WO2007105234A2

WO2007105234A2 - A PROCESS FOR THE PREPARATION OF ISOMERS OF 11-[3-(DIMETHYLAMINO)PROPYLIDENE]-6, 11-DIHYDRODIBENZ [b, e] OXEPIN-2-ACETIC ACID HYDROCHLORIDE AND POLYMORPHS THEREOF

Info

Publication number: WO2007105234A2
Application number: PCT/IN2007/000104
Authority: WO
Inventors: Venkatasubramanian Radhakrishnan Tarur; Nandu Baban Bhise; Dhananjay Govind Sathe; Avinash Venkataraman Naidu; Umesh Parashram Aher; Sachin Shivaji Patil; Sudhir Anangpal Varma; Kamlesh Digambar Sawant; Tushar Anil Naik; Rakesh Ramchandra Amre
Original assignee: Usv Limited
Priority date: 2006-03-14
Filing date: 2007-03-05
Publication date: 2007-09-20
Also published as: WO2007105234A3

Abstract

The present invention relates to an improved process for the preparation of 1 1 -(Z)-[3- (Dimethylamino) propyl idene] -6, 1 l-dihydrodibenz[b,e]oxepin-2-acetic acid (Olopatadine hydrochloride) by reaction of l l-oxo-6, l l -dihydrodibenz[b,e] oxepin-2-acetic acid with Grignard reagent of l-halo-3-dimethylaminopropane and further dehydrated with or without isolation of the intermediate 1 l -(3-dimethylaminopropyl)-l l -hydroxy-6,l l- dihydrodibenz[b,e]oxepin-2-acetic acid. The present invention relates novel polymorphs of 1 1 -(Z)-[3-(Dimethylamino) propyl idene] -6, 1 l -dihydrodibenz[b,e]oxepin-2-acetic acid (Olopatadine hydrochloride). The present invention further relates to preparation of 1 1 - (E)-[3-(Dimethylamino) propylidene]-6, l l-dihydrodibenz[b,e]oxepin-2 -acetic acid hydrochloride.

Description

A process for the preparation of isomers of ll-[3-(DimethyIamino) propylidene]- 6,11-dihydrodibenz [b,e] oxepin-2-acetic acid hydrochloride and polymorphs thereof

Technical Field:

The present invention relates to an improved process for the preparation of cis and trans isomers of 1 l -[3-(Dimethylamino)propylidene]-6,l 1 -dihydrodibenz[b,e]oxepin-2 -acetic acid hydrochloride (Olopatadine hydrochloride). The invention further relates to novel polymorphic forms of Olopatadine hydrochloride.

Cis Isomer Formula (I) Trans isomer Formula (XX)

Background & Prior Art:

Olotapadine was first disclosed in U.S. Pat. Nos. 4,871,865 and 4,923,892, both assigned to Burroughs Wellcome Co. ("the Burroughs Wellcome Patents") as carboxylic acid derivatives of doxepin, which are incorporated by reference in their entirety. Olopatadine is a selective histamine Hi receptor antagonist in vitro and in vivo as demonstrated by its ability to inhibit binding and histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Olopatadine is devoid of effects on alpha-adrenergic, dopamine, muscarinic type 1 and 2, and serotonin receptors.

Olopatadine hydrochloride also known as (1 IZ)-1 1 -[3-(Dimethylamino)propylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride, is described in US 5,1 16,863 as being useful in treating allergic eyes diseases (conjunctivitis) in humans, which comprises of stabilizing conjuctival mast cells by topical administration to the human eye. The prior known processes for the preparation of Olopatadine hydrochloride having formula (I) involves the methods as described:

US 5,1 16,863 describe preparation of Olopatadine hydrochloride by three different processes. In two of the process the side chain is introduced by "Grignard reaction" and in another, it is introduced using "Wittig reaction".

Process A:

6,1 1-dihydro-l l -oxodibenz[b,e]oxepin-2-acetic acid (II) is converted to its corresponding

N-(l,l-dimethyl-2-hydroxyethyl)-l l -oxo-6, 1 l-dihydroxdibenz[b,e] oxepin-2-acetamide

(III) which is cyclised to obtain 2-(methyl(4,4-dimethyl-2-oxazoline-2yl))-l l-oxo-6,11- dihydrodibenz[b,e]oxepin (IV) (Scheme 1). Grignard reaction of oxazoline derivative

(IV) gave 1 l-(3-dimethylaminopropyl)-l l-hydroxy-2-(methyl(4,4-dimethyl-2-oxazoline- 2yl))-6,l l-dihydrodibenz[b,e]oxepin (V), which is simultaneously dehydrated and deprotected and then esterified to get ethyl l l-(3-dimethylaminopropylidine)-6,l l- dihydrodibenz[b,e]oxepin-2-acetate (VI). Hydrolysis of the compound (VI) gave the corresponding Olopatadine hydrochloride (I).

Scheme

The above process is a lengthy route involving protection and deprotection reactions. The steps leading to formation of amide (III) as well as oxazoline (IV) provides undesirable side products. Hence these steps require purification and thus result in reduced yields. Cis trans ratio of the dehydrated product (VI) is also not reported. Purity and overall yield of product (I) is not mentioned. On following the above process the obtained cis:trans ratio was 10-15:90-85.

