WO2011121607A2

WO2011121607A2 - Rasagiline and its pharmaceutically acceptable salts

Info

Publication number: WO2011121607A2
Application number: PCT/IN2011/000213
Authority: WO
Inventors: Shriprakash Dhar Dwivedi; Ashok Prasad; Mayur Ramnikbhai Patel
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2010-03-29
Filing date: 2011-03-29
Publication date: 2011-10-06
Anticipated expiration: 2012-09-29
Also published as: WO2011121607A3

Abstract

The present invention relates to rasagiline (I) and its pharmaceutically acceptable salts. The invention also relates to improved processes for the preparation of rasagiline and its pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions that include the pharmaceutically acceptable salts of rasagiline and use of the compositions for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.

Description

RASAGILINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

FIELD OF THE INVENTION

The present invention relates to rasagiline (I) and its pharmaceutically acceptable salts. The invention also relates to improved processes for the preparation of rasagiline and its pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions that include the pharmaceutically acceptable salts of rasagiline and use of the compositions for treating the signs and symptoms of idiopathic Parkinson's disease as initial mo unct therapy to levodopa.

(I)

BACKGROUND OF THE INVENTION

Rasagiline mesylate is an active pharmaceutical substance with an empirical formula of C12H13NCH4O3S and a molecular weight of 267.34. Rasagiline mesylate is the international common accepted name ' for R-(+)-N-propargyl-l -aminoindan mesylate (or (lR)-N-prop-2-yn-l -ylindan-l -amine mesylate or (] R)-2,3-dihydro-N-2- propynyl-1 H-inden-1 -amine mesylate), which is represented in Formula la.

(la)

Rasagiline is a potent, selective, irreversible monoamine oxidase-type B (MAO- B) inhibitor for the treatment of Parkinson's disease, Alzheimer disease and various types of dementia.

Rasagiline mesylate is the commercially marketed pharmaceutically active substance indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline is a selective irreversible inhibitor of the B-form of monoamine Oxidase enzyme (MAO-B). Rasagiline base and its salts are disclosed in EP Patent application No. 0436492 B l . The reference discloses hydrochloride and di-rasagiline L-tartrate salts of Rasagiline characterized by their melting points.

EP 08.12190 B l discloses preparation of rasagiline hydrochloride and mesylate salt. This patent discloses comparative stability and solubility of Rasagiline mesylate with other salts like tartrate, maleate, sulphate, hydrochloride, tosylate, fumarate, phosphate, esylate, tannate and acetate The several salts reported in EP0812190 are degradable and having less solubility.

EP Patent Application No. 1892233 Al discloses polymorphic forms of rasagiline oxalate and rasagiline edisylate. International (PCT) publication No. WO 2008/131961 Al discloses rasagiline mesylate absorbate in amorphous form. International (PCT) publication No. WO 2008/076348 A l discloses rasagiline base in crystalline form and International (PCT) publication No. WO 2009/1 18657 Al discloses rasagiline mesylate crystalline Form-I.

International (PCT) publication No. WO 2010/0007181 Al discloses rasagiline mesylate Form-I, benzoate Form-I, galactarate Form-I, gluconate amorphous Form, tosylate Form-I, phosphate amorphous Form, maleate Form-1, succinate Form-I, acetate Form-I and Form-II, tartrate Form-I, hemitartrate Form-I, fumarate Form-I and Form- II, besylate Form-I and hydrochloride single crystal data.

International (PCT) publication No. WO 201 1/003938 Al discloses salts of rasagiline with an acid, characterized in that the salt is liquid at 23°C wherein acid is R- COOH and R is a saturated or unsaturated, branched or unbranched C2-C23 alkyl.

U.S. Patent Publication 2010/0010098 A l discloses three crystalline forms of rasagiline hydrochloride i.e., Form-I, Form-II and Form-Ill.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, chemical reactivity, stability etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailablility. Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in. the crystal lattice.

Therefore, it would be desirable to prepare and characterize new rasagiline salt forms. Further, it would be desirable to have reliable processes for producing these rasagiline salts forms. Additionally, various rasagiline salt forms could be used to prepare improved pharmaceutical compositions. There is still a need to provide suitable pharmaceutically acceptable salts of rasagiline with better purity and improved stability.

SUMMARY OF THE INVENTION

In one general aspect there are provided acid addition salts of rasagiline. In particular, there are provided hydrobromide, hydrogen phosphate, 1,5-dinapsylate, 1 - napsylate, 1 ,2-diesylate, 2-napsylate, and ascorbate salts of rasagiline.

