	0.2007	5.47493	11.21
17.1620	64.01	0.2676	5.16688	9.17
17.8466	149.98	0.2676	4.97019	21.49
19.3815	697.75	0.1338	4.57992	100.00
20.3435	238.68	0.1673	4.36545	34.21
20.8512	101.26	0.2007	4.26030	14.51
21.4476	220.91	0.2342	4.14316	31.66
22.0163	158.48	0.2676	4.03740	22.71
22.5948	545.13	0.2676	3.93532	78.13
23.5959	427.90	0.2676	3.77059	61.33
24.5324	666.15	0.1171	3.62873	95.47
25.9295	373.65	0.2342	3.43629	53.55
26.7262	200.55	0.2007	3.33563	28.74
28.3633	202.52	0.2342	3.14672	29.02
29.0095	87.47	0.2007	3.07808	12.54
30.9100	76.05	0.2007	2.89302	10.90
32.5188	33.29	0.5353	2.75348	4.77
35.1122	49.25	0.3346	2.55582	7.06
36.3809	26.21	0.4015	2.46955	3.76
37.6634	13.80	0.8029	2.38836	1.98

FT-Raman analysis returns the spectrum shown in FIG. 13. The spectrum reports the characteristic bands of form ACA-1.

DSC analysis, shown in FIG. 14, highlights a broad endothermic peak approx. at 118° 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 FIG. 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 FIG. 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 FIG. 17. Main peaks at 2theta±0.3 degrees are: 6.0, 7.7, 11.2, 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
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
6.0270	655.37	0.0836	14.66460	100.00
7.7501	350.27	0.1338	11.40758	53.45
11.1820	532.12	0.0836	7.91302	81.19
12.2127	285.80	0.0836	7.24741	43.61
13.6491	73.43	0.4015	6.48778	11.20
15.0621	254.99	0.2342	5.88217	38.91
15.6654	155.17	0.1673	5.65698	23.68
16.8966	135.27	0.1004	5.24743	20.64
17.8266	77.24	0.2676	4.97571	11.79
18.9727	36.96	0.2007	4.67766	5.64
19.4482	244.27	0.2007	4.56436	37.27
20.0429	369.02	0.2342	4.43024	56.31
21.4394	113.38	0.1338	4.14472	17.30
23.0823	497.56	0.1506	3.85330	75.92
23.6943	258.69	0.1673	3.75514	39.47
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	0.1171	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	27.11	0.4015	2.39370	4.14

FT-Raman analysis returns the spectrum shown in FIG. 18. The spectrum reports the characteristic bands of form ACA-1 HT DRY.

DSC analysis, shown in FIG. 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 FIG. 20, highlights an initial weight loss of 4.8%, between approx. 25 and 115° C., reasonably associated to the evaporation of adsorbed water (confirmed by EGA analysis FIG. 21).

The DVS analysis, shown in FIG. 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 μL), 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 XRPD spectrum shown in FIG. 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
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.5317	231.81	0.0502	19.49947	24.63
9.0800	941.37	0.0836	9.73959	100.00
10.4474	83.89	0.2007	8.46772	8.91
13.6044	187.54	0.1673	6.50898	19.92
15.2283	363.44	0.0669	5.81836	38.61
15.7388	147.19	0.1338	5.63073	15.64
16.9025	115.41	0.1004	5.24563	12.26
17.2738	263.95	0.1338	5.13368	28.04
18.1760	219.19	0.1004	4.88085	23.28
18.8898	125.23	0.1338	4.69800	13.30
19.8735	263.26	0.0836	4.46761	27.97
20.4742	229.56	0.1673	4.33789	24.39
21.1878	80.34	0.2007	4.19337	8.53
21.8034	349.61	0.2007	4.07635	37.14
22.3367	350.64	0.1673	3.98022	37.25
22.7851	480.34	0.1004	3.90289	51.03
23.1223	253.60	0.1004	3.84672	26.94
25.1448	546.45	0.1171	3.54172	58.05
25.5781	487.93	0.1004	3.48270	51.83
26.1911	142.50	0.1673	3.40255	15.14
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-Raman analysis returns the spectrum shown in FIG. 24. The spectrum reports the characteristic bands of form CHF-1.

