Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
I TITLE OF THE INVENTION
"Novel Crystal Modifications of Epinastine base and hydrochloride salt thereof."

a)NAME: USV LIMITED
b)NATIONALITY: Indian Company incorporated under the Companies Act 1956
c)ADDRESS: B.S.D. Marg, Station Road, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to novel crystal modification of 3-amino-9,13b-dihydro-lH-dibenz-[c,f]imidazo[l,5-a]-azepine (Epinastine base) of formula (I) and hydrochloride salt thereof. The present invention further relates to process of producing the polymorphs of Epinastine base and its hydrochloride salt.

Formula (I)
Background of the invention:
Epinastine (3-amino-9,13b-dihydro-lH-dibenz-[c,f]imidazo[l,5-a]-azepine) belongs to the 2-aminoimidazolines and is a therapeutically active substances characterized primarily by its anti-allergenic and anti-histaminergic activity therapeutically in EP35749. It is used as the hydrochloride salt represented by formula IA.

Formula (IA)
US 4313931 (herein after refers as '931 patent) discloses 3-amino-9,13b-dihydro-lH-dibenz-[c,f]imidazo[l,5-a]-azepine (Epinastine), non-toxic pharmacologically acceptable acid addition salt thereof and process for preparing the same. This patent also discloses pharmaceutical composition containing Epinastine or its salts and method for treating
2

bronchial asthma and allergic bronchitis. The '931 patent does not discloses or discuss about the solid-state characterization of Epinastine base or its hydrochloride salt. XRPD pattern of the Epinastine hydrochloride obtained by this process is disclosed in JP 2004-300042.
US 5312916 relates to process for preparing 3-amino-9,13b-dihydro-lH-dibenz[c,f]imi-dazo[l,5-a]-azepine hydrochloride using dimethylformamide with no disclosure about solid state properties of the isolated product of Epinastine hydrochloride.
US 6403790 relates to a process for preparing Epinastine hydrochloride in the high-melting crystal modification using water as solvent. The 790 patent also discloses that Epinastine hydrochloride exists in low melting crystal modification which melts at 250-263°C and high melting crystal modification which melts at 275-281 °C.
JP 2004-300042 discloses a crystal polymorph of Epinastine hydrochloride, which is characterized by XRPD. The patent also discloses the method for producing the crystal polymorph which involves crystallizing high quality Epinastine hydrochloride from an aprotic polar solvent. XRPD pattern of the Epinastine hydrochloride obtained by following the process disclosed in US 4313931 is also disclosed in this patent.
Many organic compounds including active pharmaceutical ingredients (API's) exhibits polymorphisms and can exist in many crystalline forms. Polymorphism is the ability of the compound to exhibit more than one orientation or conformation of molecule within the crystal lattice. Drug substance exists in various polymorphic forms; differ from each other in terms of their stability, solubility, compressibility, flowability and spectroscopic properties, thus affecting dissolution, bioavailability and handling characteristics of the substance.
When the difference in the solubility of various polymorphs is sufficiently large, it may alter the drug product in vivo dissolution and hence drug product bioavailability. Rate of dissolution of an API in patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the
3

patient bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product.
Knowledge of an existence of different crystal phases and their overall physical and chemical behaviour is required for selection of polymorphic form to be used in the preparation of final dosage form. Towards this end, investigation of crystal polymorphisms is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form.
The discovery of new polymorphs with same or better pharmaceutical equivalence and bioequivalence as that of the existing polymorphs provides an opportunity to improve the performance characteristic of the pharmaceutical product.
There is disclosed in the prior art that Epinastine hydrochloride ( hereinafter referred as Epinastine HC1 ) exists in different crystal modification however, the prior art does not disclose the polymorphic forms of Epinastine base. Epinastine hydrochloride can still exist in different crystal structures other than known crystal modifications as disclosed in prior art.
Based on the known crystal modifications of Epinastine HC1, there is still considered need to have different new polymorphs of Epinastine or its salt which may exhibits better solubility and dissolution rate. It has now been found, surprisingly, new crystal structures of Epinastine and its hydrochloride salt and these new polymorphs having improved bulk handling and dissolution properties can be more valuable and practical with respect to physical and chemical stability compared to the existing crystal modifications of Epinastine.
All the polymorphic forms of Epinastine hydrochloride reported in the prior art are crystalline in nature. It is known that the amorphous form of drug substance exhibits different dissolution characteristic. Amorphous forms can have solubility, several hundred times than that of the crystalline counterparts. Thus the present invention also provides novel amorphous form of Epinastine and hydrochloride salt thereof.
4

Objects of the invention:
The object of the present invention is to provide novel crystalline forms, Form I and Form II of Epinastine base and process of preparation thereof.
Another object of the invention is to provide novel amorphous form of Epinastine base and process for preparation thereof.
Yet another object of the invention is to provide seven novel crystalline forms. Form II, Form III, Form IV, Form V, Form VI, Form VII and Form VIII of Epinastine HC1 and process for preparing them.
Another object of the present invention is to provide novel amorphous form of Epinastine HC1 and process for preparation thereof.
Still further object of the present invention is to provide pharmaceutical composition containing novel crystalline or amorphous forms of Epinastine base or its hydrochloride salt.
Another object of the present invention provides method of treatment of anti-allergic and anti-histaminergic activity with therapeutically effecting amount of the pharmaceutical composition comprising novel crystalline or amorphous forms of Epinastine base or its hydrochloride salt.
Summary of the invention:
According one aspect of the present invention novel crystalline forms, Form I and Form II and amorphous form of Epinastine base and process of preparation thereof is disclosed. According to another aspect, the present invention provides novel seven crystalline forms, Form II, Form III, Form IV, Form V, Form VI, Form VII and Form VIII and amorphous form of Epinastine HC1 and process for preparation thereof.
According to another aspect, the present invention provides pharmaceutical composition comprising novel crystalline or amorphous forms of Epinastine base or its hydrochloride salt alongwith pharmaceutically acceptable excepients..
5