In another general aspect there are provided processes for the preparation of acid addition salts of rasagiline.

' The invention may provide acid addition salts in crystalline or amorphous forms.

The invention may provide acid addition salts of rasagiline, which show better purity and physiochemical properties. The acid addition salts of rasagiline may have high purity with respect to related impurities and may have improved physiochemical properties like melting point, solubility and improved stability under various stress conditions. The invention may ALSOprovide stable acid addition salts of rasagiline.

In general, the acid addition salts of rasagiline may have purity greater than 99% by area percentage of HPLC.

In another general aspect there are provided pharmaceutical compositions that include a therapeutically effective amount of the acid addition salts of rasagiline; and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect there are provided chemically stable acid addition salts of rasagiline, which contains less than about 0.1 % (wt/wt) (R)-N,N-di(prop-2- ynyl)-2,3-dihydro-l H-inden-l -amine ("dimer impurity") upon exposure to a relative humidity of 75% at 40°C for a period of at least about three months and having a pH of 1% aqueous solution from about 3.5 to about 7.0.

In another general aspect there are provided chemically stable acid addition salts of rasagiline, which contains less than about 0.1 % (wt/wt) 2,3-dihydro-l H-inden- 1 -one oxime, ("oxime impurity") upon exposure to a relative humidity of 75% at 40°C for a period of at least about three months and having a pH of 1 % aqueous solution from about 3.5 to about 7.0.

In another general aspect there are provided chemically stable acid addition salts of rasagiline, which contains less than about 0.1 % (wt/wt) (R)-N,N-di(prop-2- ynyl)-2,3-dihydro-l H-inden-l -amine ("dimer impurity") upon exposure to a relative humidity of 60% at 25°C for a period of at least about three months and having a -pH of 1% aqueous solution from about 3.5 to about 7.0.

In another general aspect there are provided chemically stable acid addition salts of rasagiline, which contains less than about 0.1 % (wt/wt) 2,3-dihydro-lH-inden- 1-one oxime, ("oxime impurity") upon exposure to a relative humidity of 60% at 25°C for a period of at least about three months and having a pH of 1% aqueous solution from about 3.5 to about 7.0.

The invention may produce acid addition salts of rasagiline having enantiomeric purity greater than 99.75%.

In another general aspect there are also provided processes for converting the acid addition salts of rasagiline to mesylate salt of rasagiline. In particular, there are provided processes for converting rasagiline hydrobromide or rasagiline hydrogen phosphate to rasagiline mesylate.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG.l illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline hydrobromide Form-I.

FIG.2 illustrates representative I spectra for rasagiline hydrobromide Form-I.

FIG.3 illustrates a representative TGA pattern for rasagiline hydrobromide Form-I. FIG.4 illustrates a representative powder X-ray diffraction (PXRD) pattern for amorphous rasagiline hydrobromide.

FIG.5 illustrates a representative powder X-ray diffraction (PXRD) pattern for crystalline rasagiline hydrogen phosphate.

FIG.6 illustrates representative IR spectra for crystalline rasagiline hydrogen phosphate.

FIG.7 illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline mesylate Form-I.

FIG.8 illustrates representative IR spectra for rasagiline mesylate Form-I.

FIG.9 illustrates a representative powder X-ray diffraction (PXRD) for rasagiline 1 ,2- edisylate Form-II.

FIG.10 illustrates a representative DSC graph for rasagiline 1 ,2-edisyIate Form-II. FIG.ll illustrates a representative powder X-ray diffraction (PXRD) for crystalline rasagiline 2-napsylate.

FIG.12 illustrates a representative DSC graph for crystalline rasagiline 2-napsylate. FIG.13 illustrates a representative powder X-ray diffraction (PXRD) for crystalline rasagiline 1,5-dinapsylate Form-I.

FIG.14 illustrates a representative DSC graph for rasagiline 1 ,5-dinapsylate Form-1. FIG.15 illustrates a representative powder X-ray diffraction (PXRD) for rasagiline 1,5- dinapsylate Form-II.

FIG.16 illustrates a representative DSC graph for rasagiline 1 ,5-dinapsylate Form-II. FlG.17illustrates a representative powder X-ray diffraction (PXRD) for crystalline rasagiline 1-napsylate.

