DESC:
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR THE PREPARATION OF BILASTINE”

Glenmark Pharmaceutical Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

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 a process for the preparation of bilastine.

BACKGROUND OF THE INVENTION
Bilastine is a selective antagonist of H1 receptors, useful in the treatment of allergic reactions and pathological processes mediated by histamine, especially for treating rhinoconjunctivitis and urticaria. Bilastine is chemically known as 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropanoic acid,
and represented by formula (I):

Formula I
United States patent No. US 5,877,187 discloses bilastine and its process for preparation.
The present invention provides an economical, efficient, and ecofriendly process for the preparation of stable amorphous bilastine.
The present invention also provides an economical, efficient, and ecofriendly process for the preparation of stable crystalline Form 2 and stable crystalline Form 3 of bilastine.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, esters, water or mixtures thereof to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, the present invention provides an amorphous bilastine.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising slurrying bilastine in ethyl acetate.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) dissolving bislatine in n-pentanol to form reaction mass;
b) adding seed of Form 2 of bilastine to the reaction mass of step (a); and
c) isolating Form 2 of bilastine.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for 10-15 hours to obtain Form 2 of bilastine.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for 50-70 hours to obtain Form 3 of bilastine.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) dissolving bislatine in a mixture of ethanol and water to form reaction mass;
b) heating the reaction mass of step (a), followed by cooling to get a precipitated solid; and
c) filtering and drying the precipitated solid of step (b) to obtain Form 3 of bilastine.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating amorphous bilastine with ethyl acetate to form reaction mixture; and
b) isolating Form 3 of bilastine from reaction mixture of step (a).
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising keeping amorphous bilastine in air oven at 60 °C under humid condition for 12 hours.
In one embodiment, the present invention provides a process for the preparation of bilastine, the process comprising
a) treating bilastine with benzyl amine to form benzyl amine salt of bilastine,
b) converting benzyl amine salt of bilastine to bilastine.
In one embodiment, the present invention provides benzyl amine salt of bilastine.
In one embodiment, the present invention provides benzyl amine salt of bilastine, characterized by 1HNMR.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a X-Ray powder diffraction (XRPD) of amorphous bilastine.
Figure 2 is a Thermogravimetric Analysis (TGA) of amorphous bilastine.
Figure 3 is a 1HNMR of bilastine benzyl amine salt.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, esters, water or mixtures thereof to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, in step (a) hydrocarbons may be selected from the group consisting of toluene, xylene, pentane, hexane, n-heptane, octane, cyclohexane and the like; halogenated hydrocarbons may be selected from the group consisting of methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene and the like; alcohols may be selected from the group consisting of methanol, ethanol, isopropanol (IPA), n-butanol, t-butanol, 1-butanol, n-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; esters may be selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate and the like.
In one embodiment, in step (b) removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required.
In one embodiment, the solution may also be completely evaporated, for example in, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of halogenated hydrocarbons, esters, alcohols, water or mixtures thereof to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, halogenated hydrocarbons, esters, alcohols used in step (a) is as described supra.
In one embodiment, solvent in step (b) is removed from the solution by concentrating the solution, or completely evaporating the solvent.
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of halogenated hydrocarbons, alcohols to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, halogenated hydrocarbons and alcohols used in step (a) is as described supra.
In one embodiment, solvent in step (b) is removed from the solution by concentrating the solution, or completely evaporating the solvent.
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a halogenated hydrocarbons to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, halogenated hydrocarbons used in step (a) is as described supra.
In one embodiment, solvent in step (b) is removed from the solution by completely evaporating the solvent.
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of hydrocarbons, halogenated hydrocarbons, esters, alcohols, ketones, nitriles, ethers, amides, dialkylsulfoxides, water or mixtures thereof to form solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
In one embodiment, the hydrocarbons, halogenated hydrocarbons, esters and alcohols used in step (a) is as described supra.
In one embodiment, in step (a), ketones may be selected from the group consisting of acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; nitriles may be selected from the group consisting of acetonitrile, propionitrile, butyronitrile, benzonitrile and the like; ethers may be selected from the group consisting of methyl-tert-butyl ether, diethyl ether, tetrahydrofuran (THF), dioxane and the like; amides may be selected from the group consisting of dimethylformamide, diethylacetamide, N-methylformamide and the like; dialkylsulfoxide may be selected from the group consisting of dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide and the like.