Process B:

Methyl l l-oxo-6,l l-dihydrodibenz[b,e] oxepin-2-acetate (VII) is reduced by lithium aluminum hydride to get 1 l-hydroxy-2(2-hydroxyethyl)-6,l l -dihydrodibenz[b,e] oxepin (VIII) (Scheme 2) which is then protected with trityl group to obtain 1 1 -hydroxy-2-(2- triphenylmethyloxy ethyl)-6, l l-dihydrodibenz[b,e] oxepin (IX) which is oxidized to obtain 1 1 -oxo-2-(2-triphenylmethyloxyethyl)-6, 1 1 -dihydrodibenz[b,e]oxepin (X). Grignard reaction on (X) gave l l-(3-dimethylaminopropyl)-l 1 -hydroxy-2-(2- triphenylmethyloxy ethyl)-6, l l -dihydrodibenz[b,e]oxepin (XI), which is dehydrated to get 11 -(3-dimethylaminopropylidene)-2-(2-tripheny Imethy loxyethyI)-6, 1 1 - dihydrodibenz[b,e] oxepin (XII). The compound (XII) is deprotected to obtain 1 1 -(3- dimethylamino propylidene)-2-(2-hydroxyethyl)-6,l l-dihydrodibenz[b,e]oxepin (XIII). Oxidation of (XIII) gave the corresponding Olopatadine hydrochloride (I).

Scheme 2

The process as disclosed above involves a lengthy synthesis requiring protection and deprotection reactions. It employs hazardous reagents like lithium aluminum hydride and Jones reagent, which pose safety and disposal problems. Purification of the final product and intermediates require column chromatography, which makes the process tedious and time consuming and also increase the solvent requirement of the process. The purity and yield of the product is not mentioned. The cis-trans ratio of the product is also not reported.

Process C:

The Wittig reaction of 1 l-oxo-6,l l-dihydrodibenz[b,e]oxepin-2-acetic acid (II) with (3- dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide provided methyl 1 1 -(3-dimethylaminopropylidine)-6, 1 1 -dihydrodibenz[b,e]oxepin-2-acetate (XIV).

Hydrolysis of (XIV) provided Olopatadine hydrochloride (I).

Scheme 3

(II) n-butyl lithium

The above process involves use of excess Wittig reagent (5 mole eq) and the n-butyl lithium employed is hazardous and causes safety problems. The process is very tedious and uneconomical. The cis trans ratio of the product is not reported. However, on following the above process, the product results in very poor yield.

The l l-(Z)-[3-(Dimethylamino) propylidene] 6,1 1 -dihydrodibenz [b,e] oxepin-2- acetic acid (Olopatadine hydrochloride) obtained by the process disclosed in prior art is hereinafter referred as polymorphic Form I.

VVO 2006/010459 discloses the Wittig reaction of a compound of formula (XXI) to obtain a compound of formula (XXII). Further, reacting the compound of formula (XXII) in the presence of a palladium catalyst to provide a compound of formula (XXIII). Hydrolysis of compound (XXIII) obtains the corresponding Olopatadine hydrochloride (I).

(XXI)

The processes disclosed in prior art suffers from a lot of disadvantages like use of multistep synthetic routes; protection and deprotection protocols, which is tedious; use of palladium catalyst, increases the process cost; use of ionic exchange resin, employs an industrially unviable operation; purification of the products is achieved using column chromatography, which is very lengthy and thus employs an industrially unviable operation; and the use of hazardous reagents like lithium aluminum hydride, n-butyl lithium and Jones reagent.

Therefore it is necessary to develop an alternative process which is viable for the preparation of olopatadine or its pharmaceutically acceptable salts on industrial scale.

WO 96/39147 describes a method for treating an allergic eye disease characterized by administering to the eye a topical ophthalmic formulation which contains either a therapeutically effective amount of Cis isomer of Olopatadine hydrochloride, trans isomer Olopatadine hydrochloride or a combination of both Cis and Trans isomers. No polymorphism has been reported yet for Olopatadine HCl.

Trans isomer Formula (XX)

Polymorphic study is of great importance, as many Active Pharmaceutical Ingredients exhibit polymorphism and some/one of the polymorphic form may exhibit high bioavailability, higher activity or better physical characteristics as compared to other polymorph. A different physical properties exhibited by different polymorphic forms are mainly due to different orientation and intermolecular interaction of adjacent molecules.

One of the most important physical properties of pharmaceutical compound that is affected due to existence of polymorphic form is the solubility. Different crystalline forms of pharmaceutical substances are reported to have different aqueous solubility. The discovery of new polymorphic forms provides an opportunity to improve the performance of the pharmaceutical product.

There is still a need to develop improved polymorphic forms of Olopatadine HCl. Surprisingly in our polymorphic study we have discovered a novel crystalline polymorphic form, Form II of Olopatadine HCl and amorphous form of Olopatadine HCl.

Summary of the Invention:

The present invention comprises a process for the preparation of Olopatadine hydrochloride by reacting of 1 l -oxo-6,1 1-dihydrodibenz [b,e]oxepin-2-acetic acid (II) with Grignard reagent of l-halo-3-dimethylamino propane (XV) to obtain the corresponding Olopatadine hydrochloride (I) with or without isolating the intermediate l l-(3-dimethylaminopropyl)- 11 -hydroxy 6, 11 -dihydrodibenz [b,e ]oxepin-2-acetic acid (XVI).

According to the present invention 1 l-oxo-6,1 1-dihydrodibenz [b,e]oxepin-2-acetic acid (II) is reacted with Grignard reagent of l-halo-3-dimethylamino propane (XV) in an ethereal solvent. The reaction mixture is treated with dilute organic acid followed by treatment with an organic solvent. The aqueous layer may be neutralized with a base and the resultant intermediate (XVI) may be extracted in a chlorinated solvent and further distilled the solvent. The residue is then charged with dilute mineral acid and heated and further cooled. Alternatively the aqueous layer may be heated and further cooled. The desired geometrical cis-isomer is then obtained by a simple extraction process using a chlorinated solvent, which yields crude Olopatadine hydrochloride containing the desired cis isomer in more than 98% purity. The crude Olopatadine hydrochloride is purified by solvent crystallization to yield cis (Z) Olopatadine hydrochloride of more than 99% purity in varying polymorphic forms.

