DESC:
FIELD OF THE INVENTION
The present invention relates to bilastine crystalline polymorphic forms and processes for their preparation thereof.
BACKGROUND OF THE INVENTION
Bilastine is chemically described as 2- [4 (2- {4 [1 - (2-ethoxy - ethyl) -1H-- benzimidazol-2-yl ] - piperidin-l-yl} ethyl) - phenyl]-2-methyl -propionic acid, bilastine is represented by the following strutural formula I.

Bilastine and its process was first described in US patent no 5,877,187.
US patent no 7,612,095 discloses bilastine crystalline form I and process for the preparation of bilastine crystalline form I. Bilastine crystalline form I having X-ray powder diffraction pattern having peaks as expressed 2? values at about 9.27, 10.90, 12.74, 15.66, 17.68, 18.32, 20.03, 21.90 and 27.35 ± 0.2 2?.
Various other patent/patent applications was disclosed other bilastine polymorphic forms in WO2014/026657, WO 2017/085258, WO 2017/191651, WO 2017/01730, WO 2017/167949, CN 103214454, CN 103788062, CN 104447683, CN 107814786 and IP.com Journal Volume 16,Issue 10A,Pages 1-26; 2016.
SUMMARY OF THE INVENTION
The present invention relates to bilastine crystalline form L1, bilastine crystalline form L2, bilastine crystalline form L3 and processes for their preparation thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts an X-ray powder diffraction pattern of crystalline bilastine form L1.
Figure 2 depicts a characteristic FT-IR spectrum of crystalline bilastine form L1.
Figure 3 depicts a characteristic DSC thermogram of crystalline bilastine form L1.
Figure 4 depicts an X-ray powder diffraction pattern of crystalline bilastine form L2.
Figure 5 depicts a characteristic FT-IR spectrum of crystalline bilastine form L2.
Figure 6 depicts a characteristic DSC thermogram of crystalline bilastine form L2.
Figure 7 depicts an X-ray powder diffraction pattern of crystalline bilastine form L3.
Figure 8 depicts a characteristic FT-IR spectrum of crystalline bilastine form L3.
Figure 9 depicts a characteristic DSC thermogram of crystalline bilastine form L3.

DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to provide bilastin crystalline forms.
Yet another aspect of the present invention relates to provide bilastine crystalline form L1, having X-ray powder diffraction pattern peaks at about 8.7°, 9.1°, 9.3°, 9.9°, 18.0°, 20.1°, 20.6°, 20.8°, 21.7° and 23.6° (± 0.2) 2?.

Table 1 provides the d-spacing values (°A), the corresponding 2? values, and the relative intensity of bilastine crystalline form L1.

Table 1
Position(± 0.2° 2 ?) d-spacing(°A) Relative Intensity (%)
8.7 10.0 28.95
9.1 9.6 78.5
9.3 9.4 68.5
9.9 8.8 27.7
18.0 4.9 100
20.1 4.4 38.2
20.6 4.2 49.3
21.7 4.0 21.1
23.6 3.7 20.6

According to present invention, bilastine crystalline form L1 is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 206.56°C.

According to present invention, bilastine crystalline form L1 is characterized by an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3696, 3649, 3369, 2973, 1678, 1598, 1572, 1512, 1438, 1331, 1173, 1115, 1033, 1050, 853, 750, 725, 693 and 675 cm-1.

According to present invention, Bilastine crystalline form L1 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 1, bilastine crystalline form L1 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 2 and DSC thermogram substantially as depicted in Figure 3.

Another aspect of the present invention provides a process for the preparation of bilastine crystalline form L1 comprising:

a) dissolving bilastine in methanol,
b) heating the reaction mass to 55°C,
c) optionally, purifing bilastine crystalline form L1, and
d) isolating bilastine crystalline form L1.

According to present invention, bilastine is dissolved in methanol.Heating the reaction mass to 55°C, cooling the reaction mass and filter the solid to give bilastine crystalline form L1.

Yet another aspect of the present invention relates to bilastine crystalline form L2 having X-ray powder diffraction pattern peaks at about 9.4°, 12.0°, 13.0°, 14.9°, 17.3°, 18.0°, 19.0°, 19.4°, 20.0°, 20.1°, 21.3°, 21.4°, 23.1° and 27.7° (± 0.2) 2?.