In one embodiment, the solvent in step (b) is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the present invention provides a process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of hydrocarbons, halogenated hydrocarbons, esters, alcohols, ketones, nitriles, ethers, amides, dialkylsulfoxides, water or mixtures thereof to form a solution; and
b) adding an anti-solvent to the solution of step (a) to form amorphous bilastine.
In one embodiment, in step (a) the hydrocarbons, halogenated hydrocarbons, esters, alcohols, ketones, nitriles, ethers, amides is as described supra.
In one embodiment, the anti-solvent in step (b) includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, pentane, heptane, hexane, cyclohexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the amorphous bilastine is isolated by any method known in the art.
In one embodiment, the method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the present invention provides a stable amorphous bilastine.
The term “stable” herein means amorphous bilastine that does not convert to any other solid form when stored at a temperature of up to about 400 °C and at a relative humidity of about 25% to about 75% for about three months and shows no change in polymorphic form by X-ray powder diffraction.
In one embodiment, the present invention provides an amorphous bilastine having purity of greater than 98% by HPLC. In particular, the purity by HPLC of greater than 99%, more particularly, the purity by HPLC of greater than 99.5%, most particularly, the purity by HPLC greater than 99.9%.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising slurrying bilastine in a suitable solvent.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising slurrying bilastine in esters, alcohols, and ketones.
In one embodiment, the esters may be selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate and the like; alcohols may be selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, t-butanol, 1-butanol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones may be selected from the group consisting of acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone and the like.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising slurrying bilastine in ester solvents.
In one embodiment, the ester solvent is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising slurrying bilastine in ethyl acetate.
In one embodiment, slurrying is done at about 35°C to about 60°C for about 1 hour to 4 hours.
In one embodiment, slurrying is done at about 40°C to about 50°C for about 1 hour to 3 hours.
In one embodiment, slurrying is done at about 45°C to about 50°C for about 2 hours.
In one embodiment, crystalline Form 2 of bilastine obtained is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, crystalline Form 2 of bilastine obtained is filtered and dried.
In one embodiment, drying may be performed for about 10 hours to about 15 hours.
In one embodiment, drying may be performed for about 10 hours to about 15 hours at a temperature of about 40°C to about 60°C.
In one embodiment, drying may be performed in vacuum dryer for about 12 hours at a temperature of about 50°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) dissolving bislatine in a solvent to form reaction mass;
b) adding seed of Form 2 of bilastine to the reaction mass of step (a); and
c) isolating Form 2 of bilastine.
In one embodiment, the solvent in step (a) is selected from alcohols, ketones, esters, ethers, nitriles, amides, hydrocarbons, halogenated hydrocarbons, water or mixtures thereof.
In one embodiment, the solvent used in step (a) is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) dissolving bislatine in alcohols to form reaction mass;
b) adding seed of Form 2 of bilastine to the reaction mass of step (a); and
c) isolating Form 2 of bilastine.
In one embodiment, the alcohols used in step (a) is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) dissolving bislatine in n-pentanol to form reaction mass;
b) adding seed of Form 2 of bilastine to the reaction mass of step (a); and
c) isolating Form 2 of bilastine.
In one embodiment, in step (a), reaction mass heated to about 90 °C for a period of about 30 minutes to about one hour and cooling the solution to about 70 °C.
In one embodiment, in step (b), seeding with Form 2 of bilastine may be performed at room temperature.
In one embodiment, in step (c), Form 2 of bilastine is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, Form 2 of bilastine obtained in step (c) is filtered and dried.
In one embodiment, drying may be performed for about 10 hours to about 15 hours.
In one embodiment, drying may be performed for about 10 hours to about 15 hours at a temperature of about 40°C to about 60°C.
In one embodiment, drying may be performed in vacuum dryer for about 12 hours at a temperature of about 50°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid to obtain Form 2 of bilastine.
In one embodiment, in step (b), the base may be selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, lithium tert. butoxide; triethylamine, diisopropylamine, dimethylaminopyridine, pyridine, diethylamine, dimethylamine and the like or aqueous mixtures thereof.
