DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL POLYMORPHIC FORMS OF BILASTINE SALT

We, RAGHAVA LIFE SCIENCES PVT LTD.,
a company incorporated under the companies act, 1956 having address at Raghava Pride, 8-2-603/1/27, Ground Floor, Krishnapuram Street, Road No. 10, Banjara Hills, Hyderabad-500034, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to novel polymorphic forms of antihistamine drug.

The present invention specifically relates to novel polymorphic forms of Bilastine salt or its pharmaceutically acceptable hydrates thereof.

The present invention specifically relates to novel polymorphic forms of Bilastine hydrochloride or its pharmaceutically acceptable hydrates of the formula (II).
Formula (II)

The present invention more specifically relates to novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).
Formula (I)

The present invention further relates to a process for the preparation of novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).
Formula (I)

BACKGROUND OF THE INVENTION
Bilastine is a non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist affinity and with no apparent affinity for muscarinic receptors. Bilastine is chemically represented as 2-[4-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)ethyl) phenyl]-2-ethylpropionic aci). The chemical formula is C28H37N3O3, the molecular weight is 463.61 g/mol and the structural formula is:
Formula (III)

Bilastine is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria (hives). Bilastine is a white crystalline powder.

As per the EMA approval information, polymorphism has been observed for Bilastine. Three polymorphic forms have been identified during development of Bilastine. The active substance consists of polymorphic form I.

US 5,877,187 C1 discloses Bilastine which is mentioned as crystalline form 3 in subsequent literature.

US 7,612,095 B2 claims crystalline form 1 of Bilastine X-ray crystallography analysis and IR data. This patent discloses that Bilastine can exist in three clearly different polymorphic forms called crystalline Form 1, crystalline form 2 and crystalline form 3. This patent also discloses experimental conditions and specific solvents to produce clearly different polymorphic forms of Bilastine. The crystalline forms 1 and 2 are stable. Crystalline form 3 is not very stable and is difficult to obtain in the pure form. Both crystalline form 2 and crystalline form 3 are converted into crystalline form 1.

IN 381987 claims / disclose pure crystalline form 2 of Bilastine essential free of other polymorphic forms characterized by specific XRD data, IR and DSC.

IN 384451 claims / disclose amorphous form of Bilastine, crystalline form-M of Bilastine characterized by specific XRD data.

IN 201941046669 claims/ disclose highly pure crystalline Bilastine Form-I essentially free of other crystalline form characterized by specific XRD data, IR and DSC.

WO 2017/017301 A1 claims / disclose alpha crystalline of Bilastine and Beta crystalline form of Bilastine characterized by specific XRD data.

There are several patents/patent applications which claim or disclose Bilastine crystalline forms and/or amorphous forms. However, none of the prior art references disclose crystalline / amorphous forms of Bilastine Hydrochloride with specific XRD and DSC. The inventors of the present invention provides novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I) and process for the preparation of novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).

OBJECTIVE OF THE INVENTION
The main object of the present invention relates to novel polymorphic forms of Bilastine salt or pharmaceutically acceptable hydrates thereof.

Another objective of the present invention is to provide novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of the formula (II).

Yet another objective of the present invention is to provide novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).

Still another objective of the present invention is to provide process for the preparation of novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel polymorphic forms of Bilastine salt or pharmaceutically acceptable hydrates thereof.

In another aspect, the present invention provides novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of the formula (II).
Formula (II)

In yet another aspect, the present invention provides novel polymorphic forms of Bilastine hydrochloride monohydrate of the formula (I).
Formula (I)

In one aspect, the present invention provides novel crystalline Form R1 of Bilastine hydrochloride monohydrate characterized by peaks at 3.66, 10.55, 12.43, 16.25, 17.02, 18.88, 23.22, 24.89, 30.88, 34.35 ± 0.2º 2? value.

In another aspect, the present invention provides novel crystalline Form R1 further characterized by X-ray powder diffraction pattern having peaks at 4.36, 7.45, 8.36, 11.36, 12.77, 13.40, 14.05, 14.50, 15.05, 15.48, 15.81, 16.92, 17.14, 17.94, 19.18, 19.71, 20.45, 20.92, 21.77, 22.08, 22.54, 22.93, 23.93, 25.17, 25.80, 26.71, 27.91, 28.07, 28.85, 29.56, 31.21, 31.75, 32.28, 32.86, 33.54, 34.75, 35.78, 36.95, 37.75, 39.82 ± 0.2º 2? values.