FIG.18 illustrates a representative DSC graph for crystalline rasagiline 1 -napsylate. DETAILED DESCRIPTION OF THE INVENTION

The present invention based on the surprising finding that by preparing acid addition salts of rasagiline free base in crystalline form, the formation of impurities can be minimized and better purity and chemical stability can be achieved. The inventors have developed different acid addition salts of rasagiline which exhibit improved physiochemical properties like melting point, solubility, toxicology, and improved stability under various stress conditions.

The present inventors have prepared certain salt forms of rasagiline and structurally characterized them as described herein. The salts forms are also referred as acid addition salts of rasagiline. These acid addition salts can be hydrobromide, hydrogen phosphate, 1 ,5-dinapsylate, 1 -napsylate, 1,2-diesylate, 2-napsylate, and ascorbate salts of rasagiline.

These salts can be crystalline or amorphous forms of hydrobromide, hydrogen phosphate, 1 ,5-dinapsylate, 1 -napsylate, 1 ,2-diesylate, 2-napsylate, and ascorbate. The inventors have developed processes for the preparation of these acid addition salts of rasagiline.

In one aspect of the present invention there are provided chemically stable rasagiline acid addition salts, wherein the rasagiline acid addition salts contain less than about 0.1% (wt/wt) (R)-N,N-di(prop-2-ynyl)-2,3-dihydro-l H-inden-l-amine after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity. In another aspect of the present invention there are provided chemically stable rasagiline acid addition salts, wherein the rasagiline acid addition salts contain less than about 0.1% (wt/wt) 2,3-dihydro- 1 H-inden- 1 -one oxime after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

The acid addition salts are also color stable and do not change their color after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

In another aspect of the present invention there are provided rasagiline acid addition salts having enantiomeric purity greater than 99.75%, wherein 1 % aqueous solution of the acid addition salts has a pH of from about 3.5 to about 7.0

In one aspect of the present invention, there is provided a process for the preparation of crystalline rasagiline hydrobromide, the process comprising:

(a) providing solution of rasagiline free base in one or more suitable organic solvents;

(b) adding hydrobromic acid;

(c) heating reaction mixture;

(d) adding one or more suitable anti-solvents; and

(e) isolating the crystalline rasagiline hydrobromide.

Suitable organic solvents include one or more alcoholic solvents like methanol, ethanol, isopropanol, n-butanoJ, heptanol, decanol, dodecanol, and the like. In particular, methanol may be used as a solvent.

Suitable anti-solvents include one or more of hydrocarbons like toluene, xylene, ethylbenzene, n-hexane, heptane, cyclohexane, and the like; ethers like diisopropylether, methyltert-butyl ether, tetrahydrofuran, and the like; esters like ethyl acetate, butyl acetate, isopropyl acetate, and the like.

The rasagiline free base may be dissolved in an alcoholic solvent to provide solution and concentrated hydrobromic acid may be added and reaction mixture may be heated. The reaction mixture can be heated from about 35°C to about 90°C, for example from about 50°C to about 75°C. In particular, it may be heated from about 6Q°C to about 65°C. The reaction mixture is may

be treated with one or more suitable anti-solvents The rasagiline hydrobromide isolated as crystalline Form I by conventional technique.

Particularly, the solution of rasagiline free base in alcoholic solvent may be maintained at 35°C for about 1 hour followed by the addition of cone, hydrobromic acid followed by heating. The anti-solvent may be added at an elevated temperature. ^■ The obtained crystalline rasagiline hydrobromide Form I can be isolated by known techniques reported in the art. The crystalline rasagiline hydrobromide may be further dried.

As used herein the term "isolation" may include filtration, filtration under vacuum, centrifugation, and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities, and the like prior to removal of the solvent. Any filtration system and the filtration techniques known in the art can be used.

The term "elevated temperature" used herein means, heating the reaction mixture, which is heterogeneous or homogeneous, at a temperature from about 35°C to boiling point of the solvent. In particular, it may be heated from about 35°C to about 100°C. The term "ambient temperature" used herein means, slurrying the reaction mixture either heterogeneous or homogeneous at a temperature from about 0°C to about 35°C of solvent.

"Suitable solvent" means a single or a combination of two or more solvents, "rasagiline free base" herein means (R)-isomer of rasagiline.

The rasagiline free base can be prepared by known methods in the art e.g. process described in EP 0436492 B l and US Patent No. 5,519,061.

In general, the crystalline rasagiline hydrobromide Form-I may be characterized by X-ray powder diffraction having characteristic peaks at about 16.8° and 23.5° (2Θ) and IR spectra having characteristic peaks at 3219, 2123 and 1564 cm^"1 and having water content of less than about 0.5% (wt/wt).