In one embodiment, in step (b), the acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
In one embodiment, in step (c), precipitated solid is stirred for about 20 minutes to about 2 hours.
In one embodiment, in step (d), drying may be performed for about 10 hours to about 15 hours.
In one embodiment, in step (d) drying may be performed for about 10 hours to about 15 hours at a temperature of about 45°C to about 65°C.
In one embodiment, in step (d) drying may be performed in vacuum for about 12 hours at a temperature of about 55°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 2 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with potassium hydroxide followed by treatment with hydrochloric acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for about 10 hours to about15 hours to obtain Form 2 of bilastine.
In step c), precipitated solid stirred for about 20 minutes to about 1 hour.
In one embodiment, in step (d) drying may be performed in vacuum for about 12 hours at a temperature of about 55°C.
In one embodiment, Form 2 of bilastine is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, the present invention provides a stable crystalline Form 2 of bilastine.
The term “stable” herein means crystalline Form 2 of bilastine that does not convert to any other solid form when stored at a temperature of up to about 400C and at a relative humidity of about 25% to about 75% for about three months and shows no change in polymorphic form by X-ray powder diffraction.
In one embodiment, the present invention provides crystalline Form 2 bilastine having purity of greater than 98% by HPLC. In particular, the purity by HPLC of greater than 99%, more particularly, the purity by HPLC of greater than 99.5%, most particularly, the purity by HPLC greater than 99.9%.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) dissolving bislatine in a mixture of alcohols, ketones, esters and water to form reaction mass;
b) heating the reaction mass of step (a), followed by cooling to get a precipitated solid; and
c) filtering and drying the precipitated solid of step (b) to obtain Form 3 of bilastine.
In one embodiment, the alcohols, ketones, esters used in step (a) is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) dissolving bislatine in a mixture of alcohols and water to form reaction mass;
b) heating the reaction mass of step (a), followed by cooling to get a precipitated solid; and
c) filtering and drying the precipitated solid of step (b) to obtain Form 3 of bilastine.
In one embodiment, the alcohols used in step (a) is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) dissolving bislatine in a mixture of ethanol and water to form reaction mass;
b) heating the reaction mass of step (a), followed by cooling to get a precipitated solid; and
c) filtering and drying the precipitated solid of step (b) to obtain Form 3 of bilastine.
In one embodiment, in step (a), mixture of alcohols and water may be used in any ratio.
In one embodiment, in step (a), mixture of ethanol : water may be used in any ratio preferably in 7:3.
In one embodiment, in step (b), the reaction mixture is heated at about 50 °C to about 80 °C and stirred for about 30 minutes to about 2 hours.
In one embodiment, in step (b), precipitated solid is obtained by gradually cooling of solution.
In one embodiment, Form 3 of bilastine is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed in vacuum for about 50 hours to about 70 hours at temperature about 40°C to about 70°C.
In one embodiment, drying may be performed in vacuum for about 60 hours at a temperature of about 50°C to about 60°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for about 50 hours to about 70 hours to obtain Form 3 of bilastine.
In one embodiment, base used in step (b) is as described supra.
In one embodiment, acid used in step (b) is as described supra.
In one embodiment, in step (c), precipitated solid stirred for about 20 minutes to about 2 hours.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with potassium hydroxide followed by treatment with hydrochloric acid to get a precipitated solid;
c) adding ethyl acetate to precipitated solid; and
d) filtering and drying the solid for about 50 hours to about 70 hours to obtain Form 3 of bilastine.
In one embodiment, in step (c), precipitated solid stirred for about 20 minutes to about 1 hour.
In one embodiment, in step (d) drying may be performed in vacuum for about 60 hours at a temperature of about 55°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating amorphous bilastine with esters to form reaction mixture; and
b) isolating Form 3 of bilastine from reaction mixture of step (a).
In one embodiment, ester solvent used in step (a) is as described supra.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising:
a) treating amorphous bilastine with ethyl acetate to form reaction mixture; and
b) isolating Form 3 of bilastine from reaction mixture of step (a).
In one embodiment, in step (a), reaction mixture is stirred for about 30 minutes to about one hour or longer at temperature range of about 40°C to about 55°C and then cooled to room temperature.
In one embodiment, in step (b), Form 3 of bilastine is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, Form 3 of bilastine obtained in step (b) is filtered and dried.