In one aspect, the present invention provides novel crystalline form R1 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing four characteristic endothermic peaks in the range of 120ºC -130ºC, 180ºC -190ºC, 205ºC-215ºC and 280ºC-290ºC.

In one aspect, the present invention provides novel crystalline form R1 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing four characteristic endothermic peaks at 126.01ºC, 186.78ºC, 210.47ºC and 285.41ºC.

In one aspect, the present invention provides novel crystalline Form R2 of Bilastine hydrochloride monohydrate characterized by peaks at 15.56, 18.18, 22.96, 24.39, 26.76, 28.79, 30.01, 30.32, 33.07, 33.57, 33.85, 37.75, 39.01 ± 0.2º 2? value.

In another aspect, the present invention provides novel crystalline Form R2 further characterized by X-ray powder diffraction pattern having peaks at 4.40, 7.43, 8.38, 11.41, 12.77, 13.42, 14.49, 15.03, 15.22, 15.83, 16.90, 17.27, 17.95, 19.19, 19.72, 19.91, 20.45, 20.88, 21.80, 22.07, 22.53, 22.87, 23.94, 25.17, 25.97, 26.54, 27.82, 28.12, 28.78, 29.59, 31.20, 31.76, 32.30, 32.84, 33.47, 34.75, 35.80, 36.81, 36.95, 39.75 ± 0.2º 2? values.

In one aspect, the present invention provides novel crystalline Form R2 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing three characteristic endothermic peaks and one exothermic peak, wherein one endothermic peak is in the range of 125ºC-135ºC, other two endothermic peaks are in the range of 210ºC-225ºC and exothermic peak in the range of 155ºC-165ºC.

In one aspect, the present invention provides novel crystalline Form R2 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing three characteristic endothermic peaks at 131.04ºC, 214.67ºC, 220.38ºC and exothermic peak at 159.59ºC.

In one aspect, the present invention provides novel amorphous Form R3 of Bilastine hydrochloride monohydrate characterized by peaks at 14.89, 27.03, 29.00 ± 0.2º 2? values.

In one aspect, the present invention provides novel amorphous Form R3 further characterized by X-ray powder diffraction pattern having peaks at 7.52, 12.69, 13.47, 14.06, 15.30, 18.54, 19.05, 20.14, 20.95, 22.14, 22.64, 25.76, 28.07, 31.06 ± 0.2º 2? values.

In one aspect, the present invention provides novel amorphous form R3 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing multiple characteristic endothermic peaks in the range of 120ºC-130ºC and 165ºC-175ºC.

In one aspect, the present invention provides novel amorphous form R3 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing two characteristic endothermic peaks at 126.95ºC and 168.95ºC.

In another aspect, the present invention provides a process for the preparation of novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of Formula (I) which comprises the steps:
i) providing a solution of Bilastine of Formula (III) in an alcoholic solvent or non-polar organic solvents at 25-30ºC under nitrogen atmosphere,
ii) adding hydrochloride solution of alcoholic solvent or esters solvents followed by heating, stirring and cooling or distilling and degassing,
iii) charging alcoholic solvent or ether solvent or seed material of Bilastine hydrochloride monohydrate of Formula (I), stirring, cooling followed by stirring,
iv) filtering and washing with alcoholic solvent or ether solvent, drying, raising the oven temperature to 50-100ºC and further drying, and
v) raising the oven temperature to 50-100ºC and drying to obtain novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of Formula (I).

In another aspect, the present invention provides a process for the preparation of novel polymorphic Form R1 or Form R2 or Form R3 of Bilastine hydrochloride monohydrate of Formula (I) which comprises the steps:
i) providing a solution of Bilastine of Formula (III) in ethanol or isopropanol or dichloromethane at 25-30ºC under nitrogen atmosphere,
ii) adding isopropanol hydrochloride solution or ethyl acetate hydrochloride followed by heating followed by stirring and cooling or distilling and degassing,
iii) charging isopropanol or methyl tert-butylether or seed material of Bilastine hydrochloride monohydrate of Formula (I), stirring, cooling followed by stirring,
iv) filtering and washing with isopropanol or methyl tert-butylether, drying, raising the oven temperature to 50-100ºC and further drying, and
v) raising the oven temperature to 50-100ºC and drying to obtain novel polymorphic Form R1 or Form R2 or Form R3 of Bilastine hydrochloride monohydrate of Formula (I).