The reaction mixture (aqueous layer) after the extraction of the cis isomer is further concentrated and the residue eluted on a silica gel column to obtain crystalline Olopatadine HCl (trans isomer)(XX).

Objectives of the Invention:

An object is to provide an economical, commercially viable industrial process to make Olopatadine hydrochloride.

Another object is to provide a process using an economical Grignard reagent without having to protect or deprotect any of the intermediates.

A further object of present invention is to provide highly pure Olopatadine hydrochloride in a single purification step.

Another object of the present invention is to provide novel polymorphic forms of Olopatadine hydrochloride.

Brief Description of the Figures:

Fig. 1 Shows the X-ray Diffraction Diagram of Olopatadine HCl pure Form I Fig. 2 Shows the X-ray Diffraction Diagram of Olopatadine HCl pure Form II Fig. 3 Shows the X-ray Diffraction Diagram of amorphous cis Olopatadine HCl Fig. 4 Shows the X-ray Diffraction Diagram of Trans Olopatadine HCl

Detailed Description:

While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

As used herein the term 'solution' means to cover clear solution or partial solution or slurry or suspensions or emulsions etc.

According to one embodiment, there is provided a process for preparation of Olopatadine hydrochloride (Scheme 4) comprising the steps of:

a. reacting 1 l-oxo-6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid (II)

(H)

with Grignard reagent of l-halo-3 -dimethyl amino propane of the formula(XV) in an ethereal solvent at a temperature between -5° C to 35° C;

XMg(CH₂)3N(CH₃)2 (XV)

(X=Cl, Br or I).

b. charging dilute organic acid and followed by washing with an organic solvent; c. neutralizing the aqueous layer with a base to obtain 1 l -(3-dimethylaminopropyl)- 1 1 -hydroxy-6, 1 1- dihydrodibenz [b,e]-2- oxepin acetic acid of the formula (XVl)

(XIV) d. extracting compound (XVI) in a chlorinated solvent and further distilling the solvent to obtain residue; e. charging the residue with dilute mineral acid and heating compound (XIV) at a temperature between 50° C to 1 10° C followed by cooling the reaction mass; f. isolating the cis olopatadine hydrochloride by extracting into chlorinated solvent; followed by precipitating the cis-Olopatadine using anti solvent; g. purifying cis Olopatadine hydrochloride (I) from a single or mixture of organic solvents; and

Cis Isomer Formula (I)

h. recovering the trans-isomer (XX) from the aqueous residue by eluting through a silica gel column using mixture of chlorinated solvent and alcoholic solvents.

Trans isomer Formula (XX)

ccordance with the above embodiment, the reaction of (II) with Grignard reagent of l-halo-3-dimethylaminopropane (XV) is carried out in an ethereal solvent, selected from tetrahydrofuran or diethyl ether, wherein the weight ratio of Grignard reagent to compound (II) is 1 : 1 to 4 (mole equivalent). The temperature is maintained between -5° C to 35° C. The reaction mixture is stirred at a temperature between 25° C to 35° C for about 5 to 15 hrs. The reaction mixture is further charged with a dilute organic acid selected from acetic acid or formic acid and further washed the reaction mixture with an organic solvent selected from ethyl acetate, toluene or diethyl ether. The aqueous layer is neutralized with a base selected from liquor ammonia, sodium hydroxide solution sodium bicarbonate solution or sodium carbonate solution.

The resultant intermediate l-(3-dimethylaminopropyl)-l l-hydroxy-6,l 1-dihydro dibenz[b,e] oxepin-2 -acetic acid (XVI) is then isolated using a chlorinated solvent such as methylene chloride or chloroform and further dissolved in mineral acid and then heated at temperature ranging from 30° C to 1 10° C and further cooled the reaction mass. The desired geometrical cis-isomer is selectively isolated by a simple extraction process using a chlorinated solvent, which yields Olopatadine hydrochloride containing the desired cis isomer in more than 98% purity. The cis:trans ratio of Olopatadine hydrochloride as obtained from the present process is 30:70.

The cis-Olopatadine hydrochloride is purified by solvent crystallization to yield cis (Z) Olopatadine hydrochloride of more than 99% purity in varying polymorphic forms.

The cis -Olopatadine hydrochloride is extracted with a chlorinated solvent selected from methylene chloride or chloroform and further distilled to obtain a residue. The residue is then treated with an organic solvent (anti-solvent) selected from aliphatic nitrile preferably acetonitrile or aliphatic ketone preferably acetone, ethyl methyl ketone or methyl isobutyl ketone to precipitate the desired cis-isomer in more pure form.

In another embodiment of the invention, the aqueous layer remained after the solvent extraction of cis-isomer is further concentrated and the residue thus obtained is eluted on a silica gel column to obtain crystalline Olopatadine HCl (trans isomer)(XX). In another embodiment of the present invention, cis-Olopatadine Hydrochloride thus obtained is purified by a mixture of solvents. The solvents may be selected from polar protic solvents, alcohols, cyclic ethers, aromatic hydrocarbon, chlorinated hydrocarbons, aliphatic hydrocarbons, aliphatic ketones, esters and nitriles. The alcohol may be methanol, ethanol or isopropanol. The polar aprotic solvent may be Dimethyl formamide (DMF), Dimethyl sulfoxide (DMSO) or N, N-Dimethyl acetamide (DMA). The ethers may be selected from tetrahydrofuran, and 1 , 4-dioxane, diethyl ether, diisopropyl ether and methyl tertiarybutyl ether; the aromatic hydrocarbon used is toluene, chlorinated hydrocarbons used are chloroform, methylene dichloride (MDC), aliphatic hydrocarbons may be n-hexane, heptane, esters used are ethyl acetate, butyl acetate, ketones may be acetone, 2-butanone and aliphatic nitrile may be acetonitrile.