In one embodiment, drying may be performed for about 10 hours to about 15 hours, preferably for about 12 hours.
In one embodiment, drying may be performed in vacuum dryer at a temperature of about 40°C to about 60°C, preferably at a temperature of about 50°C.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising keeping amorphous bilastine in an air oven at about 55 °C to about 60 °C under humid condition for about 10 hours to about 15 hours.
In one embodiment, the present invention provides a process for the preparation of crystalline Form 3 of bilastine, the process comprising keeping amorphous bilastine in air oven at 60 °C under humid condition for about 12 hours.
In one embodiment, the present invention provides a stable crystalline Form 3 of bilastine.
The term “stable” herein means crystalline Form 3 of bilastine that does not convert to any other solid form when stored at a temperature of up to about 400C and at a relative humidity of about 25% to about 75% for about three months and shows no change in polymorphic form by X-ray powder diffraction.
In one embodiment, the present invention provides crystalline Form 3 bilastine having purity of greater than 98% by HPLC. In particular, the purity by HPLC of greater than 99%, more particularly, the purity by HPLC of greater than 99.5%, most particularly, the purity by HPLC greater than 99.9%.
In one embodiment, the present invention provides benzyl amine salt of bilastine.
In one embodiment, the present invention provides benzyl amine salt of bilastine characterized by proton NMR spectrum having peaks at about d 1.02 (t, 3H), 1.41 (s, 6H), 1.88(m, 4H), 2.07-2.13(m, 2H), 2.49 (t, 2H), 2.71 (t, 2H), 3.00(m, 3H), 3.31(q, 2H), 3.63(t, 2H), 3.81(s, 2H), 4.41(t, 2H), 5.57(br, s4H), 7.12-7.19(m, 4H), 7.24-7.39(m, 7H), 7.50-7.57(m, 2H).
In one embodiment, the present invention provides benzyl amine salt of bilastine characterized by proton NMR spectrum as depicted in Figure 3.
In one embodiment, the present invention provides a process for the preparation of bilastine, the process comprising:
a) treating bilastine with benzyl amine to form benzyl amine salt of bilastine,
b) converting benzyl amine salt of bilastine to bilastine.
In one embodiment, the solvent used in step (a) includes but is not limited to halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; and the like; water; or mixtures thereof.
In one embodiment, suitable temperature for step (a) may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a completion of reaction. The stirring time may range from about 30 minutes to about 1 hour, or longer.
In one embodiment, benzyl amine salt of bilastine obtained in step (a) is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, bilastine obtained in step (b) is filtered and dried.
In one embodiment, bilastine is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed in air oven at a temperature of about 40°C to about 70°C, preferably at a temperature of about 50°C to about 60°C.
In another embodiment, benzyl amine salt of bilastine may be used in preparation of amorphous bilastine.
In another embodiment, benzyl amine salt of bilastine may be used in preparation of crystalline Form 1 of bilastine.
In another embodiment, benzyl amine salt of bilastine may be used in the preparation of crystalline Form 2 of bilastine and crystalline Form 3 of bilastine
In one embodiment, the present invention provides a process for the preparation of bilastine of formula I, comprising:
a) reacting a compound of formula III,

Formula III
wherein R is C1-C5 alkyl, preferably methyl or ethyl,
with a compound of formula IV or its salt,

Formula IV
in the presence of a solvent and a base to form a compound of formula IIa;

Formula IIa
wherein R is C1-C5 alkyl, preferably methyl or ethyl
b) hydrolyzing the compound of formula IIa to a compound of formula I.
In one embodiment, in step (a) the solvent includes, but is not limited to amides such as dimethylformamide, diethylacetamide, N-methylformamide and the like; dialkylsulfoxide such as dimethylsulfoxide (DMSO), diethylsulfoxide, dibutylsulfoxide and the like; alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, t-butanol, 1-butanol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile, butyronitrile, benzonitrile and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate and the like; ether such as methyl-tert-butyl ether, diethyl ether, tetrahydrofuran (THF), dioxane and the like; hydrocarbons such as toluene, xylene, pentane, hexane, n-heptane, octane, cyclohexane and the like; The halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene and the like; water; or mixtures thereof.
In one embodiment, in step (a) the base may be selected from an inorganic base or organic base.