BRIEF DESCRIPTION OF DRAWINGS
Fig.1: Represents X-ray powder diffraction pattern of crystalline Form R1 of Bilastine hydrochloride monohydrate obtained in ethanol and isopropanol solvents.
Fig.2: Represents DSC of crystalline Form R1 of Bilastine hydrochloride monohydrate obtained in ethanol and isopropanol solvents.
Fig.3: Represents X-ray powder diffraction pattern of crystalline Form R2 of Bilastine hydrochloride monohydrate obtained in isopropanol solvent.
Fig.4: Represents DSC of crystalline Form R2 of Bilastine hydrochloride monohydrate obtained in isopropanol solvent.
Fig.5: Represents X-ray powder diffraction pattern of amorphous Form R3 of Bilastine hydrochloride monohydrate obtained in dichloromethane and methyl tert-butylether solvents.
Fig.6: Represents DSC of amorphous Form R3 of Bilastine hydrochloride monohydrate obtained in dichloromethane and methyl tert-butylether solvents.

DETAILED DESCRIPTION OF THE INVENTION
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

In an embodiment, the present invention provides novel crystalline Form R1 of Bilastine hydrochloride monohydrate characterized by X-ray powder diffraction pattern shown in Figure 1 and DSC shown in Figure 2.

In another embodiment, the present invention provides novel crystalline Form R2 of Bilastine hydrochloride monohydrate characterized by X-ray powder diffraction pattern shown in Figure 3 and DSC shown in Figure 4.

In another embodiment, the present invention provides novel amorphous Form R3 of Bilastine hydrochloride monohydrate characterized by X-ray powder diffraction pattern shown in Figure 5 and DSC shown in Figure 6.

In one embodiment, the novel crystalline Form R1 of Bilastine hydrochloride monohydrate characterized by peaks at 3.66, 10.55, 12.43, 16.25, 17.02, 18.88, 23.22, 24.89, 30.88, 34.35 ± 0.2º 2? value.

In another embodiment, the novel crystalline Form R1 characterized by X-ray powder diffraction pattern having peaks at 3.66, 4.36, 7.45, 8.36, 10.55, 11.36, 12.43, 12.77, 13.40, 14.05, 14.50, 15.05, 15.48, 15.81, 16.25, 16.92, 17.02, 17.14, 17.94, 18.88, 19.18, 19.71, 20.45, 20.92, 21.77, 22.08, 22.54, 22.93, 23.22, 23.93, 24.89, 25.17, 25.80, 26.71, 27.91, 28.07, 28.85, 29.56, 30.88, 31.21, 31.75, 32.28, 32.86, 33.54, 34.35, 34.75, 35.78, 36.95, 37.75, 39.82 ± 0.2º 2? values.

In yet another embodiment, novel crystalline Form R1 of Bilastine hydrochloride monohydrate is characterized by X-ray powder diffraction pattern having 2? values, the interplanar spacing (d values) and relative intensities (I/I0) as shown in the table given below:

S.No 2? values Interplanar spacing (d) [Å] I/I0
1. 3.66 24.08 2.6
2. 4.36 20.25 6.9
3. 7.45 11.84 67.2
4. 8.36 10.56 1.7
5. 10.55 8.37 13.1
6. 11.36 7.78 20.6
7. 12.43 7.11 19.0
8. 12.77 6.92 3.5
9. 13.40 6.59 2.7
10. 14.05 6.29 16.0
11. 14.50 6.10 42.4
12. 15.05 5.87 100.0
13. 15.48 5.71 15.1
14. 15.81 5.60 16.3
15. 16.25 5.44 21.3
16. 16.92 5.23 57.1
17. 17.02 5.20 49.8
18. 17.14 5.16 79.5
19. 17.94 4.93 19.4
20. 18.41 4.81 6.6
21. 18.88 4.69 10.8
22. 19.18 4.62 35.4
23. 19.71 4.50 24.5
24. 20.45 4.33 22.7
25. 20.92 4.24 99.9
26. 21.77 4.07 24.5
27. 22.08 4.02 55.6
28. 22.54 3.94 26.8
29. 22.93 3.87 28.0
30. 23.22 3.82 11.0
31. 23.93 3.71 7.6
32. 24.89 3.57 9.1
33. 25.17 3.53 5.2
34. 25.80 3.45 3.5
35. 26.71 3.33 13.7
36. 27.91 3.19 14.3
37. 28.07 3.17 16.3
38. 28.85 3.09 12.0
39. 29.56 3.01 3.6
40. 30.88 2.89 1.5
41. 31.21 2.86 6.8
42. 31.75 2.81 7.2
43. 32.28 2.77 4.4
44. 32.86 2.72 5.6
45. 33.54 2.66 5.2
46. 34.35 2.60 4.0
47. 34.75 2.57 1.9
48. 35.78 2.50 3.5
49. 36.95 2.43 6.5
50. 37.75 2.38 3.2
51. 39.82 2.26 1.5