The product thus obtained has a purity of greater than 99% and is polymorphic form I. The particles size of Olopatadine HCl Form I is in the range of 10-100 μ, preferably in the range of 10-30 μ.

In another embodiment of the present invention, Olopatadine hydrochloride is purified by solvent crystallization using methanol and the product obtained has purity greater than 99%, and is designated herein as novel polymorphic form II. The particles size (d^) of Olopatadine HCl Form II is in the range of 20-100 μ, preferably 30-50 μ.

In a further embodiment of the present invention, Olopatadine hydrochloride purified by lyophilisation or spray drying provides a novel amorphous form which gives essentially of a very broad, diffused X-ray reflection; and therefore designated herein as amorphous under X-Ray powder diffraction.

According to another embodiment of the present invention there is provided one pot process for preparation of Olopatadine hydrochloride with out isolating the intermediate (XVI) (Scheme 4) comprising the steps of; a. reacting 1 l-oxo-6, 1 l-dihydrodibenz[b,e]oxepiπ-2-acetic acid (II)

with Grigπard reagent of l-halo-3 -dimethyl amino propane of the formula (XV) in an ethereal solvent at temperature -5° C to 35° C;

XMg(CH₂)3N(CH₃)2 (XV)

(X=Cl, Br or I).

b. charging the reaction mass with dilute mineral acid at temperature -5° C to 20° C followed by washing with an organic solvent to isolate the aqueous layer; c. heating the aqueous layer to a temperature between 50° C to 1 10° C followed by cooling the reaction mass; d. isolating cis-olopatadine hydrochloride by extracting into a chlorinated solvent followed by precipitating the cis Olopatadine hydrochloride(I) by treating with anti solvent;

Cis-isomer Formula (I)

e. purifying the cis- Olopatadine hydrochloride from a single or mixture of organic solvents and f. recovering the trans-isomer (XX) from the aqueous residue by eluting through a silica gel column using mixture of chlorinated solvent and alcoholic solvents.

Trans isomer Formula (XX)

In accordance with the above embodiment of the present invention, reaction of (II) with Grignard reagent of 1 -halo-3-dimethylaminopropane (XV) is carried out in an ethereal solvent, selected from tetrahydrofuran or diethyl ether, wherein the weight ratio of Grignard reagent to compound (II) is 1 :1 to 4 (mole equivalent). The reaction temperature is maintained between -5° C to 35°. The reaction mixture is stirred at a temperature between 25° C to 35° C for about 5 to 15 hrs and further charged with mineral acid. The reaction mixture is then washed with an organic solvent selected from ethyl acetate, toluene or diethyl ether. The aqueous layer of the reaction mixture is further heated to a temperature between 40° C to 110° C and further cooled the reaction mixture. The desired geometrical cis-isomer is selectively isolated by a simple extraction process using a chlorinated solvent, which yields crude Olopatadine hydrochloride containing the desired cis isomer in more than 98% purity. The cis:trans ratio of Olopatadine hydrochloride (I) as obtained from the present process is 30:70.

The crude Olopatadine hydrochloride is isolated by extracting with a chlorinated solvent selected from methylene chloride or chloroform and further distilled to obtain a residue. The residue is then treated with an organic solvent (anti-solvent) selected from aliphatic nitrile preferably acetonitrile or aliphatic ketone preferably acetone, ethyl methyl ketone or methyl isobutyl ketone to precipitate the desired product in more pure form.

The reaction mixture (aqueous layer) after extraction of the cis isomer is further concentrated and the residue eluted on a silica gel column to obtain crystalline Olopatadine HCI (trans isomer)(XX).

In another embodiment of the present invention, the purification of Cis Olopatadine Hydrochloride is carried out using mixture of organic solvents to obtain the product in purity greater than 99%. The solvents may be selected from a group consisting of polar aprotic solvents, alcohols, ethers, aromatic hydrocarbon, chlorinated hydrocarbons, aliphatic hydrocarbons, aliphatic ketones, esters and nitriles. The alcohol may be methanol, ethanol or isopropanol. The polar aprotic solvent may be Dimethyl formamide (DMF), Dimethyl sulfoxide (DMSO) or N, N-Dimethyl acetamide (DMA). The ethers may be selected from tetrahydrofuran and 1, 4 dioxane, diethyl ether, diisopropyl ether and methyl tertiarybutyl ether; the aromatic hydrocarbon used is toluene; chlorinated hydrocarbons used are chloroform or methylene dichloride (MDC); aliphatic hydrocarbons may be selected from n-hexane and heptane; esters used are ethyl acetate or butyl acetate, ketones may be selected from acetone or 2-butanone and aliphatic nitrile may be acetonitrile.

The product thus obtained is polymorphic form I has a purity of greater than 99%.

In another embodiment of the present invention, Olopatadine hydrochloride is purified by solvent crystallization using methanol and the product obtained has purity greater than 99%, and is novel polymorphic form II.

In a further embodiment of the present invention, Olopatadine hydrochloride purified by lyophilisation or spray drying yields a novel amorphous form which gives essentially of a very broad, diffused X-ray reflection; and therefore designated as amorphous under X- Ray powder diffraction.

Yet, in another embodiment, the present invention discloses pharmaceutical dosage forms comprising olopatadine hydrochloride manufactured according to the processes disclosed.

Scheme 4

1

Olopatadine hydrochloride Olopatadine hydrochloride Cis isomer Trans isomer

The crystalline 'Form I' of Olapatadine hydrochloride has X-ray powder diffraction pattern as substantially as shown in the Figure 1 and the characteristic peaks with their 2 theta value and corresponding d spacing are listed in the table 1 as given below. Table 1

The polymorphic Form II of Cis Olopatadine hydrochloride is obtained when Olopatadine HCl is crystallized from methanol. The XRPD of Form II is given in Fig. 2

Form II of Cis Olopatadine hydrochloride is obtained by vacuum evaporation of a solution of Olopatadine HCl in methanol. Form II is also obtained by suspending amorphous form of Cis Olopatadine in methanol.