According to another aspect, the present invention provides method of treatment of antiallergic and anti-histaminergic activity administering a pharmaceutical composition therapeutically effective amount of crystalline or amorphous forms of Epinastine base or its hydrochloride salt alongwith pharmaceutically acceptable excepients.
Brief description of figures:
FIG. 1 is a characteristic X-ray Powder diffraction pattern of Epinastine base Form I. FIG. 2 is a characteristic X-ray Powder diffraction pattern of Epinastine base Form II. FIG. 3 is a characteristic X-ray Powder diffraction pattern of amorphous Epinastine base. FIG. 4 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form II. FIG. 5 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form III. FIG. 6 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form IV. FIG. 7 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form V. FIG. 8 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form VI. FIG. 9 is a characteristic X-ray Powder diffraction pattern Epinastine HC1 Form VII. FIG. 10 is a characteristic X-ray Powder diffraction pattern of Epinastine HC1 Form VIII. FIG. 11 is a characteristic X-ray Powder diffraction pattern of amorphous Epinastine HC1.
Description of the present invention:
The present invention describes novel crystalline forms, Form I and Form II of Epinastine base and seven crystalline forms, Form II, Form III, Form IV, Form V, Form VI, Form VII and Form VIII of Epinastine HC1.
In accordance with the present invention there is also provided process for preparation of crystalline forms of Epinastine base and its hydrochloride salt.
The present invention further provides amorphous form of Epinastine base and its hydrochloride salt and process for preparation thereof.
According to one embodiment of the invention there is provided novel crystalline Form I of Epinastine base.
6

Another embodiment of the invention provides process for preparing the crystalline Form I of Epinastine base comprising the steps of,
a) dissolving Epinastine base in a solublizing solvent;
b) cooling the obtained solution;
c) isolating the separated product and
d) drying the isolated product
The solublizing solvent is selected from group comprising aliphatic ketones, nitriles and C1-C4 alcohols.
The ketone is selected from the group comprising acetone, ethyl methyl ketone, diethyl ketone preferably acetone. Nitrile used is acetonitrile and alcohols are selected from group consisting of methanol, ethanol, 1- propanol, 2-propanol (IPA), butanol preferably IPA.
In preferred embodiment Epinastine base is dissolved at reflux temperature of the solvent selected for dissolution, preferably at temperature of 60-80°C. The obtained solution is cooled to temperature 5-10°C and stirred for 2-8 hours at the same temperature. The separated solid is isolated by filtration followed by drying at temperature range of 30-90°C preferably 65°C to get Epinastine base Form I.
In another embodiment of the present invention process for preparation of crystalline Epinastine base Form I comprises the following steps;
a) dissolving Epinastine base in a solublizing solvent;
b) adding suitable anti-solvent;
c) isolating the separated solid and
d) drying the isolated product.
The solublizing solvent is selected from group comprising polar aprotic solvent, aliphatic cyclic ethers and chlorinated hydrocarbons.
7

The polar aprotic solvent is selected from dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA). The aliphatic cyclic ether is selected from 1,4 - dioxane or tetrahydrofuran (THF) or mixtures thereof, preferably 1,4-dioxane. The chlorinated hydrocarbon is selected from chloroform or methylene dichloride (MDC) preferably MDC.
The anti-solvent is selected from the group comprising aliphatic ketones, esters, hydrocarbons, ethers, aromatic hydrocarbons and water.
The ketone is selected from acetone, 2-butanone, diethyl ketone or mixtures thereof, preferably acetone. Ester is selected from methyl acetate, ethyl acetate, butyl acetate or mixtures thereof, preferably ethyl acetate. Ether is selected from diethyl ether (DEE), diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE) preferably DIPE. Hydrocarbon is selected from n-hexane and n-heptane preferably n-hexane and aromatic hydrocarbon is selected from toluene and xylene preferably toluene.
In preferred embodiment of the invention, Epinastine base is dissolved in solubilizing solvent at reflux temperature, preferably at temperature 40-80°C and anti-solvent is added. The obtained solution is then cooled to temperature of 0- 30°C and stirred for 2-8 hours at the same temperature. The separated solid is isolated by filtration followed by drying at temperature 65°C to get Form I of Epinastine base.
In accordance with the present invention Epinastine base Form I thus obtained is characterized by the following XRPD peaks given below,

Pos. f°2Th.l Rel. Int. [%1
5.89 2.18
8.73 3.58
11.65 48.31
13.87 71.73
14.30 3.13
15.09 19.58
16.13 13.88
17.14 28.82
17.49 12.80
8