In another embodiment, the present invention provides novel crystalline form R1 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing four characteristic endothermic peaks in the range of 120ºC -130ºC, 180ºC -190ºC, 205ºC-215ºC and 280ºC-290ºC.

In one embodiment, the novel crystalline Form R2 of Bilastine hydrochloride monohydrate characterized by peaks at 15.56, 18.18, 22.96, 24.39, 26.76, 28.79, 30.01, 30.32, 33.07, 33.57, 33.85, 37.75, 39.01 ± 0.2º 2? value.

In another embodiment, the novel crystalline Form R2 characterized by X-ray powder diffraction pattern having peaks at 4.40, 7.43, 8.38, 11.41, 12.77, 13.42, 14.49, 15.03, 15.22, 15.56, 15.83, 16.90, 17.27, 17.95, 18.18, 19.19, 19.72, 19.91, 20.45, 20.88, 21.80, 22.07, 22.53, 22.87, 22.96, 23.94, 24.39, 25.17, 25.97, 26.54, 26.76, 27.82, 28.12, 28.78, 28.79, 29.59, 30.01, 30.32, 31.20, 31.76, 32.30, 32.84, 33.07, 33.47, 33.57, 33.85, 34.75, 35.80, 36.81, 36.95, 37.75, 39.01, 39.75 ± 0.2º 2? values.

In yet another embodiment, novel crystalline Form R2 of Bilastine hydrochloride monohydrate is characterized by X-ray powder diffraction pattern having 2? values, the interplanar spacing (d values) and relative intensities (I/I0) as shown in the table given below:

S.No 2? values Interplanar spacing (d) [Å] I/I0
1. 4.40 20.02 14.1
2. 7.43 11.88 73.4
3. 8.38 10.53 2.3
4. 11.41 7.74 31.5
5. 12.77 6.92 0.6
6. 13.42 6.59 5.8
7. 14.49 6.10 46.4
8. 15.03 5.88 99.8
9. 15.22 5.81 49.2
10. 15.56 5.68 14.1
11. 15.83 5.59 18.4
12. 16.90 5.23 47.2
13. 17.27 5.13 41.9
14. 17.95 4.93 31.4
15. 18.18 4.87 9.9
16. 19.19 4.62 41.6
17. 19.72 4.49 1.8
18. 19.91 4.45 2.1
19. 20.45 4.33 25.6
20. 20.88 4.24 100.0
21. 21.80 4.07 27.0
22. 22.07 4.02 58.9
23. 22.53 3.94 35.9
24. 22.87 3.88 23.8
25. 22.96 3.87 30.8
26. 23.94 3.71 11.5
27. 24.39 3.64 3.1
28. 25.17 3.53 7.4
29. 25.97 3.42 1.0
30. 26.54 3.35 13.0
31. 26.76 3.32 18.3
32. 27.82 3.20 20.6
33. 28.12 3.17 21.0
34. 28.78 3.09 16.9
35. 28.79 3.09 16.7
36. 29.59 3.01 5.5
37. 30.01 2.97 1.3
38. 30.32 2.94 1.9
39. 31.20 2.86 7.9
40. 31.76 2.81 9.7
41. 32.30 2.76 5.8
42. 32.84 2.72 5.6
43. 33.07 2.70 3.7
44. 33.47 2.67 5.4
45. 33.57 2.66 5.6
46. 33.85 2.64 2.0
47. 34.75 2.57 2.6
48. 35.80 2.50 4.9
49. 36.81 2.43 6.0
50. 36.95 2.43 5.2
51. 37.75 2.38 3.5
52. 39.01 2.30 1.1
53. 39.75 2.26 2.7

In another embodiment, the present invention provides novel crystalline Form R2 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing three characteristic endothermic peaks and one exothermic peak, wherein one endothermic peak is in the range of 125ºC-135ºC, other two endothermic peaks are in the range of 210ºC-225ºC and exothermic peak is in the range of 155ºC-165ºC.