In one embodiment, the inorganic base may be selected from alkali metal or alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like
In one embodiment, the organic base may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, 4-Bromo-N,N-dimethylaniline, pyridine, piperidine, 2-bromopyridine, 3-bromopyridine, 4-bromopyridine, 4-dimethylaminopyridine, Di-tert butyl pyridine, 2,6-Di-tert-butyl-4-methylpyridine, Quinoline, tri-n-butylamine, N-methylmorpholine, 2,6-Lutidine, imidazole, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene.
In one embodiment, the reaction of compound of formula III with a compound of formula IV may be carried out in the temperature of about 50 °C to about 85 °C.
In one embodiment, the compound of formula IIa is isolated by any method known in the art.
In one embodiment, the method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the compound of formula IIa may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum.
In one embodiment, hydrolyzing performed in presence of a base.
In one embodiment, the base may be selected from an inorganic base or organic base as described supra.
In one embodiment, hydrolyzing may be performed in presence of a solvent.
In one embodiment, the solvent is as described supra.
In one embodiment, the compound of formula I is isolated by any method known in the art.
In one embodiment, the method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the compound of formula I may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like.
Instrumental settings for XRPD: X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” optimized to 50 sec.
Instrumental settings for TGA: Instrument Name: TGA Q 500; Method: 5-8 mg of sample was taken in platinum pan and heated at 100C/minute from 0 to 4000C.
Instrumental settings for proton NMR: Instrument Name: Bruker-400 MHz; 1H NMR spectra were recorded in DMSO-d6.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1: Preparation of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H- benzo[d]imidazole-2-yl) piperidin-1yl) ethyl) phenyl)-2-methylpropanoate
(Formula IIa wherein R is methyl)
To a stirred suspension of 2-methyl-2-{4-2(toluene-4-sulfonyloxy)-ethyl] phenyl}-propionic acid methyl ester and (20gm) and 1-(2-ethoxyethyl)-2-(piperidine-4-yl)-1H benzo[d] imidazole hydrochloride (19.76gm) In a mixture of dimethylfomamide and acetone at 25-30°C was added potassium carbonate (22.01gm). The reaction mixture was warmed to 80-85°C and stirred for 8-9 hours. After completion of reaction, cooled the reaction mass to 20-30°C and water was added slowly under stirring. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and dried over Na2SO4. The organic layer was evaporated under vacuum to give formula 2 as an oil (24.2gm) which was taken in cyclohexane (100ml) and stirred for 2 hours at 10-150C. The precipitated solid was filtered and dried under vacuum to obtain titled compound (20gm) as a white solid.
1H NMR (400 MHz in DMSO-d6): d 1.15 (t, 3H), 1.59 (s, 6H), 2.04 (bs, 2H), 2.17-2.22 (m, 4H), 2.65-2.69 (m, 2H), 2.82-2.86 (m, 2H), 3.03-3.04(m, 1H), 3.18 (d, 2H), 3.42 (q, 2H), 3.67 (s, 3H), 3.75 (t, 2H), 4.35 (t, 2H), 7.21-7.34(m, 7H), 7.76 (m, 1H).
Example 2: Preparation of amorphous bilastine
To a stirred solution of formula 2 (14.2 gm) in methanol and water at 20-30°C was added lithium hydroxide (2.18gm). Reaction mass was heated to 65-70 °C and stirred for 10-12 hours. After completion of reaction, distilled off solvent under vacuum. Reaction mass was taken in water and aqueous layer was washed with ether. After washing, pH was adjusted from 6.5-7.0 with 2N HCl solution. Aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water and dried over Na2SO4. The solvent was evaporated under vacuum to obtain titled compound. Yield: 9.1gm.
1H NMR (400 MHz in DMSO-d6): d 1.02 (t, 3H), 1.46 (s, 6H), 1.88(m, 4H), 2.08-2.15(m, 2H), 2.50 (t, 2H), 2.73 (t, 2H), 3.02(m, 3H), 3.32(q, 2H), 3.65(t, 2H), 4.41(t, 2H), 7.14-7.27(m, 6H), 7.50-7.57(m, 2H).
Example 3: Preparation of bilastine as per US5877187.