The crystalline 'Form II' of Olopatadine hydrochloride has X-ray powder diffraction pattern as substantially as shown in the Figure 2 and the characteristic peaks with their 2 theta value and corresponding d spacing are listed in the table 2 as given below. Table 2

Amorphous form of Cis Olopatadine HCl is obtained by lyophilization or by spray drying. The solution of of Cis Olopatadine Olopatadine HCl in polar protic solvents is subjected lyophilization or vacuum evaporation or spray drying to get the amorphous form. The polar protic solvents used for dissolution are lower alcohols or water. The lower alcohols are selected from methanol, ethanol, n-propanol preferably methanol. The solution of Cis Olopatadine.HCl is spray dried at an inlet temperature range of 60⁰C to 140⁰C and at an outlet temperature range of 40 to 9O⁰C.

The XRPD of Amorphous Form which gives essentially of a very broad, diffused X-ray reflection as shown in Fig. 3. The crystalline Trans Olopatadine hydrochloride has X-ray powder diffraction pattern as substantially as shown in the Figure 4 and the characteristic peaks with their 2 theta value and corresponding d spacing are listed in the table 3 as given below.

Table 3

The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner. Examples:

Example 1

1 1 -(3-dimethylaminopropyl)- 1 1 -hydroxy-6, 1 1 -dihydrodibenz[b,e]oxepin-2 -acetic acid

(XVl)

3-dimethylaminopropyl magnesium chloride is obtained by reacting 28.5 g of magnesium with 300 g 3-dimethylaminopropylchloride in 470 ml of tetrahydrofuran under a nitrogen atmosphere using 4 g of dibromoethane and 1.24 g iodine as catalyst.

To the above solution was added a solution of 100 g l l -oxo-6,1 1- dihydrodibenz[b,e]oxepin-2 -acetic acid (II) in 470 ml of tetrahydrofuran at a temperature of 5-10° C. After the addition the reaction mixture was gradually brought to RT and stirred for 13 hrs.

Acetic acid (150 ml) was added at 25-35° C to the reaction mixture followed by 375 ml water and washed the reaction mixture with 600 ml ethyl acetate. The aqueous layer was neutralized to pH 7 using liq. ammonia and 275 ml of water was distilled out under vacuum. The resultant residue was extracted with 600 ml methylene chloride and distilled the solvent under reduced pressure to obtain 1 1 -(3-dimethylaminopropyl)- 1 1-hydroxy-

6,1 l-dihydrodibenz[b,e] oxepin-2-acetic acid (XVI).

Yield: 105.9 g (80%)

NMR (CDCl₃ δ, ppm) : 2.20-2.33 (m, 2H), 2.56 (s, 6H), 2.6-2.8 (m, 4H), 3.62 (s,2H),

4.9-5.3 (m 2H.), 6.8-7.9 (m, 7H).

Mass spectrum(e/s M+l) : 356 M⁺

Example 2

Olopatadine hydrochloride crude

(105g) 1 l-(3-dimethylaminopropyl)-l 1 -hydroxy-6, 1 l-dihydrodibenz[b,e] oxepin-2-acetic acid (XVI) was dissolved in 750 ml of dilute HCl (1 : 1). The reaction mixture was heated for 30 mins at 90° C, cooled the reaction mixture to room temperature and extracted with

600 ml methylene chloride and distilled the solvent under reduced pressure to obtain a residue. (200 ml) Acetone was added to the resultant residue to precipitate the product as a white solid. The white solid was filtered and dried to obtain crude Olopatadine hydrochloride.

Yield: 23 g (25.43%)

Purity: cis isomer - 98 %; trans isomer - less thanl%. Example 3

Olopatadine hydrochloride crude (one pot reaction)

3-dimethylaminopropyl magnesium chloride obtained by reacting 28.5 g of magnesium with 300 g 3-dimethylaminopropylchloride in 470 ml of tetrahydrofuran under a nitrogen atmosphere using 4 g of dibromoethane and 1.24 g iodine as catalyst. To the above solution was added a solution of 1 l-oxo-6,1 l -dihydrodibenz[b,e]oxepin-2-acetic acid (II)

(100 g) in (470 ml) tetrahydrofuran at temperature of 5-10° C. After the addition, the reaction mixture was gradually brought to RT and stirred for 13 hrs.

750 ml of dilute HCl (1 :1) was added to the above reaction mixture at 5-10° C and washed the reaction mass with 600 ml ethyl acetate. The aqueous layer was heated for 30 mins at 90° C, cooled the reaction mixture to room temperature and extracted with 600 ml methylene chloride and distilled the solvent under reduced pressure to obtain a residue.

200 ml acetone was added to the resultant residue to precipitate the product as white solid. The white solid was filtered and dried to obtain crude Olopatadine hydrochloride.

Yield: 27.9 g (20%)

Purity: cis isomer - 98 %; trans isomer - less than l%

Example 4

Recovery of Trans Olopatadine Hydrochloride

The aqueous layer remained after the methylene dichloride extraction, from examples 2 and 3, was concentrated under reduced pressure. The residue was eluted through a silica gel column using dichloromethane /Methanol (80:20) to obtain 93.4 g of Olopatadine hydrochloride Trans isomer.