18.15 100
19.04 35.28
19.89 56.45
21.81 24.99
22.33 7.80
22.65 6.71
23.06 21.59
23.33 18.19
23.79 24.86
24.15 25.99
24.51 6.30
25.26 35.77
26.16 35.83
26.63 26.98
27.19 19.41
27.79 16.60
28.66 16.31
29.05 14.70
30.33 11.19
31.45 8.56
32.42 6.34
33.47 4.52
33.80 5.22
36.32 4.90
36.67 6.21
37.64 6.04
39.64 2.79
40.45 1.81
42.10 3.03
42.96 2.12
43.89 3.91
48.49 1.18
Another embodiment of the present invention provides new crystalline Form II of Epinastine base.
In another embodiment of the invention process for preparation of Epinastine base Form II according to the invention comprises the following steps,
a) dissolving Epinastine base in a solublizing solvent to obtain a solution;
b) pouring anti-solvent to obtain solution;
c) stirring the suspension for several hours and
d) isolating the product and drying
9

The solublizing solvent is selected from group comprising alcohols, aliphatic cyclic ethers or mixtures thereof.
The alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol (IPA), butanol more preferably IPA. Aliphatic cyclic ether is selected from 1,4-dioxane, tetrahydrofuran preferably 1,4-dioxane.
The anti-solvent selected is any suitable solvent which is miscible with the above solublizing solvents most preferably water.
In preferred embodiment of the invention Epinastine base is dissolved in solubilizing solvent at reflux temperature of individual solvent selected for dissolution, preferably at temperature 60-80°C. The anti-solvent is poured into the obtained solution at temperature of 0-5°C and stirred at 5-10°C for 2-4 hours. The separated solid is isolated by filtration followed by drying at 65°C to get Epinastine Form II.
Epinastine base Form II thus obtained is characterized by the following XRPD peaks which are shown in the following table below,

Pos. [°2Th.l Rel. Int. [%1
5.18 0.70
10.23 100
12.73 2.09
13.83 0.20
15.29 12.34
16.50 2.58
19.68 1.25
20.39 10.44
20.86 11.54
22.08 0.50
24.30 7.71
25.53 2.44
26.48 0.54
27.76 0.53
29.13 1.11
20.07 1.45
30.40 2.39
31.51 0.45
34.10 3.80
10

35.40 2.27
35.97 16.90
39.22 2.13
40.55 2.27
41.31 2.20
46.73 2.95
47.18 0.59
According to another embodiment, the present invention provides a novel amorphous form of Epinastine. The amorphous Epinastine is characterized by, having broad x-ray diffraction spectrum as in figure 3.
Another embodiment of the present invention provides process for the preparation of amorphous Epinastine. Amorphous Form of Epinastine base according to the present invention is prepared by dissolving Epinastine base in a suitable solubilizing solvent at temperature range of 30-50°C or at reflux temperature of the suitable solvent selected for dissolution and the solvent is removed from the obtained clear solution by vacuum drying or spray drying technique to get amorphous Epinastine.
The solublizing solvent is selected from alcohol, chlorinated hydrocarbons or mixture thereof.
The alcohol is selected from methanol, ethanol, preferably methanol. The chlorinated hydrocarbon is selected from methylene dichloride (MDC) or chloroform preferably methylene dichloride.
The concentration of Epinatin base used is 5-15% preferably 8-12 %.w/v.
The spray drying is carried out at inlet temperature of 40 to 170°C, preferably 160°C and
outlet temperature of 35-85°C, preferably 65°C.
The vacuum evaporation is carried out at temperature about 65°C.
Epinastine HCl obtained by following the process disclosed in US 4313931 is designated herein as 'Form V of Epinastine hydrochloride.
11

Another embodiment the present invention provides new form of Epinastine hydrochloride designated as, Form II and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form II comprises the steps of,
a) suspending Epinastine base in solublizing solvent;
b) adding acid to the obtained suspension;
c) warming the solution to get clear solution and
d) cooling and isolating the separated solid.
Epinastine base can be of any polymorphic form preferably Form II, used for making novel form of Epinastine HCl. The solubilizing solvent may be aqueous solvent selected from alcohols, ketone, water or mixtures thereof, preferably water, selected such that Epinastine base is insoluble but its hydrochloride salt is freely soluble. The acid used is hydrochloric acid.
In preferred embodiment of the invention, Epinastine base is suspended in solubilizing solvent and an acid is added to the obtained suspension. The solution is warmed at temperature about 50-60°C to get clear solution. The clear solution is cooled to -10 to 5°C preferably 0-5°C followed by stirring and further cooled at temperature 10-15°C for 30 min. The separated solid is then filtered and dried at 25-30°C to get Form II of Epinastine HCl.
Epinastine hydrochloride Form II thus obtained is characterized by the following XRPD peaks which are shown in the following table below,

Pos. [°2Th.] Rel. Int. [%1
8.46 7.20
9.29 76.16
10.19 79.93
12.50 10.09
13.27 21.75
14.72 16.61
16.24 11.06
16.80 7.28
12

17.45 39.45
18.44 57.90
18.91 18.26
19.33 8.38
19.66 9.51
20.75 15.82
22.10 42.18
22.70 8.43
23.36 24.35
24.20 100
24.73 15.18
25.58 29.40
26.47 11.88
27.71 49.72
28.31 30.90
28.97 43.01
29.40 22.31
30.45 19.23
31.31 18.36
31.86 40.69
33.76 9.81
34.52 14.07
35.12 16.64
36.39 8.37
37.15 19.48
38.36 21.94
38.66 13.89
42.07 17.07
44.48 6.12
47.49 4.80
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as, Form III and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form III comprises the steps of,
a) dissolving Epinastine hydrochloride in a solublizing solvent;
b) optionally adding anti-solvent;
c) stirring the solution for several hours.
d) isolating the product and drying
13