The crystalline rasagiline hydrobromide Form-I may be further characterized by X-ray powder diffraction (PXRD) pattern with peaks at about 9.3°, 1 1.6°, 16.8°, 20.3°, 23.5°, 23.7° and 25.1 ° (2Θ). The crystalline rasagiline hydrobromide may be characterized by a PXRD pattern substantially as depicted in FIG. 1.

The crystalline rasagiline hydrobromide Form-I can also be characterized by IR spectra 3219, 2347, 2123, 1840, 1564, 1477, 1460, 1435, 1313, 1091, 1024, 894 and 765 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 2.

The present invention provides crystalline rasagiline hydrobromide, which has about 0.5% water by weight, for example, it contains about 0.25% of water by weight. In particular, it may contain about 0.1% of water by weight. The crystalline rasagiline hydrobromide may also be characterized by a weight loss measured by thermal gravimetric analysis (TGA) of about 0.5% by weight and as substantially depicted in FIG. 3. Thus, crystalline rasagiline hydrobromide is anhydrous.

The crystalline rasagiline hydrobromide may have particle size distributions, wherein the 10^th volume percentile particle size (Dio) is less than about 50 μιη, the 50th volume percentile particle size (D₅₀) is less than about 250 μιη, or the 90^th volume percentile particle size (D90) is less than about 500 μιη, or any combination thereof.

In another aspect, the present invention provides stable crystalline rasagiline hydrobromide that contains less than about 0.1 % (wt/wt) (R)-N,N-di(prop-2-ynyl)-2,3- dihydro-lH-inden-1 -amine "dimer" and less than about 0.1 % (wt/wt) 2,3-dihydro-l H- inden-l-one oxime "oxime" after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

Stability Data of crystalline rasagiline hydrobromide

ND = Not Detected

In another aspect, the present invention provides amorphous form of rasagiline hydrobromide characterized by X-ray powder diffraction substantially as depicted in FIG.4

In another aspect there is provided a process for the preparation of amorphous . rasagiline hydrobromide, the process comprising:

a) providing a solution or suspension of rasagiline hydrobromide in one or more suitable solvents; and b) isolating the rasagiline hydrobromide in the amorphous form.

In general, the solution of rasagiline free base may be obtained by dissolving rasagiline hydrobromide in one or more suitable solvents. Alternatively, a reaction mixture containing rasagiline hydrobromide that is obtained in the course of its synthesis may be used directly.

Suitable solvents that may be used in step a) include but are not limited to water; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 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; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, chlorinated hydrocarbons like methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile, and polar aprotic solvents like Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, and the like; and mixtures thereof.

In general, the amorphous form of rasagiline hydrobromide may be isolated by removing the solvents. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and. the like or any other suitable technique.

Alternatively, the amorphous form of rasagiline hydrobromide may be isolated by addition of one or more suitable anti-solvents to the solution obtain in step a). The solution may be concentrated before adding the anti-solvent. Suitable anti-solvents that may be used can be selected from hydrocarbons like hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, and the like.

Particularly, the amorphous rasagiline hydrobromide may be obtained by using a spray drying technique. The process includes spray drying a solution of rasagiline hydrobromide (feed stock), which can be prepared by any of the methods known in the art or by methods as discussed below, wherein crystalline rasagiline hydrobromide may be used. The feedstock may be dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying may be carried out under the following parameters.

Any known form of rasagiline hydrobromide or the filtered cake that is obtained as an end result of the reaction or reaction mass comprising rasagiline hydrobromide or solution comprising rasagiline hydrobromide, can be used for the preparation of feed stock, for example, the crystalline rasagiline hydrobromide described herein above can be used.

In general, the feed stock of rasagiline hydrobromide may be prepared by dissolving crystalline or wet cake of rasagiline hydrobromide in one or more solvents which include, for example, ketones, C alcohols, C₂-6 acetates, acetonitrile, methylene dichloride, water or mixtures thereof.

In another aspect of the present invention, there is provided a crystalline form of rasagiline hydrogen phosphate.

The crystalline form of rasagiline hydrogen phosphate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 5.3°, 10.7°, 16.3°, 19.8°, and 27. Γ (2Θ) and IR spectra having characteristic peaks at 3271, 2123, 1433, and 764 cm^"1.