Yield 67%

Purity : Trans isomer 99.35% cis-isomer-less than 0.5%

Preparation of Polymorphic Form I

Example 5

2Og of Olopatadine HCl was dissolved in a mixture of 220 ml Ethanol and 420 ml of acetonitrile. The solution was refluxed for 1 hr, filtered hot, and the solvent was distilled off from the filtrate. The mixture was gradually cooled to 10- 150C. The solid obtained was filtered, washed with acetone and dried at 60-70⁰C to obtain Olopatadine HCl polymorphic Form I (17g). (Yield = 85%)

Example 6

0.5g of Olopatadine HCl was dissolved in 5ml DMF at 65°C. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to yield polymorphic Form I. (Yield = 65 %)

Example 7

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. The hot solution was allowed to cool to room temperature. To this 20 ml of Di isopropyl ether was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 98%)

Example 8

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. The hot solution was allowed to cool to room temperature. To this 40 ml of Dioxane was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 84%)

Example 9

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. The hot solution was allowed to cool to room temperature. To this 25 ml of THF was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 82%)

Example 10

0.5g of Olopatadine HCI was dissolved in 10 ml DMF at 65°C. The hot solution was allowed to cool to room temperature. To this 20 ml of Acetone was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 64%) Example 1 1

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. To this clear solution 30 ml of Iso propyl alcohol was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 68%)

Example 12

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. To this clear solution 25 ml of Ethyl acetate was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 88 %)

Example 13

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. To this clear solution 40 ml of methylene dichloride was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 66 %)

Example 14

0.5g of Olopatadine HCl was dissolved in 10 ml DMF at 65°C. To this clear solution 20 ml of Toluene was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form 1. (Yield = 68 %)

Example 15

Olopatadine HCl (0.5 g) was dissolved in DMF (10 ml) at 65°C. To this clear solution 50 ml of Acetonitrile was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 74%)

Example 16

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C .The hot solution was allowed to cool to room temperature. To this 10 ml of Dioxane was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 73 %)

Example 17

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65⁰C .The hot solution was allowed to cool to room temperature. To this 20 ml of THF was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 76%)

Example 18

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C .The hot solution was allowed to cool to room temperature. To this 15 ml of Acetone was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 82 %)

Example 19

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65⁰C .To this clear solution 10 ml of Iso propyl alcohol was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 68%)

Example 20

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C .To this clear solution 10 ml of n- propanol was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 66%)

Example 21

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C .To this clear solution 10 ml of Ethyl acetate was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 64 %)

Example 22

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C. To this clear solution 10 ml of methylene dichloride was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 72 %)

Example 23

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C .To this clear solution 30 ml of Chloroform was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 66 %)

Example 24

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C. To this clear solution 10 ml of Toluene was added. The solution was stirred at 10-15°C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 88 %)

Example 25

0.5g of Olopatadine HCl was dissolved in 3 ml DMSO at 65°C. To this clear solution 10 ml of Acetonitrile was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 54%)

Example 26

0.5g of Olopatadine HCl was dissolved in 5ml DMA at 65°C. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 86 %)

Example 27

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65⁰C. The hot solution was allowed to cool to room temperature. To this 20 ml of Di isopropyl ether was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 45%)

Example 28

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. The hot solution was allowed to cool to room temperature. To this 30 ml of Dioxane was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 61%)

Example 29

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. The hot solution was allowed to cool to room temperature. To this 30 ml of THF was added. The solution was stirred at at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 63%)

Example 30

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65⁰C. The hot solution was allowed to cool to room temperature. To this 20 ml of Acetone was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 64%)

Example 31

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. To this clear solution 25 ml of Iso propyl alcohol was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 74%)

Example 32

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. To this clear solution 20 ml of Ethyl acetate was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 48 %)

Example 33

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. To this clear solution 40 ml of Acetonitrile was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 66 %)

Example 34

0.5g of Olopatadine HCl was dissolved in 15 ml DMA at 65°C. To this clear solution 20 ml of Toluene was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 94 %)

Example 35

0.5g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. The hot solution was allowed to cool to room temperature. To this 30 ml of Di isopropyl ether was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65⁰C to get Form I. (Yield = 76 %) Example 36

0.5g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. The hot solution was allowed to cool to room temperature. To this 50 ml of THF was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 45%)

Example 37

0.5g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. The hot solution was allowed to cool to room temperature. To this 70 ml of Acetone was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 48 %)

Example 38

0.5g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. To this clear solution 30 ml of Iso propyl alcohol was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 68%)

Example 39

0.5g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. To this clear solution 30 ml of Ethyl acetate was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 72 %)

Example 40

0.5g of Olopatadine HCl was dissolved in 50 ml Ethanol at reflux temperature. The hot solution was allowed to cool to room temperature. To this 50 ml of Di iso propyl ether was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 68 %)

Example 41

0.5g of Olopatadine HCl was dissolved in 50 ml Ethanol at reflux temperature. To this clear solution 50 ml of hexane was added. The solution was stirred at 10-15⁰C for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 74%)

Example 42

0.5g of Olopatadine HCl was dissolved in 50 ml Ethanol at reflux temperature. To this clear solution 60 ml of Ethyl acetate was added. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form I. (Yield = 66 %)

Preparation of Polymorphic Form II

Example 43

1 g of Olopatadine HCl was dissolved in 10 ml Methanol at reflux temperature. The solution was cooled to room temperature. The solution was stirred at the same temperature for 3 Hrs. The solid obtained was filtered and dried at 65°C to get Form II. (Yield = 80 %)

Example 44

1 g of Olopatadine HCl was dissolved in 20 ml Methanol at reflux temperature. The solution was evaporated under vacuum at 55°C temperature to get the solid. The solid obtained by this method was maintained at same temperature and pressure to remove any traces of solvent. The solid obtained was isolated as Form II. (Yield = 86%)

Example 45

1 g of Amorphous Olopatadine HCl was suspended in 10 ml Methanol at room temperature. The solution was stirred at same temperature for 2 hrs. The solid obtained was isolated as Form II. (Yield = 86%)

Preparation of Amorphous Form

Example 46

Aqueous solution of 8-10% Olopatadine HCl in water was frozen using dry ice and dried by lyophilization for 24 hours to isolate amorphous form.