DSC analysis, shown in FIG. 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 FIG. 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 FIG. 27).

Example 6 FOA-1

Lenvatinib Mesylate (50-100 mg) was dissolved in formic acid (100-200 μL), 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 XRPD spectrum shown in FIG. 28. Main peaks at 2theta±0.3 degrees are: 4.7, 10.5, 11.9, 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
Pos.	Height	FWHM	d-spacing	Rel. Int.
[°2Th.]	[cts]	[°2Th.]	[Å]	[%]
4.7056	8638.17	0.0669	18.77925	100.00
9.4334	1236.23	0.0669	9.37550	14.31
9.7391	150.90	0.0669	9.08188	1.75
10.5531	443.43	0.1004	8.38312	5.13
11.0441	52.64	0.1338	8.01150	0.61
11.9195	391.67	0.0836	7.42503	4.53
14.1605	175.57	0.1338	6.25457	2.03
14.8579	220.85	0.0669	5.96256	2.56
15.6284	552.32	0.1171	5.67027	6.39
16.1269	259.53	0.1004	5.49611	3.00
16.7771	451.35	0.0669	5.28455	5.23
17.5530	309.73	0.1338	5.05266	3.59
18.7042	449.91	0.0836	4.74419	5.21
19.5635	309.62	0.1506	4.53771	3.58
20.2838	155.01	0.1004	4.37818	1.79
20.8501	423.22	0.1171	4.26051	4.90
21.3861	1092.05	0.1171	4.15493	12.64
22.4273	645.95	0.1338	3.96434	7.48
22.8760	922.21	0.1338	3.88758	10.68
23.7231	817.47	0.0669	3.75065	9.46
24.4829	135.44	0.0502	3.63596	1.57
24.9629	445.68	0.1338	3.56711	5.16
25.3105	1456.27	0.1338	3.51891	16.86
26.1156	386.09	0.1338	3.41223	4.47
26.7493	101.25	0.1338	3.33281	1.17
27.1948	198.26	0.0836	3.27921	2.30
27.8395	307.72	0.0669	3.20473	3.56
30.0595	71.07	0.2676	2.97291	0.82
31.0830	30.99	0.1338	2.87731	0.36
31.5576	35.35	0.2007	2.83512	0.41
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	2.29115	0.96

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

The TGA analysis, shown in FIG. 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 FIG. 31).

Example 7: H₂O-1

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-1 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° C./10⁻² atm.

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

The new crystal form H₂O-1 is characterized by the XRPD spectrum shown in FIG. 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
Pos.	FWHM	Area	Height	Rel. Int.
[°2Th.]	[°2Th.]	[cts*°2Th.]	[cts]	[%]
4.516	0.2895	184.8	504.5	100
5.1194	0.2691	44.1	140.81	27.91
6.0497	0.3396	18.39	43.5	8.62
9.0617	0.7832	94.94	96.36	19.1
10.4869	0.6148	83.66	113.89	22.58
14.079	0.7454	95.37	99.99	19.82
16.5072	0.5667	108.54	99.76	19.77
19.8636	0.7933	272.15	178.67	35.42
24.0138	0.68	285.02	218.3	43.27
26.8983	0.7933	102.01	66.97	13.28

FT-Raman analysis returns the spectrum shown in FIG. 33. The spectrum reports the characteristic bands of form H₂O-1.

DSC analysis, shown in FIG. 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 FIG. 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 FIG. 36).

In DVS analysis, shown in FIG. 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.

Claims

1. A polymorph of Lenvatinib mesylate which is a crystal form, designated as form ACA-1 HT DRY, characterized by an XRPD spectrum (Kα1) showing the main peaks at 2theta ±0.3 degrees 6.0, 7.7, 11.2, 13.6, 19.4, 20.0, 23.1, 26.9.