The crystalline form of rasagiline hydrogen phosphate may be further characterized by X-ray powder diffraction (PXRD) pattern with peaks at about 5.3°, 7.7°, 10.7°, 14.1°, 16.3°, 19.8°, 21. , 21.6°, 23.7°, 27.1°, and 28.8° (20). The crystalline Form of rasagiline hydrogen phosphate may be further characterized by a PXRD pattern substantially as depicted in FIG. 5. The crystalline form of rasagiline hydrogen phosphate can also be characterized by IR spectra 3271, 2123, 2584, 2349, 1433, 1027, 948, 765, 744, 696 and 503 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 6.

In another aspect of the invention there is provided a process for the preparation of crystalline form of rasagiline hydrogen phosphate. The process includes contacting rasagiline free base with phosphoric acid in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the crystalline form of rasagiline hydrogen phosphate.

The suitable solvents comprise one or more of C₁ -C5 alcohol solvents, water and mixtures thereof. In particular, the Q-Cs alcohol solvent is isopropanol. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of crystalline form of rasagiline hydrogen phosphate include treating rasagiline free base in one or more alcoholic solvents and treating with cone, phosphoric acid at about 25°C to 80°C, for example, at about 40°C, followed by cooling to room temperature.

The crystalline rasagiline hydrogen phosphate may have particle size distributions, wherein the 10^th volume percentile particle size (D₁₀) is less than about 20 μπι, the 50th volume percentile particle size (D50) is less than about 50 μηι, or the 90^th volume percentile particle size (D90) is less than about 250 μιη, or any combination thereof.

In another aspect, the present invention provides stable crystalline rasagiline hydrogen phosphate that contains less than about 0.1% (wt/wt) (R)-N,N-di(prop-2- ynyl)-2,3-dihydro-lH-inden-l -amine "dimer" and less than about 0.1 % (wt/wt) 2,3- dihydro-l H-inden-l -one oxime "oxime" after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

Stability Data of crystalline rasagiline hydrogen phosphate

powder powder powder powder powder

Related Substances

1. Dimer ND ND ND ND ND

2. Oxime ND ND ND ND ND

3. Total Impurities 0.06 0.07 0.08 0.08 0.08

Polymorphism Crystalline Crystalline Crystalline Crystalline Crystalline

ND = Not Detected

In another aspect of the present invention there is provided a crystalline Form-I

of rasagiline mesylate.

The rasagiline mesylate crystalline Form I of the present invention may be

characterized by X-ray powder diffraction pattern having characteristic peaks at about

8.8°, 13.4°, 18.0° and 22.6° (20) and IR spectra having characteristic peaks at 3277,

2588, 2351 , 1481, 1047 and 559 cm^'1. -

The crystalline Form I of rasagiline mesylate may be further characterized by

X-ray powder diffraction (PXRD) pattern with peaks at about 8.8°, 13.4°, 16.9°, 18.0°,

17.3°, 24.2° and 27.2° (20). The Form-I may be further characterized by a PXRD

pattern substantially as depicted in FIG. 7.

The crystalline Form I of rasagiline mesylate can also be characterized by IR

spectra 3277, 3221 , 2667, 2588, 2351 , 2127, 1627, 1481 , 1207, 1 155, 1047, 765, 646,

559 and 540 cm^'1. The Form-1 may also be characterized by IR spectra substantially as

depicted in FIG. 8.

In yet another aspect, there is provided a process for the preparation of

crystalline Form-I of rasagiline mesylate (la),

the process comprising:

(a) treating rasagiline hydrobromide with a base to obtain rasagiline free base;

(b) providing solution of the rasagiline free base in one or more suitable solvents;

(c) adding methanesulphonic acid; and

(d) isolating the crystalline Form-I of rasagaline mesylate.

In general, the embodiments of the process may include treating rasagiline

hydrobromide with a base. Suitable base can be selected from one or more of alkali metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal bicarbonates, hydrides like sodium hydride, alkoxides like sodium methoxide, potassium t-butoxide, ammonia and the like to obtain rasagiline free base by removal of the solvents.

In particular, the rasagiline hydrobromide can be treated with a base in one or more suitable solvents selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, n-butyl acetate, methylene dichloride, toluene, xylene, methyl t- butylether, diisopropyl ether, dimethylformamide, dimethylacetamide-, acetonitrile, N- methylpyrrolidone, dimethylsulfoxide, and the like.

The reaction with a base can be preferably carried out at an ambient temperature to an elevated temperature, for example, at about 25°C to about 60°C. The rasagiline free base thus obtained can be treated with a suitable organic solvent selected from one or more of methanol, ethanol, isopropanol, acetone, methylisobutyl ketone, ethyl acetate, toluene, acetonitrile etc to obtain solution. The solution may be further treated with methane sulphonic acid and isolating crystalline Form-I of rasagiline mesylate by filtration and drying.