Epinastine hydrochloride selected for making novel form of Epinastine hydrochloride can be of any polymorphic forms preferably Form II. The solublizing solvent is selected from the group comprising of C1-C4 alcohols, chlorinated hydrocarbons and aliphatic cyclic ethers.
The alcohol is selected from the group of methanol, ethanol, 1-propanol, IPA, butanol preferably 2-propanol. Chlorinated hydrocarbons selected are methylene dichloride (MDC) or chloroform preferably MDC. The aliphatic cyclic ether is selected from 1,4-dioxane or tetrahydrofuran (THF).
The anti-solvent is selected from group of aliphatic acyclic ethers, hydrocarbons and esters.
The aliphatic acyclic ether is selected from DEE, DIPE or MTBE preferably DIPE. Hydrocarbon is selected from pentane, hexane, heptane preferably hexane and ester is selected from ethyl acetate, butyl acetate, isopropyl acetate preferably ethyl acetate.
The anti-solvent is added at 30-50°C preferably 25-35°C. The suspension is further cooled and stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form III of Epinastine hydrochloride.
In preferred embodiment of the invention Epinastine hydrochloride is dissolved in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. Optionally adding anti-solvent at temperature 30-50°C preferably 25-35°C. The suspension is further cooled and stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form III of Epinastine hydrochloride.
Epinastine hydrochloride Form III thus obtained is characterized by the following XRPD peaks which are shown in the following table below,
Pos. [°2Th.] Rel. Int. [%]
5.62 100
8.86 27.15
11.27 37.99
12.77 5.88
14

13.18 16.22
13.67 22.13
14.77 16.41
15.43 20.21
16.93 21.69
17.38 19.14
17.74 37.66
18.23 9.51
18.83 13.69
20.17 9.24
20.73 3.27
21.30 29.55
21.80 13.18
22.60 13.94
23.46 21.78
23.81 16.41
24.52 21.7
25.00 27.55
25.51 8.84
25.94 10.19
26.46 17.61
27.17 6.8
27.49 9.74
28.20 31.58
29.26 5.99
29.75 9.56
30.23 8.2
32.54 11.02
33.78 5.08
34.96 3.64
39.29 4.04
40.97 4.96
42.61 2.15
46.71 2.82
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as Form IV and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form IV comprises the steps of,
a) dissolving Epinastine HC1 in a solublizing solvent;
b) adding anti-solvent to the obtained solution;
c) stirring the suspension for several hours.
15

d) isolating the product and drying
Epinastine hydrochloride selected for making novel form of Epinastine hydrochloride can be of any polymorphic forms preferably Form II.
The solublizing solvent is selected from the group of CrC4 alcohols such as methanol, ethanol, 2-propanol, preferably methanol.
The anti-solvent is selected from a group of aliphatic acyclic ethers, aromatic hydrocarbons and esters or mixtures thereof. The aliphatic acyclic ethers selected are DEE, DIPE or MTBE preferably DIPE. Aromatic hydrocarbons selected are toluene, xylene preferably toluene and esters selected are ethyl acetate, butyl acetate, iso propyl acetate preferably ethyl acetate.
The anti-solvent is added at 30-50°C preferably 25-35°C. The suspension is further stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form IV of Epinastine hydrochloride.
In preferred embodiment of the invention Epinastine hydrochloride is dissolved in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. The anti-solvent is added at 30-50°C preferably 25-35°C. The suspension is further stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form IV of Epinastine hydrochloride.
Epinastine hydrochloride Form IV thus obtained is characterized by the following XRPD peaks which are shown in the following table below,
Pos. [°2Th.] Rel. Int. [%]
8.71 3.21
9.22 22.02
9.86 37.27
10.36 16.13
10.95 12.21
11.59 32.27
11.79 9.92
12.37 8.09
16

12.89 12.09
13.18 15.73
13.41 12.48
15.57 14.67
16.91 15.80
17.37 17.76
18.39 35.81
18.90 27.13
19.86 23.12
20.78 100
21.13 48.51
21.70 20.52
22.57 18.74
23.16 53.2
24.48 20.46
25.48 17.38
25.92 27.09
26.45 29.72
27.56 24.98
28.58 22.02
29.14 20.39
30.43 15.04
31.92 9.48
32.98 8.37
34.05 6.20
36.44 1.61
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as Form V and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form V comprises the steps of,
a) suspending Epinastine HC1 in solubilizing solvent;
b) optionally adding anti-solvent to the obtained solution;
c) stirring the solution for several hours and
d) isolating the product and drying.
Epinastine hydrochloride selected for making novel form of Epinastine hydrochloride can be of any polymorphic form, preferably Form II.
17

The solublizing solvent is selected from C]-C4 alcohols such as methanol, ethanol, 2-propanol, preferably ethanol and aromatic hydrocarbon such as toluene, xylene preferably toluene.
The anti-solvent is selected from a group of aliphatic acyclic ether such as DEE, DIPE or MTBE.
In preferred embodiment of the invention Epinastine hydrochloride is suspended in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. Optionally anti-solvent is added at 30-50°C preferably 25-35°C. The solution is further stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form V of Epinastine hydrochloride.
Epinastine hydrochloride Form V thus obtained is characterized by the following XRPD peaks which are shown in the following table below,