To a stirred solution of formula 2 (6.0 m) in methanol and water (300 mL, 7:3) at 20-30°C was added lithium hydroxide (0.91gm). Reaction mass was heated to 65-70°C and stirred for 10 to 12 hours. After completion of reaction, distilled off solvent under vacuum. Reaction mass was taken in 50 ml water and aqueous layer was washed with ether (50ml x 2times). After washing, pH was adjusted from 6.5-7.0 with 2N HCl solution. Aqueous layer was stirred for 2 hour. The precipitated solid was filtered and dried in vacuum oven at 50°C to obtain titled compound. Yield: 5.40gm.
Example 4: Preparation of benzyl amine salt of bilastine
To a stirred solution of formula 2 (14.2gm) in methanol/tetrahydrofuran/water (710 mL) at 20-30°C was added lithium hydroxide (2.18gm). Reaction mass was warmed to 65-70°C and stirred for 10-12 hours. After completion of reaction, distilled off solvent under vacuum. Reaction mass was taken in water and aqueous layer was washed with ether. After washing, pH was adjusted from 6.5-7.0 with 2N HCl solution. Aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water and benzyl amine (1.12gm) was added. The reaction mixture was refluxed for 60 minutes and dichloromethane was distilled off to get a residue which was taken in 25 ml ethyl acetate and stirred for 60 minutes. The precipitated solid was filtered and dried in oven at 50°C to obtain titled compound (15gm).
1H NMR (400 MHz in DMSO-d6): d 1.02 (t, 3H), 1.41 (s, 6H), 1.88(m, 4H), 2.07-2.13(m, 2H), 2.49 (t, 2H), 2.71 (t, 2H), 3.00(m, 3H), 3.31(q, 2H), 3.63(t, 2H), 3.81(s, 2H), 4.41(t, 2H), 5.57(br, s4H), 7.12-7.19(m, 4H), 7.24-7.39(m, 7H), 7.50-7.57(m, 2H).
Example 5: Preparation of amorphous bilastine
Benzyl amine salt of bilastine was taken in methylene dichloride and pH was adjusted to 2 to 3 using 2N HCl solution. Aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water and distilled off to get titled compound.
Example 6: Preparation of Form 3 of bilastine
To a stirred solution of formula 2 (14.2gm) in methanol/tetrahydrofuran/water (710 mL) at 20-30°C was added lithium hydroxide (2.18gm). Reaction mass was warmed to 65-70 °C and stirred for 10 to 12 hours. After completion of reaction, distilled off solvent under vacuum. Reaction mass was taken in water and aqueous layer was washed with ether. After washing, pH was adjusted from 6.5-7.0 with 2N HCl solution. Aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water and dried over Na2SO4, evaporated solvent under vacuum to give solid. Whereupon the solid was stirred in ethyl acetate at 45-50°C, filtered and dried in air dryer for 12 hours at 60°C to get titled compound.
Example 7: Preparation of Form 3 of bilastine
Amorphous bilastine was taken in ethyl acetate and stirred at 45-50 °C for one hour. Reaction mixture was cooled to 25-30°C, filtered and dried in vacuum dryer for 12 hour at 50 °C to get titled compound.
Example 8: Preparation of Form 3 of bilastine.
Amorphous bilastine was kept in air oven at 60°C under humidity condition for 12 hours. Amorphous form of bilastine was converted to Form 3 of bilastine.
Example 9: Preparation of Form 3 of bilastine
Bilastine (10.0 gm) was dissolved in water (120 ml). pH of reaction mass adjusted to 10.20 and filtered to get clear solution using potassium hydroxide solution. Clear solution was transferred to round bottom flask and pH of reaction mass adjusted pH 6.10 using 2N HCl. Solid was precipitated and ethyl acetate added and stirred for 30 minutes. Filtered solid and dried in vacuum for 60 hours at about 55°C under vacuum to get titled compound.
Example 10: Preparation of Form 2 of bilastine
Bilastine (10.0gm) was dissolved in water (120ml). pH of reaction mass adjusted to 10.20 and filtered to get clear solution using potassium hydroxide solution. Clear solution was transferred to round bottom flask and pH of reaction mass adjusted pH 6.10 using 2N HCl. Solid was precipitated and ethyl acetate added and stirred for 30 minutes. Filtered solid and dried in vacuum for about 12 hours at about 55°C under vacuum to get titled compound.