The rasagiline free base suspension in acetone can be treated with methanesulphonic acid to obtain rasagiline mesylate Form-1. The reaction can be carried out at 25°C to about 40°C.

In another aspect of the present invention there is provided a crystalline Form-II of rasagiline 1 ,2-edisylate.

The crystalline Form-II of rasagiline 1 ,2-edisylate may be characterized by one or both of X-ray powder diffraction peaks at about 6.6°, 8.1°, 11.9°, 12.3°, 13.0°, 13.5°, 19.5°, 20.5°, 21.7°, 22.2°, 23.2°, 24.2°, 25.2°, 27.3° and 29.5° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.9.

The crystalline Form-II of rasagiline 1,2-edisylate may be further characterized by endothermic peak at about 99.5°C in differential scanning calorimetry analysis substantially as depicted in FIG.10.

In another aspect of the invention there is provided a process for the preparation of crystalline Form-II of rasagiline 1 ,2-edisylate. The process includes contacting rasagiline free base with ethane 1 ,2-disulfonic acid, optionally, in the presence of one , or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the crystalline Form-II of rasagiline 1 ,2-edisylate. The suitable solvents comprise one or more of C 1 -C5 ketonic solvents, water and mixtures thereof. In particular, the C1 -C5 ketonic solvent is acetone. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of crystalline Form-II of rasagiline 1,2-edisylate includes treating rasagiline free base in one or more ketonic solvents and treating with ethane 1 ,2-disulfonic acid at about 25°C to 70°C, for example, at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 25°C and may be maintained at this temperature for about 1 hour to 5 hours under stirring.

In another aspect of the present invention there is provided a crystalline rasagiline 2-napsylate.

The crystalline rasagiline 2-napsylate may be characterized by one or both of X- ray powder diffraction peaks at about 9.3°, 1 1.3°, 13.9°, 17.5°, 17.8°, 18.4°, 20.1°, 21.3°, 22.8°, 23.8°, 25.8°, 27.1° and 35.0° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.1 1.

The crystalline rasagiline 2-napsylate may be further characterized by endothermic peak at about 148.9°C in differential scanning calorimetry analysis substantially as depicted in FIG.12.

In another aspect of the invention there is provided a process for the preparation of crystalline rasagiline 2-napsylate. The process includes contacting rasagiline free base with naphthalene 2-sulfonic acid, optionally, in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti- solvents, and isolating the crystalline rasagiline 2-napsylate.

The suitable solvents comprise one or more of C1 -C5 ketonic solvents, water and mixtures thereof. In particular, the C1 -C5 ketonic solvent is acetone. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of crystalline rasagiline 2- napsylate comprising treating rasagiline free base in one or more ketonic solvents to obtain solution and treating with naphthalene 2-sulfonic acid at about 25°C to 70°C, for example, at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 0°C to obtain crystalline rasagiline 2-napsylate.

The invention provides crystalline rasagiline 1 ,5-dinapsylate.

Particularly, there is provided a crystalline Form-I of rasagiline 1,5-dinapsylate. The crystalline Form-I of rasagiline 1 ,5-dinapsylate may be characterized by one or both of X-ray powder diffraction peaks at about 8.7°, 1 1 .0°, 1 1 .8°, 15.3°, 16.6°, 17.7°, 18.3°, 20.5°, 21.9°, 23.0°, 23.9°, 24.5°, 26. Γ, 27.1° and 31.1° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.13.

The crystalline Form-I of rasagiline 1 ,5-dinapsylate may be_. further characterized by two endothermic peaks at about 197.1°C and at about 221.7°C in differential scanning calorimetry analysis substantially as depicted in FIG.14.

In another aspect of the invention there is provided a process for the preparation of crystalline Form-I of rasagiline 1 ,5-dinapsylate. The process includes contacting rasagiline free base with 1 mole equivalent of naphthalene 1 ,5-disulfonic acid, optionally, in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the crystalline Form- I of rasagiline 1,5-dinapsylate.

The embodiments of the process for the preparation of crystalline Form-I of rasagiline 1,5-dinapsylate include treating rasagiline free base in one or more ketonic solvents and treating with 1 mole equivalent of naphthalene 1,5-disulfonic acid at about 25°C to 70°C, for example, at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 25°C and may be maintained for about 1 hour to 5 hours under stirring.