Pos. [°2Th.l Rel. Int. [%]
5.81 5.81
8.62 10.45
10.32 32.43
11.12 7.92
11.57 26.42
12.79 21.28
13.13 21.99
14.06 5.22
14.37 6.89
14.91 5.62
15.48 30.88
17.29 38.18
18.09 5.50
19.38 19.10
19.86 31.74
20.53 18.80
20.81 100
21.08 19.07
21.43 22.36
21.63 32.21
22.24 17.69
22.89 10.62
23.90 14.73
18

24.39 12.77
24.81 15.20
25.88 20.22
26.23 11.69
27.21 13.15
27.80 30.98
28.19 14.56
28.47 26.66
29.03 14.16
30.58 5.06
31.19 9.36
31.81 6.56
32.43 8.43
34.97 4.45
36.56 4.18
37.49 2.20
40.33 2.18
41.24 2.69
43.21 2.19
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as Form VI and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form VI comprises the steps of,
d) dissolving Epinastine HC1 in solublizing solvent;
e) adding anti-solvent to the obtained solution;
f) stirring the suspension for several hours and
g) isolating the product and drying
Epinastine hydrochloride selected for making novel form of Epinastine hydrochloride can be of any polymorphic forms preferably Form II.
The solublizing solvent is selected from the group of C1-C4 alcohols, cyclic ethers and chlorinated hydrocarbons. The alcohols selected are methanol, ethanol, 2-propanol, preferably ethanol. The aliphatic cyclic ethers selected are 1,4-Dioxane, THF preferably 1,4-dioxane and chlorinated hydrocarbon is selected from methylenedichloride (MDC), chloroform preferably MDC.
19

The anti-solvent is selected from a group of aliphatic acyclic ethers or hydrocarbons. The aliphatic acyclic ether is selected from DEE, DIPE or MTBE and aliphatic hydrocarbon is selected from n-pentane, n-hexane or n-heptane preferably n-hexane.
In preferred embodiment of the invention, Epinastine hydrochloride is dissolved in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. The anti-solvent is added at 30-50°C preferably 25-35°C. The suspension is further cooled and stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form VI of Epinastine hydrochloride.
Epinastine hydrochloride Form VI thus obtained is characterized by the following XRPD peaks which are shown in the following table below,

Pos. f°2Th.l Rel. Int. [%1
10.34 100
11.17 3.2
13.27 2.62
14.25 16.23
16.87 32.00
18.00 18.97
18.17 13.57
18.55 3.17
19.65 7.41
20.34 63.81
20.60 26.48
20.99 17.93
22.21 69.24
22.80 8.94
24.02 52.60
24.91 38.53
25.83 16.76
26.57 24.48
27.11 33.27
27.48 16.74
28.96 17.40
29.42 15.26
30.14 21.31
31.01 21.34
31.44 16.39
32.65 5.73
33.72 6.53
20

34.32 5.40
34.94 8.54
36.47 6.85
37.69 9.20
39.25 5.15
40.20 5.18
40.73 4.16
43.31 6.07
44.07 5.61
44.67 5.31
45.13 6.66
47.51 7.92
49.14 5.12
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as, Form VII and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form VII comprises the steps of,
a) dissolving Epinastine HC1 in a solublizing solvent;
b) adding anti-solvent to the obtained solution;
c) stirring the solution for several hours and
d) isolating the product and drying
Epinastine HC1 selected for making novel form of Epinastine HC1 can be of any polymorphic forms preferably Form II.
The solublizing solvent is selected from the group of cyclic ethers and polar aprotic solvents. The aliphatic cyclic ether is selected from 1,4-dioxane, tetrahydrofuran (THF) preferably 1,4-dioxane and polar aprotic solvent is selected from dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide (DMA) preferably DMF.
The anti-solvent is selected from a group of aliphatic ketones and esters. The aliphatic ketone is selected from acetone, 2-butanone, diethyl ketone preferably acetone and ester is selected from ethyl acetate, butyl acetate, iso propyl acetate, preferably ethyl acetate.
21

In preferred embodiment of the invention, Epinastine hydrochloride is dissolved in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. The anti-solvent is added at 30-50°C preferably 25-35°C. The suspension is further cooled and stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form VII of Epinastine hydrochloride.
Epinastine hydrochloride Form VII thus obtained is characterized by the following XRPD peaks which are shown in the following table below,
Pos. r°2Th.1 Rel. Int. {%]

5.91 26.86
8.62 13.05
10.39 49.08
11.12 4.77
11.57 30.85
11.77 18.25
12.83 17.15
13.15 17.33
13.76 5.96
14.43 11.11
14.97 8.82
15.28 17.82
15.49 27.43
17.22 20.97
17.66 9.88
18.20 9.97
18.95 4.25
19.35 26.84
19.92 26.53
20.53 18.84
20.75 100
21.11 14.10
21.60 47.40
21.86 17.39
22.44 19.22
22.91 12.86
23.96 12.74
24.19 13.46
24.51 19.85
25.49 14.70
25.76 7.33
25.94 23.79
26.39 19.37
27.38 24.34
22