In yet another embodiment, the novel amorphous Form R3 of Bilastine hydrochloride monohydrate characterized by peaks at 14.89, 27.03, 29.00 ± 0.2º 2? values.

In another embodiment, the novel amorphous Form R3 characterized by X-ray powder diffraction pattern having peaks at 7.52, 12.69, 13.47, 14.06, 14.89, 15.30, 18.54, 19.05, 20.14, 20.95, 22.14, 22.64, 25.76, 27.03, 28.07, 29.00, 31.06 ± 0.2º 2? values.

In yet another embodiment, novel amorphous Form R3 of Bilastine hydrochloride monohydrate is characterized by X-ray powder diffraction pattern having 2? values, the interplanar spacing (d values) and relative intensities (I/I0) as shown in the table given below:

S.No 2? values Interplanar spacing (d) [Å] I/I0
1. 7.52 11.75 18.02
2. 12.69 6.97 15.73
3. 13.47 6.56 52.53
4. 14.06 6.29 39.64
5. 14.89 5.94 83.72
6. 15.30 5.78 69.14
7. 18.54 4.78 85.56
8. 19.05 4.65 84.39
9. 20.14 4.40 80.74
10. 20.95 4.24 91.40
11. 22.14 4.01 56.88
12. 22.64 3.92 100.00
13. 25.76 3.45 33.06
14. 27.03 3.29 31.14
15. 28.07 3.17 22.17
16. 29.00 3.07 21.12
17. 31.06 2.87 16.60

In another embodiment, the novel amorphous form R3 of Bilastine hydrochloride monohydrate of the formula I having a DSC thermogram spectrum showing two characteristic endothermic peaks in the range of 120ºC-130ºC and 165ºC-175ºC.

In another embodiment, the novel polymorphic forms R, R2 and R3 of Bilastine hydrochloride monohydrate of the formula I have water content in the range of 3.0 to 3.5% (w/w) by Karl Fischer.

Solvents used in the present invention are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; "non-polar organic solvents" such as benzene, toluene, xylene, hexane, cyclohexane, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof. Preferably used solvents include ethanol, isopropanol, ethyl acetate, methyl tert-butylether and dichloromethane.

The novel polymorphic Forms R1, R2 and R3 of Bilastine hydrochloride monohydrate of the present invention are stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The novel polymorphic Forms R1, R2 and R3 of Bilastine hydrochloride monohydrate of the present invention are also suitable for formulating into different dosage forms.

In a preferred embodiment, the present invention provides a pharmaceutical composition of novel polymorphic Forms R1, R2 and R3 of Bilastine hydrochloride monohydrate along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, lubricants and or anti-adherents.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising novel Bilastine hydrochloride cocrystals may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using procedures such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1: Process for preparing novel crystalline Form R1 of Bilastine hydrochloride monohydrate

150 ml of ethanol was charged into RB flask at 25-30ºC under nitrogen atmosphere. 100 gms of Bilastine was charged into RB flask at 25-30ºC under nitrogen atmosphere and stirred for 20-30 min at 25-30ºC under nitrogen atmosphere. 110 ml of isopropanol hydrochloride was added slowly at 25-30ºC under nitrogen atmosphere and heated to 50-55ºC. The reaction mass was stirred for 45.0-60.0 min at 50-55ºC and cooled to 25-30ºC. 150 ml of isopropanol was charged at 25-30ºC under nitrogen atmosphere and stirred for 30-45 min at 25-30ºC. The reaction mass was cooled to 0-5ºC and stirred for 60-90 min at 0-5ºC. The obtained material was filtered and washed with 100 ml of chilled (0-5ºC) isopropanol at 0-5ºC. Dried for 20-30 min, unloaded the wet material and weight was checked. The obtained material was dried under vacuum for 1.0-2.0 hrs at 25-30ºC. Oven temperature was raised to 40-45ºC and dried under vacuum for 4.0-5.0 hrs at 40-45ºC. Oven temperature was raised to 70-75ºC and dried under vacuum for 8.0-10.0 hrs at 70-75ºC to obtain crystalline Form R1 of Bilastine hydrochloride monohydrate (yield: 90.0gm; purity: 99.99%).