Example 11: Preparation of Form 3 of bilastine
Bilastine (7.0gm) dissolved in a mixture of ethanol: water (7:3). Reaction mass was heated to about 60-70°C and stirred for one hour to get clear solution. Clear solution was cooled gradually to get precipitation. Precipitated Solid was stirred for about 24 hours. Filtered solid and dried in vacuum for about 60 hours at about 55°C under vacuum to get titled compound.
Example 12: Preparation of Form 2 of bilastine
To a stirred solution of formula 2 (50.0gm) in methanol and water at 20-30°C was added lithium hydroxide (8.78gm). Reaction mass was heated to 65-70°C and stirred for 10 to 12 hours. After completion of reaction, distilled off solvent under vacuum. Reaction mass was taken in water and aqueous layer was washed with ether. After washing, pH was adjusted from 6.5-7.0 with 2N HCl solution. Aqueous layer was stirred for 2 hour. The precipitated solid was filtered and dried in vacuum oven at 50°C to get bilastine. Yield: 44.0gm. 20.0gm of obtained bilastine dissolved in methylene dichloride and methanol. Heated reaction mixture to get clear solution and distilled off solvent under vacuum to give solid. Further, the solid was stirred in ethyl acetate for 2 hour at 45-50°C, filtered and dried in air dryer for 12 hours at 50°C to get titled compound.
Example 13: Preparation of Form 2 of bilastine
Bilastine (10.0gm) was dissolved in n-pentanol (250 ml). Reaction mass was heated to about 90°C and maintained for about 30 minutes, filtered through filter paper to get clear solution. Clear solution was transferred to round bottom flask and again heated to about 90°C and gradually cooled to about 70°C. Seeding of Form 2 of bilastine was done and reaction mass was cooled to room temperature. Precipitated solid was filtered using Buchner funnel and dried in vacuum dryer for about 12 hours at about 50°C to get titled compound.

,CLAIMS:WE CLAIM
1] A process for the preparation of amorphous bilastine, the process comprising:
a) providing bilastine in a solvent selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, esters, water or mixtures thereof to form a solution; and
b) removing the solvent from the solution of step (a) to obtain amorphous bilastine.
2] The process as claimed in claim 1, wherein the halogenated hydrocarbon solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, carbon tetrachloride.
3] The process as claimed in claim 1, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
4] A process for the preparation of Form 2 of bilastine, the process comprising slurrying bilastine in ethyl acetate.
5] The process as claimed in claim 4, wherein slurrying is done at about 40°C to about 50 °C.
6] A process for the preparation of Form 2 of bilastine, the process comprising:
a) dissolving bislatine in n-pentanol to form reaction mass;
b) adding seed of Form 2 of bilastine to the reaction mass of step (a); and
c) isolating Form 2 of bilastine.
7] A process for the preparation of Form 2 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for about 10 hours to 15 hours to obtain Form 2 of bilastine.
8] A process for the preparation of Form 3 of bilastine, the process comprising:
a) treating bislatine in water to form slurry;
b) treating the slurry with a base followed by treatment with an acid to get a precipitated solid;
c) adding ethyl acetate to the precipitated solid; and
d) filtering and drying the solid for about 50 hours to about 70 hours to obtain Form 3 of bilastine.
OR
a) dissolving bislatine in a mixture of ethanol and water to form reaction mass;
b) heating the reaction mass of step a), followed by cooling to get a precipitated solid;
c) filtering and drying the precipitated solid of step (b) to obtain Form 3 of bilastine.
OR
a) treating amorphous bilastine with ethyl acetate to form reaction mixture; and
b) isolating Form 3 of bilastine from reaction mixture of step (a).
OR
keeping amorphous bilastine in air oven at 60 °C under humid condition for 12 hours.
9] A process for the preparation of bilastine, the process comprising:
a) treating bilastine with benzyl amine to form benzyl amine salt of bilastine;
b) converting benzyl amine salt of bilastine to bilastine.
10] Benzyl amine salt of bilastine characterized by 1HNMR spectrum having peaks at d 1.02, 1.41, 1.88, 2.07-2.13, 2.49, 2.71, 3.00, 3.31, 3.63, 3.81, 4.41, 5.57, 7.12-7.19, 7.24-7.39, 7.50-7.57.