27.83 35.16
28.46 31.47
29.10 10.81
29.95 10.94
31.36 10.47
31.90 8.34
According to another embodiment the present invention provides new form of Epinastine hydrochloride designated as, Form VIII and process for preparation thereof.
In another embodiment of the present invention the process for preparing Epinastine hydrochloride Form VIII comprises the steps of,
a) dissolving Epinastine HC1 in a solublizing solvent;
b) optionally adding anti-solvent to the obtained solution;
c) stirring the suspension for several hours and
d) isolating the product and drying
Epinastine HC1 selected for making novel form of Epinastine HC1 can be of any polymorphic forms preferably Form II.
The solublizing solvent is selected from the group of chlorinated hydrocarbons and nitriles. The chlorinated hydrocarbon is selected from methylenedichloride (MDC), chloroform preferably MDC and nitrile used is acetonitrile.
The anti-solvent is selected from group of aliphatic ketones and ethers. The aliphatic ketone is selected from acetone, 2-butanone, diethyl ketone preferably acetone and ether is selected from DEE, DIPE and MTBE.
In preferred embodiment of the invention, Epinastine hydrochloride is dissolved in suitable solubilizing solvent at reflux temperature preferably at temperature 50-60°C. Optionally adding the anti-solvent at temperature 30-50°C preferably 25-35°C. The suspension is further cooled and stirred at 5-10°C for 2-4 hours. The separated solid is filtered and dried at 50-60°C to get the novel Form VIII of Epinastine hydrochloride.
23

Epinastine hydrochloride Form VIII thus obtained is characterized by the following

XRPD peaks which are shown in
Pos. [°2Th.]
5.94
9.08
11.79
13.81
14.22
14.99
15.29
15.51
17.64
18.30
18.99
19.60
21.53
21.89
22.19
22.49
22.95
24.20
24.98
25.52
25.82
26.47
27.09
27.40
28.79
29.97
30.26
30.46
31.09
31.85
32.70
33.03
35.00
35.56
36.70
37.59
38.84
39.53
40.41
43.26

; following table below,
Rel. Int. [%] 88.32 7.13 61.54 27.19 24.28 17 100 26.74 29.85 36.83 13.08 73.77 67.58 78.32 23.49 50.62 11.91 80.71 52.74 55.23 24.36 63.35 24.21 89.21 31.37 41.99 37.71 30.49 9.66 11.93 10.41 16.80 11.51 9.95 9.79 6.23 7.82 10.27 18.00 8.00

24

According to another embodiment the present invention provides a novel amorphous form of Epinastine HCl. The amorphous Epinastine hydrochloride in accordance with the present invention is characterized by, having broad x-ray diffraction spectrum as in figure 11.
Another embodiment of the present invention provides process for the preparation of amorphous Epinastine hydrochloride
Preferably, Epinastine hydrochloride is dissolved in a suitable solubilizing solvent at a temperature range of 40-50°C and the solvent is removed from the obtained solution by vacuum drying or spray drying or lyophilization technique to get amorphous Epinastine HCl.
The solubilizing solvent is selected from water and alcohol or a mixture thereof preferably water. The alcohol is selected from methanol and ethanol preferably methanol. The concentration of Epinatin HCl in solution is 5-15% preferably 8-12 % w/v.
The spray dried is carried out at inlet temperature of 40 to 170°C, preferably 160°C and
outlet temperature of 35-85°C, preferably 65°C.
The vacuum evaporation is carried out at temperature ranges from 65-85°C.
The lyophilization is carried out by freeze drying an aqueous solution of Epinastine
hydrochloride at temperature -20 to -80°C under vacuum preferably -40°C for 24-48
hours.
The crystallization process hitherto described to prepare the novel polymorphs consists of dissolving Epinastine base or Epinastine HCl in the selected solvent either with or without heating, preferably with heating at or near boiling point of the solvent. Cooling the resultant solution to -10°C to 5°C for several hours to regenerate the solid. Isolating the precipitated solids and drying the isolated solids at about ambient to 65°C temperature.
The solvent and anti-solvent combination process described to prepare the novel polymorphs consist of dissolving Epinastine base or Epinastine HCl in the suitable
25

solvent. The dissolution may be carried out at room temperature or under reflux condition. Adding anti-solvent to the resulting solution under warm condition to get polymorphs of Epinastine base or Epinastine HC1. The anti-solvent addition is carried out at room temperature or at temperature of 25-35°C. Isolating the precipitated solids by filtration and drying the isolated solids at about ambient temperature to 65°C or at room temperature.
The novel polymorphs of Epinastine base and Epinastine HC1 in accordance with the present invention are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Ka (A. = 1.5406 A) radiation with scanning range between 4-50 9 at scanning speed of 2°/min.
EXAMPLES Epinastine Base - Form I
Example 1
0.5g of Epinastine base was dissolved in 10 ml isopropanol reflux temperature. The obtained solution was filtered to remove any insoluble material. The solution was cooled and stirred at 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 2
0.5g of Epinastine base was dissolved in 60 ml acetonitrile at reflux temperature. The solution obtained was filtered to remove any insoluble material. The solution was then cooled and stirred at 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 3
0.5 g of Epinastine base was dissolved in 60 ml acetone at reflux temperature. The solution was filtered to remove any insoluble material. To the obtained solution 120 ml n-hexane was added dropwise and the solution was cooled to 0-5°C and stirred for 4-8
26

hours at the same temperature. The solid separated was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 4
0.5g of Epinastine base was dissolved in 6 ml dimethylsulphoxide at temperature 55-60°C and the obtained solution was filtered to remove any insoluble material. To this obtained solution 30 ml acetone was added dropwise and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 5
0.5g of Epinastine base was dissolved in 6 ml dimethylsulphoxide at temperature 55-60°C and the obtained solution was filtered to remove any insoluble material. 20 ml water was added to this obtained solution and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 6
0.5g of Epinastine base was dissolved in 10 ml methylenedichloride at temperature 40-45°C and the obtained solution was filtered to remove any insoluble material. 30 ml DIPE was added dropwise to this solution and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65 °C to get Epinastine Form I.
Example 7
0.5g of Epinastine base was dissolved in 10 ml MDC at temperature 40-45°C and the solution obtained was filtered to remove any insoluble material. 30 ml hexane was added to this solution and stirred at temperature 25-30°C for 3 Hrs. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
27