Example 2: Process for preparing novel crystalline Form R2 of Bilastine hydrochloride monohydrate

600 ml of isopropanol was charged into RB flask at 25-30ºC under nitrogen atmosphere. 100 gms of Bilastine was charged into RB flask at 25-30ºC under nitrogen atmosphere and stirred for 20-30 min at 25-30ºC under nitrogen atmosphere. 126 ml of isopropanol hydrochloride was added slowly at 25-30ºC under nitrogen atmosphere and heated to 60-65ºC. The reaction mass was stirred for 45.0-60.0 min at 60-65ºC and cooled to 25-30ºC. 1 gm of Bilastine hydrochloride monohydrate seed material was charged at 25-30ºC under nitrogen atmosphere and stirred for 30-45 min at 25-30ºC. The reaction mass was cooled to 0-5ºC and stirred for 60-90 min at 0-5ºC. The obtained material was filtered and washed with 100 ml of chilled (0-5ºC) isopropanol at 0-5ºC. Dried for 20-30 min, unloaded the wet material and weight was checked. The obtained material was dried under vacuum for 1.0-2.0 hrs at 25-30ºC. Oven temperature was raised to 40-45ºC and dried under vacuum for 4.0-5.0 hrs at 40-45ºC. Oven temperature was raised to 70-75ºC and dried under vacuum for 8.0-10.0 hrs at 70-75ºC to obtain crystalline Form R2 of Bilastine hydrochloride monohydrate (yield: 100.0gm ; purity: 99.86%, unknown impurity: 0.07%).

Example 3: Process for preparing novel amorphous Form R3 of Bilastine hydrochloride monohydrate

3000 ml of dichloromethane was charged into RB flask at 25-30ºC under nitrogen atmosphere. 100 gms of Bilastine was charged into RB flask at 25-30ºC under nitrogen atmosphere and stirred for 20-30 min at 25-30ºC under nitrogen atmosphere. 126 ml of ethyl acetate hydrochloride was added slowly at 25-30ºC under nitrogen atmosphere and stirred the reaction mass for 45.0-60.0 min at 25-30ºC. Solvent was distilled under vacuum at below 40ºC and the crude was degassed under vacuum at below 45ºC. 1000 ml of methyl tert-butylether was charged at 25-30ºC under nitrogen atmosphere and stirred for 60-90 min at 25-30ºC. The obtained material was filtered and washed with 100 ml of methyl tert-butylether at 25-30ºC. Dried for 20-30 min, unloaded the wet material and weight was checked. The obtained material was dried under vacuum for 1.0-2.0 hrs at 25-30ºC. Oven temperature was raised to 40-45ºC and dried under vacuum for 4.0-5.0 hrs at 40-45ºC. Oven temperature was raised to 70-75ºC and dried under vacuum for 8.0-10.0 hrs at 70-75ºC to obtain amorphous Form R3 of Bilastine hydrochloride monohydrate (yield: 106.6gm ; purity: 99.89%). ,CLAIMS:We Claim:
1. Novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of the formula (II).
Formula (II)

2. Novel polymorphic forms of Bilastine hydrochloride as claimed in claim 1 as monohydrate of the formula
Formula (I)

3. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 2 (Form R1) in crystalline nature characterized by peaks at 3.66, 10.55, 12.43, 16.25, 17.02, 18.88, 23.22, 24.89, 30.88, 34.35 ± 0.2º 2? value.

4. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 3 further characterized by peaks at 4.36, 7.45, 8.36, 11.36, 12.77, 13.40, 14.05, 14.50, 15.05, 15.48, 15.81, 16.92, 17.14, 17.94, 19.18, 19.71, 20.45, 20.92, 21.77, 22.08, 22.54, 22.93, 23.93, 25.17, 25.80, 26.71, 27.91, 28.07, 28.85, 29.56, 31.21, 31.75, 32.28, 32.86, 33.54, 34.75, 35.78, 36.95, 37.75, 39.82 ± 0.2º 2? values.

5. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 3 having a DSC thermogram spectrum showing four characteristic endothermic peaks in the range of 120ºC -130ºC, 180ºC -190ºC, 205ºC-215ºC and 280ºC-290ºC.

6. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 3 having a DSC thermogram spectrum showing four characteristic endothermic peaks at 126.01ºC, 186.78ºC, 210.47ºC and 285.41ºC.

7. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 2 (Form R2) crystalline in nature characterized by peaks at 15.56, 18.18, 22.96, 24.39, 26.76, 28.79, 30.01, 30.32, 33.07, 33.57, 33.85, 37.75, 39.01 ± 0.2º 2? value.

8. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 7, further characterised by X-ray powder diffraction pattern having peaks at 4.40, 7.43, 8.38, 11.41, 12.77, 13.42, 14.49, 15.03, 15.22, 15.83, 16.90, 17.27, 17.95, 19.19, 19.72, 19.91, 20.45, 20.88, 21.80, 22.07, 22.53, 22.87, 23.94, 25.17, 25.97, 26.54, 27.82, 28.12, 28.78, 29.59, 31.20, 31.76, 32.30, 32.84, 33.47, 34.75, 35.80, 36.81, 36.95, 39.75 ± 0.2º 2? values.

9. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 7 having a DSC thermogram spectrum showing one endothermic peak in the range of 125ºC-135ºC, other two endothermic peaks are in the range of 210ºC-225ºC and exothermic peak in the range of 155ºC-165ºC.

10. Novel polymorphic forms of Bilastine hydrochloride monohydrate as claimed in claim 7 having a DSC thermogram spectrum showing three characteristic endothermic peaks at 131.04ºC, 214.67ºC, 220.38ºC and exothermic peak at 159.59ºC.

11. Bilastine hydrochloride monohydrate Form R3 essentially amorphous in nature.

12. The amorphous Bilastine hydrochloride monohydrate Form R3 as claimed in claim 11 further characterized by peaks at 14.89, 27.03, 29.00 ± 0.2º 2? values.
13. The amorphous Bilastine hydrochloride monohydrate Form R3 as claimed in claim 12, further characterised by X-ray powder diffraction pattern having peaks at 7.52, 12.69, 13.47, 14.06, 15.30, 18.54, 19.05, 20.14, 20.95, 22.14, 22.64, 25.76, 28.07, 31.06 ± 0.2º 2? values.

14. The amorphous Bilastine hydrochloride monohydrate Form R3 as claimed in claim 12 having a DSC thermogram spectrum showing multiple characteristic endothermic peaks in the range of 120ºC-130ºC and 165ºC-175ºC.

15. The amorphous Bilastine hydrochloride monohydrate Form R3 as claimed in claim 12 having a DSC thermogram spectrum showing two characteristic endothermic peaks at 126.95ºC and 168.95ºC.

16. A process for preparation of novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of Formula (I) claimed in claim 1, which comprises the steps:
vi) providing a solution of Bilastine of Formula (III) in an alcoholic solvent or non-polar organic solvents at 25-30ºC under nitrogen atmosphere,
vii) adding hydrochloride solution of alcoholic solvent or esters solvents followed by heating, stirring and cooling or distilling and degassing,
viii) charging alcoholic solvent or ether solvent or seed material of Bilastine hydrochloride monohydrate of Formula (I), stirring, cooling followed by stirring,
ix) filtering and washing with alcoholic solvent or ether solvent, drying, raising the oven temperature to 50-100ºC and further drying, and
x) raising the oven temperature to 50-100ºC and drying to obtain novel polymorphic forms of Bilastine hydrochloride or pharmaceutically acceptable hydrates of Formula (I).

17. A process for preparation of novel polymorphic Form R1 or Form R2 or Form R3 of Bilastine hydrochloride monohydrate of Formula (I) claimed in claims 3, 7, 11, which comprises the steps:
i) providing a solution of Bilastine of Formula (III) in ethanol or isopropanol or dichloromethane at 25-30ºC under nitrogen atmosphere,
ii) adding isopropanol hydrochloride solution or ethyl acetate hydrochloride followed by heating followed by stirring and cooling or distilling and degassing,
iii) charging isopropanol or methyl tert-butylether or seed material of Bilastine hydrochloride monohydrate of Formula (I), stirring, cooling followed by stirring,
iv) filtering and washing with isopropanol or methyl tert-butylether, drying, raising the oven temperature to 50-100ºC and further drying, and
v) raising the oven temperature to 50-100ºC and drying to obtain novel polymorphic Form R1 or Form R2 or Form R3 of Bilastine hydrochloride monohydrate of Formula (I).

Dated this Eighteenth (18th) day of February, 2023

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883