Table 2 provides the d-spacing values (°A), the corresponding 2? values, and the relative intensity of bilastine crystalline form L2:
Table 2
Position(± 0.2° 2 ?) d-spacing(°A) Relative Intensity (%)
9.4 9.37 53.6
12.0 7.34 86.1
13.0 6.78 23.3
14.9 5.93 59.9
17.3 5.11 27
18.0 4.92 36
19.0 4.66 100
19.4 4.54 22.4
20.0 4.43 70.3
20.1 4.40 92.7
21.3 4.15 25.5
21.4 4.13 22.3
23.1 3.83 90.4
27.7 3.21 20.3

According to present invention, Bilastine crystalline form L2 is characterized by differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 206.4°C.
According to present invention, crystalline form L2 is characterized by an infrared (IR) absorption spectrum having characteristic peaks expressed in cm-1 at about 3493, 3399, 3047, 2859, 2892, 2925, 2963, 2801, 2156, 1662, 1601, 1512, 1496, 1463, 1450, 1360, 1352, 1295, 1206, 1171, 1029, 944, 907, 851, 792 and 693 cm-1.
According to present invention, bilastine crystalline form L2 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 4, bilastine crystalline form L2 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 5 and DSC thermogram substantially as depicted in Figure 6.

Yet another aspect of the present invention provides a process for the preparation of bilastine crystalline form L2, comprising the steps of:

a) dissolving bilastine in tetrahydrofuran,
b) heating the reaction mass to 55°C, and
c) optionally, step b adding to precooled tetrahydrofuran solution, and
d) isolating bilastine crystalline form L2.

According to the present invention, dissolving bilastine in tetrahydrofuran.Heating the reaction mass to 55°C, raction mass adding to precooled tetrahydrofuran solution.Filter the solid to obatine bilastine crystalline form L2.

In yet another aspect of the present invention to provide bilastine crystalline form L3, characterized by an XRPD pattern substantially having 2? peaks at 8.6°, 10.8°, 11.4°, 12.1°, 13.3°, 13.8°, 14.4°, 14.9°, 16.0°, 17.5°, 18.4°, 18.7°, 19.9°, 20.0°, 20.1°, 20.6°, 20.9°, 21.3°, 21.6°, 22.5°, 23.2°, 23.4° and 26.1° (± 0.2).

Table 3 provides the d-spacing values (°A), the corresponding 2 ? values, and the relative intensity of bilastine crystalline form L3:
Table 3
Position(± 0.2° 2 ?) d-spacing(°A) Relative Intensity (%)
8.6 10.18 100
10.8 8.16 22.6
11.4 7.69 50.2
12.1 7.28 40.3
13.3 6.6 34.3
13.8 6.40 52.8
14.4 6.13 23.3
14.9 5.93 34
16.0 5.51 25.6
17.5 5.03 89.9
18.4 4.79 55
18.7 4.73 44.7
19.9 4.44 42
20.0 4.43 48
20.1 4.39 30.2
20.6 4.29 35.3
20.9 4.23 47.2
21.3 4.16 21.5
21.6 4.09 21.1
22.5 3.94 22.3
23.2 3.82 31.1
23.4 3.79 23.9
26.1 3.40 26.0

According to present invention, bilastine crystalline form L3 is characterized by differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 206.8°C.
According to present invention, bilastine crystalline form L3 is characterized by an infrared (IR) absorption spectrum with characteristic peaks expressed about 3648, 3372, 3052, 2971, 2932, 2870, 1680, 1644, 1613, 1512, 1447, 1388, 1295, 1159, 1070, 934, 869, 853, 795, 757 and 693 cm-1.
According to present invention, bilastine crystalline form L3 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 7, bilastine crystalline form L3 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 8 and DSC thermogram substantially as depicted in Figure 9.
Yet another aspect of the present invention provides a process for the preparation of Bilastine crystalline form L3, comprising the steps of:
a) dissolving bilastine in methanol,
b) heating the reaction mass to 60°C,
c) adding water, and
d) isolating bilastine crystalline form L3.

According to the present invention, dissolving bilastine in methanol. Heat the reaction mass to 60°C, adding water. Stirring the reaction mass, cool the mass and filter the solid to obatine bilastine crystalline form L3.

According to the present invention, wherein isolating crystalline Bilastine polymorphic form L1, L2 and L3 by filtration or centrifugation having a purity more than 99.9% by HPLC method.

Experimental Method:

1) HPLC Instrument and method details:
Instrument : HPLC equipped with Pump, injector, UV detector and Recorder.
Column : Zorbax SB-Aq (4.6 x 250mm), 5µm.
Wavelength : UV Detector 215 nm
Flow rate : 1.5mL/min
Injection volume : 5?L.
Auto sampler temperature: 10°C
Column oven temperature: 20°C.

2) Powder diffraction pattern Instrument and method details:
The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.540 Å), running at 45 kV and 40 mA.