Example 47

A solution of 8-10 % Olopatadine HCl in water is spray dried at inlet temperature of 100- 120⁰C and outlet temperature of 70-80⁰C under nitrogen flow to obtain amorphous form.

Example 48

A solution of 5-7 % Olopatadine HCl in methanol is spray dried at inlet temperature of

65-75⁰C and outlet temperature of 45-55⁰C under nitrogen flow to obtain amorphous form.

Claims

We Claim,

1. A process for the preparation of Olopatadine hydrochloride comprising the steps of;

a. reacting 1 l-oxo-6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid (II)

(ID with Grignard reagent of l-halo-3-dimethyl amino propane of the formula(XV) in an ethereal solvent at a temperature between -5° C to 35° C;

XMg(CH₂)3N(CH₃)₂ (XV)

(X=Cl, Br or I).

b. charging dilute organic acid and followed by washing with an organic solvent to isolate the aqueous layer; c. neutralizing the aqueous layer with a base to obtain 1 1 -(3- dimethylaminopropyl)-l l-hydroxy-6,l l- dihydrodibenz [b,e]-2- oxepin acetic acid of the formula (XVI)

(XlV) d. extracting compound (XVI) in a chlorinated solvent and further distilling the solvent to obtain residue; e. charging the residue with dilute mineral acid and heating compound (XIV) at a temperature between 50° C to 1 10° C followed by cooling the reaction mass; f. isolating the cis olopatadine hydrochloride by extracting into chlorinated solvent; followed by precipitating the cis-Olopatadine (I) using anti solvent; g. purifying cis Olopatadine hydrochloride (I) from mixture of organic solvents; and

Cis-iosmer Formula (I) h. recovering the trans-isomer (XX) from the aqueous residue by eluting through a silica gel column using mixture of chlorinated solvent and alcoholic solvents.

Trans isomer Formula(XX)

2. The process as claimed in claim 1, wherein the ethereal solvent used in step (a) is tetrahydrofuran or diethylether.

3. The process as claimed in claim 1 , wherein the addition of compound (II) to the reagent (XV) is step (a) is carried out at temperature -5° C to 35° C.

4. The process as claimed in claim 1, wherein the reaction mixture in step (a) is stirred at temperature 25° C to 35° C for 5 to 15 hrs.

5. The process as claimed in claim 1, wherein the organic acid in step (b) is acetic acid or formic acid.

6. The process as claimed in claim 1 , wherein base used in step (c) for neutralization is selected from liquor ammonia, sodium hydroxide solution, sodium bicarbonate solution and sodium carbonate solution.

7. The process as claimed in claim 1, wherein the organic solvent used in step (b) is selected from ethyl acetate, toluene and diethyl ether.

8. The process as claimed in claim 1, wherein the chlorinated solvent used in step (d) is methylene chloride or chloroform.

9. The process as claimed in claim 1, wherein the mineral acid used in step (e) is hydrochloric acid.

10. The process as claimed in claim 1, wherein the chlorinated solvent used in step (f) is methylene chloride or chloroform.

11. The process as claimed in claim 1, wherein the anti solvent used in step (f), is aliphatic nitrile or aliphatic ketone.

12. The process as claimed in claim 1 1, wherein the aliphatic nitrile is acetonitrile.

13. The process as claimed in claim 11, wherein the aliphatic ketone is selected from acetone, ethyl methyl ketone and methyl isobutyl ketone.

14. The process as claimed in claim 1, wherein the solvents used for purification in step (g) is selected from the group consisting of polar aprotic solvents, alcohols, ethers, aromatic hydrocarbon, chlorinated hydrocarbons, aliphatic hydrocarbons, aliphatic ketones, esters and nitriles

15. The process as claimed in claim 14, wherein the alcohol is selected from methanol, ethanol and isopropanol.

16. The process as claimed in claim 14, wherein the polar aprotic solvent is selected from N,N-dimethyl formamide, Dimethyl sulfoxide and Dimethyl acetamide

17. The process as claimed in claim 14, wherein the aliphatic nitrile is acetonitrile.

18. The process as claimed in claim 14, wherein the ethers are selected from tetrahydrofiiran, 1,4-Dioxane, diethyl ether, di iso propyl ether and methyl tert- butyl ether.

19. The process as claimed in claim 14, wherein the aliphatic ketones is acetone or butanone.

20. The process as claimed in claim 14, wherein the ester is ethyl acetate or butyl acetate.

21. The process as claimed in claim 14, wherein the aromatic hydrocarbon is toluene.

22. The process as claimed in claim 14, wherein the aliphatic hydrocarbon is hexane or heptane.

23. The process as claimed in claim 14, wherein the chlorinated hydrocarbon is selected methylene dichloride, chloroform and ethylene dichloride.

24. The process as claimed in claim 1, wherein step (h) the chlorinated solvent is methylene chloride and chloroform.

25. The process as claimed in claim 1, wherein step (h), the alcoholic solvent used is selected from methanol, ethanol and isopropanol.

26. A one-pot process for the preparation of Olopatadine hydrochloride comprising the steps of; a. reacting 1 1 -oxo-6, 1 1 -dihydrodibenz[b,e]oxepin-2 -acetic acid (II)

Il with Grignard reagent of l-halo-3 -dimethyl amino propane of the formula (XV) in an ethereal solvent at temperature -5° C to 35° C;

XMg(CH₂)3N(CH₃)2 (XV)

(X=Cl, Br or I).

b. charging the reaction mass with dilute mineral acid at temperature -5° C to 20° C followed by washing with an organic solvent to isolate the aqueous layer; c. heating the aqueous layer to a temperature between 50° C to 110° C followed by cooling the reaction mass; d. isolating cis-olopatadine hydrochloride by extracting into a chlorinated solvent followed by precipitating the cis Olopatadine hydrochloride by treating with anti solvent; e. purifying the cis- Olopatadine hydrochloride(I) from mixture of organic solvents and

Cis isomer (I) f. recovering the trans-isomer (XX) from the aqueous residue by eluting through a silica gel column using mixture of chlorinated solvent and alcoholic solvents.