Example 8
0.5g of Epinastine base was dissolved in 10 ml methylenedichloride at temperature 40-45°C. The solution was filtered to remove any insoluble material. 50 ml toluene was added to this solution dropwise and the solution was stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 9
0.5g of Epinastine base was dissolved in 10 ml methylenedichloride at temperature 40-45°C and the obtained solution was filtered to remove any insoluble material. 30 ml ethyl acetate was added to this solution dropwise and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 10
0.5g of Epinastine was base dissolved in 6 ml 1,4-dioxane at reflux temperature and the obtained solution was filtered to remove any insoluble material. 30 ml toluene was added to this solution dropwise and stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 11
0.5g of Epinastine base was dissolved in 6 ml 1,4-dioxane at reflux temperature and the obtained solution was filtered to remove any insoluble material. 40 ml acetone was added to this solution and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 12
0.5g of Epinastine base was dissolved in 6 ml 1,4-dioxane at reflux temperature and the obtained solution was filtered to remove any insoluble material. 25 ml hexane was added to this solution and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
28

Example 13
0.5g of Epinastine base was dissolved in 6 ml 1,4-dioxane at reflux temperature and the solution was filtered to remove any insoluble material. 35 ml ethyl acetate was added to this solution dropwise and stirred at temperature 0-5°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 14
0.5g of Epinastine base was dissolved in 12 ml tetrahydrofuran at reflux temperature and the solution was filtered to remove any insoluble material. 30 ml water was added to the the obtained clear solution. The solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 15
0.5g of Epinastine base was dissolved in 12 ml tetrahydrofuran at reflux temperature and the solution was filtered to remove any insoluble material. 30 ml hexane was added dropwise to this solution and stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Example 17
0.5g of Epinastine base was dissolved in 12 ml tetrahydrofuran at reflux temperature and the solution was filtered to remove any insoluble material. 30 ml DIPE was added dropwise to this solution and the solution was stirred at temperature 25-30°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form I.
Epinastine Base - Form II
Example 18
0.5g of Epinastine base was dissolved in 10 ml isopropanol at reflux temperature and the solution was filtered to remove any insoluble material. 30 ml water was poured in the clear solution obtained at temperature 0-5°C and stirred at the same temperature for 3
29

hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form II.
Example 19
0.5g of Epinastine base was dissolved in 6 ml dioxane at reflux temperature and the solution was filtered to remove any insoluble material. 30 ml water was poured in to the clear solution obtained at temperature 0-5°C and stirred at temperature 0-5°C for 3 hours The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine Form II.
Epinastine Base - Amorphous Form
Example 20
5 g Epinastine base was dissolved in 10 ml methanol at temperature range of 40-50°C. The obtained clear solution was concentrated under vacuum at temperature 65°C to get amorphous Epinastine.
Example 21
5 g Epinastine base was dissolved in 10 ml methylenedichloride at a temperature range of 40-50 °C. The obtained clear solution was concentrated under vacuum at temperature 65°C to get amorphous Epinastine.
Example 22
Epinastine base was dissolved in methanol at temperature range of 30-40 °C. The obtained solution was spray dried at the inlet temperature 120° C and outlet temperature 65°C to get amorphous Epinastine.
Example 23
Epinastine base was dissolved in methylenedichloride at a temperature range of 30-40 °C. Concentration of Epinastine used for spray drying is about 10 % weight/volume. The obtaioned solution was spray dried at the inlet temperature 120° C and outlet temperature 65°C to get amorphous Epinastine.
30

Epinastine HC1 - Form II
Example 24
llg Epinastine base was suspended in 15 ml water at temperature 30-40 °C. 4 ml concentrated HC1 (35.4%) was added to this suspension dropwise and the solution was warmed to 50-60° to dissolve the solid. The solution was filtered and cooled to temperature 0-5°C. The separated solid was further cooled to 10-15°C for 30 minutes and the separated solid was filtered and dried at temperature 25-30°C to get Epinastine hydrochloride Form II.
Epinastine. HC1 - Form III
Example 25
0.5g Epinastine HC1 was dissolved in 10 ml isopropyl alcohol at reflux temperature. 50 ml DIPE was added to the clear solution obtained. The solution stirred at temperature 5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 26
0.5g Epinastine HC1 was dissolved in 10 ml isopropyl alcohol at reflux temperature. 50 ml hexane was added to the obtained clear solution. The solution was stirred at temperature 5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 27
0.5g Epinastine HC1 is dissolved in 10 ml methylenedichloride at reflux temperature. 30 ml DIPE was added to the obtained clear solution. The solution was stirred at temperature 5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 28
0.5g Epinastine HC1 is dissolved in 15 ml methylenedichloride at reflux temperature. 30
ml ethyl acetate was added to this clear solution and the solution was stirred at
31