In another aspect of the present invention there is provided a crystalline Form-II of rasagiline 1 ,5-dinapsylate. .

The crystalline Form-II of rasagiline 1 ,5-dinapsylate may be characterized by one or both of X-ray powder diffraction peaks at about 8.3°, 9.5°, 12.2°, 14.2°, 14.8°, 16.3°, 16.6°, 17.0°, 21.9°, 22.1 °, 22.8°, 24.4°, 25.8°, 27.4° and 29.8° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.15. The crystalline Form-II of rasagiline 1 ,5-dinapsylate may be further characterized by endothermic peak at about 223.3°C in differential scanning calorimetry analysis substantially as depicted in FIG.l 6.

In another aspect of the invention there is provided a process for the preparation of crystalline Form-II of rasagiline 1 ,5-dinapsylate. The process includes contacting rasagiline free base with 0.5 mole of naphthalene 1 ,5-disulfonic acid in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the crystalline Form-II of rasagiline 1,5- dinapsylate.

The suitable solvents comprise one or more of C1 -C5 ketonic solvents, water and mixtures thereof. In particular, the CpC₅ ketonic solvent is acetone. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of crystalline Form-II of rasagiline 1 ,5-dinapsylate include treating rasagiline free base in one or more ketonic solvents and treating with 0.5 mole of naphthalene 1 ,5-disulfonic acid at about 25°C to 70°C, for example at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 25°C and may be maintained at this temperature for about 1 hour to 5 hours under stirring.

In another aspect of the present invention there is provided a crystalline rasagiline 1-napsylate.

The crystalline rasagiline 1 -napsylate may be characterized by one or both of X- ray powder diffraction peaks at about 6.2°, 8.6°, 8.9°, 12.6°, 14.6°, 15.8°, 16.5°, 20.2°, 21.2°, 22.5°, 23.2°, 25.3°, 28.8°, 30.4° and 31.8° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.l 7.

The crystalline rasagiline 1 -napsylate may be further characterized by endothermic peak at about 128.2°C in differential scanning calorimetry analysis substantially as depicted in FIG.18.

In another aspect of the invention there is provided a process for the preparation of crystalline rasagiline 1-napsylate. The process includes contacting rasagiline free base with naphthalene 1 -sulfonic acid, optionally, in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti- solvents, and isolating the crystalline rasagiline 1 -napsylate. The suitable solvents comprise one or more of C1 -C5 ketonic solvents, water and mixtures thereof. In particular, the C1 -C5 ketonic solvent is acetone. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of crystalline rasagiline 1- napsylate include treating rasagiline free base in one or more ketonic solvents and treating with naphthalene 1 -sulfonic acid at about 25°C to 70°C, for example, at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 0°C to isolate crystalline rasagiline 1-napsylate.

In another aspect of the present invention there is provided rasagiline ascorbate.

In another aspect of the invention there is provided a process for the preparation of rasagiline ascorbate, the process comprising contacting rasagiline free base with ascorbic acid, in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the rasagiline ascorbate.

The suitable solvents comprise one or more of C1 -C5 alcoholic solvents, water and mixtures thereof. In particular, the C]-C₅ alcoholic solvent is methanol. An anti- solvent can be optionally added. The suitable anti-solvent can be selected from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like.

The embodiments of the process for the preparation of rasagiline ascorbate include treating rasagiline free base in one or more alcoholic solvent and treating with ascorbic acid at about 25°C to 70°C, for example, at about 55°C and stirred for 30 min. The reaction mixture may be cooled to 0°C to isolate crystalline rasagiline ascorbate. The invention further provides rasagiline ascorbate salt in amorphous form.

In a still further aspect there is provided a process for the preparation of amorphous rasagiline ascorbate, the process comprising one or more of the following steps:

a) providing a solution of rasagiline ascorbate in one or more solvents; and

b) isolating the rasagiline ascorbate amorphous form.

In general, a solution of rasagiline ascorbate can be obtained by dissolving rasagiline ascorbate in one or more suitable solvents. Alternatively, a reaction mixture containing rasagiline ascorbate that is obtained in the course of its synthesis may be used directly.

Suitable solvents that may be used in step a) include but are not limited to water; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 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; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, chlorinated hydrocarbons like methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile, and polar aprotic solvents like Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and the like; and mixtures thereof.