Trans isomer (XX)

27. The process as claimed in claim 26, wherein the ethereal solvent used in step (a) is tetrahydrofuran or diethylether.

28. The process as claimed in claim 26, wherein the reaction mixture in step (a), is stirred at temperature 25° C to 35° C for 5 to 15 hrs.

29. The process as claimed in claim 26, wherein the mineral acid used in step (b) is hydrochloric acid.

30. The process as claimed in claim 26, wherein the organic solvent used in step (b) is selected from ethyl acetate, toluene or diethyl ether.

31. The process as claimed in claim 26, wherein the chlorinated solvent in step (d) is methylene chloride or chloroform.

32. The process as claimed in claim 26, wherein the anti solvent in step (d) is selected from aliphatic nitrile or aliphatic ketone.

33. The process as claimed in claim 26, wherein the aliphatic nitrile is acetonitrile.

34. The process as claimed in claim 26, wherein the aliphatic ketone is selected from acetone, ethyl methyl ketone or methylisobutyl ketone.

35. The process as claimed in claim 26, wherein the purification in step (e) is achieved using a mixture of solvents selected from polar aprotic solvents, alcohols, ethers, aromatic hydrocarbon, chlorinated hydrocarbons, aliphatic hydrocarbons, aliphatic ketones, esters and nitriles

36. The process as claimed in claim 35, wherein the alcohol is selected from methanol, ethanol and isopropanol.

37. The process as claimed in claim 35, wherein the polar aprotic solvent is selected from N,N- dimethyl formamide, Dimethyl sulfoxide, Dimethyl acetamide.

38. The process as claimed in claim 35, wherein the aliphatic nitrile is acetonitrile.

39. The process as claimed in claim 35 wherein the ether is selected from tetrahydrofuran, 1,4-Dioxane, diethyl ether, di iso propyl ether or methyl tert- butyl ether.

40. The process as claimed in claim 35, wherein the aliphatic ketone is acetone or butanone.

41. The process as claimed in claim35 , wherein the ester is ethyl acetate or butyl acetate.

42. The process as claimed in claim 35, wherein the aromatic hydrocarbon is toluene.

43. The process as claimed in claim 35, wherein the aliphatic hydrocarbon is hexane or heptane.

44. The process as claimed in claim 35, wherein the chlorinated hydrocarbon is selected from methylene dichloride, chloroform and ethylene dichloride.

45. The process as claimed in claim 26, wherein the chlorinated solvent used in step(f) is methylene chloride or chloroform.

46. The process as claimed in claim 26, wherein the alcoholic solvent used in step(f) is selected from methanol, ethanol and isopropanol.

47. A novel crystalline polymorphic form of Cis 1 l -(Z)-[3-(Dimethylamino) propylidene]-6, l 1-dihydrodibenz [b,e] oxepin-2 -acetic acid HCl (olopatadine.HCl) designated as Form II, which is characterized by the X-ray powder diffraction pattern having peaks at about 2Θ: 9.25, 10.60, 13.09, 13.38, 14.97, 16.73, 17.14, 17.93, 18.39, 18.69, 19.35, 19.60, 20.30, 21.12, 22.1 1, 22.72, 23.14, 23.44, 23.93, 25.09, 25.85, 26.59, 28.91, 30.02, 31.81 ± Θ2 degrees.

48. A process for making polymorphic Form ILof Cis Olopatadine HCl.comprising, i. Dissolving Cis Olopatadine HCl as obtained by the process claimed in claim 1 or 26 in methanol at an ambient temperature to an elevated temperature to form a solution. ii. Cooling the solution to room temperature followed by stirring the solution till the solid precipitated; iii. isolating the precipitated solid and drying the product.

49. The process as claimed in claim 48, wherein the elevated temperature is the temperature between 50 to 70⁰C, preferably 65⁰C.

50. The process as claimed in claim 48, wherein cooling is done between -5 to 30⁰C, preferably at 10-15⁰C.

51. The process as claimed in claim 48, wherein the drying is done between 30⁰C to 90⁰C, preferably at 65°C.

52. A process for making Form II of Cis Olopatadine HCl comprising vacuum evaporation of a solution of Cis Olopatadine HCl in methanol.

53. A process for making Form II comprising, suspending amorphous form of Cis Olopatadine HCl in methanol followed by stirring to precipitate Form II.

54. Amorphous Form of Cis 1 l-(Z)-[3-(Dimethylamino) propylidene]-6,l l- dihydrodibenz [b,e] oxepin-2-acetic acid HCl (Cis olopatadine.HCl) characterized by X-ray powder diffraction pattern.

55. A process for preparation of amorphous form of Cis Olopatadine HCl by vacuum evaporation, wherein the solvent is water.

56. A process for preparation of amorphous form of Cis Olopatadine HCl by lyophilization of solution of Olopatadine.HCl in a polar protic solvent.

57. The process as claimed in claim 56 wherein, the polar protic solvents is selected from methanol, ethanol, n-propanol and water.

58. A process for preparation of amorphous form of Cis Olopatadine HCl by spray drying the solution of Cis Olopatadine HCl in polar protic solvent.

59. The process as claimed in claim 58 wherein the solution of Cis Olopatadine HCl is spray dried at the inlet temperature range of 60⁰C to 140⁰C.

60. The process as claimed in claim 58 wherein the solution of Cis Olopatadine HCl is spray dried at the outlet temperature range of 40 to 90⁰C.

61. A pharmaceutical composition characterized in that the olopatadine hydrochloride manufactured according to anyone of the preceding claim is formulated into a pharmaceutical dosage form.