temperature 5-10°C for 3 hours. Separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 29
0.5g Epinastine HCl is dissolved in 15 ml methylenedichloride at reflux temperature. The obtained solution was cooled and stirred at temperature 5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 30
0.5g Epinastine HCl is dissolved in 6 ml 1,4-dioxane at temperature 50-60°. 20 ml ethyl acetate was added to the clear solution add. The solution was stirred at temperature 5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Example 31
0.5g Epinastine HCl is suspended in 30 ml tetrahydrofuran at reflux temperature. The obtained solution was cooled and stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form III.
Epinastine. HCl - Form IV
Example 32
0.5g Epinastine HCl is dissolved in 5 ml methanol at temperature 50-60°C. 30 ml DIPE was added to the clear solution obtained and the solution was stirred at temperature 5-10°C for 3 hours The separated solid was isolated by filtration and dried at temperature 65 °C to get Epinastine hydrochloride Form IV.
Example 33
0.5g Epinastine HCl is dissolved in 5 ml 1,4-dioxane at temperature 50-60°. 40 ml ethyl
acetate was added to the clear solution obtained. The solution was stirred at temperature
32

5-10°C for 3 hours and the separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form IV
Example 34
0.5g Epinastine HCl is dissolved in 5 ml methanol at temperature 50-60°. A mixture of 40 ml DIPE and 40 ml toluene was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 Hrs. Separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form IV.
Epinastine. HCl - Form V
Example 35
0.5g Epinastine HCl is dissolved in 10 ml ethanol at temperature 50-60°C. 40 ml DIPE was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form V.
Example 36
0.5g Epinastine HCl is suspended in 30 ml toluene at reflux temperature. The solution
was cooled and stirred at temperature 5-10°C for 3 hours and the separated solid was
isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form
V.
Epinastine. HCl - Form VI
Example 37
0.5g Epinastine HCl is dissolved in 10 ml ethanol at reflux temperature. 60 ml hexane was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VI.
33

Example 38
0.5g Epinastine HC1 is dissolved in 15 ml methylenedichloride at reflux temperature. 60 ml hexane was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VI.
Example 39
0.5g Epinastine HC1 is dissolved in 6 ml 1,4-dioxane at temperature 50-60°C. 30 ml DIPE was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VI.
Epinastine. HC1 - Form VII
Example 40
0.5g Epinastine HC1 is dissolved in 6 ml 1,4-dioxane at temperature 50-60°C. 30 ml acetone was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VII.
Example 41
0.5g Epinastine HC1 is dissolved in 4 ml dimethylformamide at temperature 50-60°C. 20 ml ethyl acetate was added to the obtained clear solution and the solution was stirred at temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VII.
Epinastine. HC1 - Form VIII
Example 42
0.5g Epinastine HC1 is dissolved in 15 ml methylenedichloride at reflux temperature. 30 ml acetone was added to the obtained clear solution and the solution was stirred at
34

temperature 5-10°C for 3 hours. The separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VIII.
Example 43
0.5g Epinastine HCl is dissolved in 10 ml acetonitrile at reflux temperature. The solid seperates out from the clear solution at reflux temperature. The solution was stirred at temperature 5-10°C for 3 hours. Separated solid was isolated by filtration and dried at temperature 65°C to get Epinastine hydrochloride Form VIII.
Example 44
0.5g Epinastine HCl is dissolved in 10 ml acetonitrile at reflux temperature. From the clear solution solid separates out at reflux. Filter the separated solid and to the filtrate add 30 ml DIPE. The solution was stirred at 5-10°C for 3 hours. Separated solid was isolated by filtration and dried at 65°C to get Epinastine hydrochloride Form VIII.
Epinastine HCl - Amorphous Form
Example 45
5 g Epinastine HCl was dissolved in 10 ml water at a temperature range of 40-50 °C. The obtained clear solution was concentrated under vacuum at temperature 85°C to get amorphous Epinastine HCl
Example 46
5 g Epinastine HCl was dissolved in 20 ml methanol at a temperature range of 40-50 °C. The obtained clear solution was concentrated under vacuum at temperature 65°C to get amorphous Epinastine HCl
Example 47
Epinastine HCl was dissolved in water at a temperature range of 30-40 °C. Concentration of Epinastine used for spray drying is about 10 % weight/volume. The sobtained solution was spray dried at the inlet temperature 140° C and outlet temperature 65°C to get amorphous Epinastine HCl.
35

Example 48
Epinastine HC1 was dissolved in methanol at a temperature range of 30-40 °C. Concentration of Epinastine used for spray drying is about 10 % weight/volume. The obtained solution was spray dried at the inlet temperature 120° C and outlet temperature 65°C to get amorphous Epinastine HC1.
Example 49
10g Epinastine HC1 was dissolved in 100 ml water at a temperature range of 40-50°C. The obtained clear solution was subjected to lyophihzation for 24-48 hrs at temperature -40"C to get amorphous Epinastine HC1
The above description is not intended to detail all modifications and variations of the invention. It will be appreciated by those skilled in the art that changes can be made to the embodiments described above without departing from the inventive concept. It is understood, therefore, that the invention is not limited to the particular embodiments described above, but is intended to cover modifications that are within the spirit and scope of the invention, as defined by the language of the following claims.
Dated this 24th day of September,2007.

36