3) Differential Scanning Calorimetry:
Differential scanning calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument 2-3mg samples were placed in crimped aluminum pans and heated from 30°C to 250°C in a dry nitrogen atmosphere at a heating rate of 10°C/minute.

4) Infra-red spectroscopy:
The IR spectroscopy was performed using a spectrum 400 using a neat liquid sample or dispersion of solid sample material in KBr.
Following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.
Examples:
Example 1
Process for the preparation of Bilastine crystalline form L1.
Bilastine (0.7 g) was dissolved in methanol (21 ml) at room temperature and heat the mass to 55°C. After completion of reaction, cool the reaction mass to -10°C and filter the mass to give the title compound.
Yield: 0.6 gm

Example 2
Process for the preparation of Bilastine crystalline form L2.
Bilastine (1 g) was dissolved in tetrahydrofuran (12 ml) at room temperature, stirred the reaction mass and heat the mass to 55°C.The mass was added to precooled tetrahydrofuran solution at 10°C, gradually raise the temperature of the reaction mass to room temperature. The obtained solid was filtered and dried under vacuum to give the title compound.
Yield: 0.79 gm

Example 3
Process for the preparation of Bilastine crystalline form L3.
Bilastine (6 g) was suspended in methanol (120 ml) at room temperature, stirred the reaction mass and slowly heat the reaction mass to 60°C. Water (60 ml) was added dropwise, stirred the reaction mass at 60°C for 20 min, cool the mass to 5°C. The obtained solid was filtered and dried under vacuum to give the title compound.
Yield: 4 gm
,CLAIMS:
1. Bilastine crystalline form L1 having X-ray powder diffraction pattern peaks at about 8.7°, 9.1°, 9.3°, 9.9°, 18.0°, 20.1°, 20.6°, 20.8°, 21.7° and 23.6° (± 0.2) 2?.

2. Bilastine crystalline form L1 having an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3696, 3649, 3369, 2973, 1678, 1598, 1572, 1512, 1438, 1331, 1173, 1115, 1033, 1050, 853, 750, 725, 693 and 675 cm-1.

3. Bilastine crystalline form L2 having X-ray powder diffraction pattern peaks at about 9.4°, 12.0°, 13.0°, 14.9°, 17.3°, 18.0°, 19.0°, 19.4°, 20.0°, 20.1°, 21.3°, 21.4°, 23.1° and 27.7° (± 0.2) 2?.

4. Bilastine crystalline form L2 having an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3493, 3399, 3047, 2859, 2892, 2925, 2963, 2801, 2156, 1662, 1601, 1512, 1496, 1463, 1450, 1360, 1352, 1295, 1206, 1171, 1029, 944, 907, 851, 792 and 693 cm-1.

5. Bilastine crystalline form L3 having X-ray powder diffraction pattern peaks at about 8.6°, 10.8, 11.4, 12.1, 13.3, 13.8, 14.4, 14.9, 16.0, 17.5, 18.4, 18.7, 19.9, 20.0, 20.1, 20.6, 20.9, 21.3, 21.6, 22.5, 23.2, 23.4 and 26.1 (± 0.2) 2?.

6. Bilastine crystalline form L3 having an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3648, 3372, 3052, 2971, 2932, 2870, 1680, 1644, 1613, 1512, 1447, 1388, 1295, 1159, 1070, 934, 869, 853, 795, 757 and 693 cm-1.

7. Bilastine crystalline form L1 obtained by a process comprising the steps of:
e) dissolving bilastine in methanol,
f) heating the reaction mass to 55°C,
g) optionally, purifing bilastine crystalline form L1, and
h) isolating bilastine crystalline form L1.

8. Bilastine crystalline form L2 obtained by a process comprising the steps of:
a) dissolving bilastine in tetrahydrofuran,
b) heating the reaction mass to 55°C,
c) optionally, step b adding to pre-cooled tetrahydrofuran solution, and
d) isolating bilastine crystalline form L2.

9. Bilastine crystalline form L3 obtained by a process comprising the steps of:
a) dissolving bilastine in methanol,
b) heating the reaction mass to 60°C,
c) adding water, and
d) isolating bilastine crystalline form L3.

10. Bilastine crystalline form, selected form the group consisting of:
a) Bilastine crystalline form L1 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 1, bilastine crystalline form L1 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 2 and DSC thermogram substantially as depicted in Figure 3,
b) Bilastine crystalline form L2 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 4, bilastine crystalline form L2 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 5 and DSC thermogram substantially as depicted in Figure 6, and
c) Bilastine crystalline form L3 having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 7, bilastine crystalline form L3 having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 8 and DSC thermogram substantially as depicted in Figure 9.