In general, the amorphous form of rasagiline ascorbate may be isolated by removing the solvents. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

Alternatively, the amorphous form of rasagiline ascorbate may be isolated by addition of one or more suitable anti-solvents to the solution obtain in step a). The solution may be concentrated before adding the anti-solvent. Suitable anti-solvents that may be used can be selected from hydrocarbons like hexanes, n-heptatte, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic hydrocarbons like toluene, xylene, chlorobenzene, ethylbenzene and the like; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2- methoxyethanol, and the like.

Particularly, the amorphous form of rasagiline ascorbate may be obtained by using a spray drying technique. The process includes spray drying a solution of rasagiline hydrobromide (feed stock), which can be prepared by any of the methods known in the art or by methods as discussed below, wherein crystalline form of rasagiline hydrobromide may be used. The feedstock may be dozed into the spray- drying instrument JISL Mini Spray-drier LSD-48 and spray drying may be carried out under the following parameters. Sr. No Parameters Conditions

a) Feed pump 10-50 rpm

b) Inlet temperature 35°-80°C

c) Outlet temperature 30°-60°C

d) Aspirator rate 1000-1500 rpm e) Vacuum for conveying the dry product 30-120 mm of Hg f) Hot air supply 2-4 Kg/cm

g) Atomizer Speed: 40,000-100,000 rpm

Any known form of rasagiline ascorbate or the filtered cake that is obtained as an end result of the reaction or reaction mass comprising rasagiline ascorbate or solution comprising rasagiline ascorbate, can be used for the preparation of feed stock, for example, the crystalline form of rasagiline ascorbate described herein above can be used.

In general, the feed stock of rasagiline ascorbate may be prepared by dissolving any known forms or wet cake of rasagiline ascorbate in one or more solvents which include, for example, ketones, C₁ -4 alcohols, C₂-6 acetates, acetonitrile, methylene dichloride, water or mixtures thereof .

The rasagiline acid addition salts of rasagiline may be characterized by Powder X-ray diffraction as follows:

(i) Characterization by Powder X-ray Diffraction

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

Instrument : X-ray Diffractometer, D/Max-2200/PC Make: Rigaku, Japan.

X- Ray : Cu/40kv/40mA

Diverging : 1°

Scattering Slit : 1°

Receiving Slit : 0.15 mm

Monochromator RS : 0.8 mm

Counter : Scintillation Counter

Scan Mode : Continuous

Scan Speed : 3.000° / Min Sampling Width 0.020

Scan Axes Two Theta / Theta

Scan Range 2.000° to 40.000°

Theta Offset 0.000 |0

The IR spectrum was measured by the KBr method.

The crystalline salts of rasagiline prepared as per the process of the present invention can further be characterized based on their various physiochemical properties like melting point, solubility and pH in 1% aqueous solution. Table 1 shows physiochemical properties:

Table 1

The flowability of rasagiline salts can be measured using the Hausner ratio, which is a value calculated by dividing the tapped density of the rasagiline salt by the freely settled bulk density of the rasagiline salt. The freely settled bulk density is calculated by pouring a known weight of material into a measuring cylinder and recording the volume. The tapped density is calculated by tapping the cylinder against a surface for a specified numbers of times and recording again the new volume. Table-2 below shows the terms used to describe the flowability character with reference to the Hausner ratio value.

Table-2

Accordingly, in one of the aspect, there is provided crystalline rasagiline hydrogen phosphate having bulk density of about 0.458 gm/ml and tap density after 500 taps of about 0.513 gm/ml and after 750 taps of about 0.541 gm/ml.

Hence, Hausner ratio of crystalline rasagiline hydrogen phosphate for 500 taps is 1.120 and for 750 taps is 1.180 which shows that crystalline rasagiline hydrogen phosphate Form-I has good flowability.

Accordingly in another aspect, there is provided crystalline rasagiline hydrobromide having bulk density of about 0.797 gm/ml and tap density after 500 taps of about 0.866 gm/ml and after 750 taps of about 0.905 gm/ml.

Hence, Hausner ratio of crystalline rasagiline hydrobromide for 500 taps is 1.085 and for 750 taps is 1 .135 which shows that crystalline rasagiline hydrobromide has excellent flowability with respect to 500 taps and good flowability with respect to 750 taps.

The invention also encompasses pharmaceutical compositions comprising rasagiline salts of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the rasagiline salts of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Any excipient commonly known and used widely in the art can be used in the pharmaceutical composition.

Carriers may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like. Binders used include, but are not limited to, water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxym ethyl cellulose, shelac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like.

Disintegrating agents may include, but are not limited to, dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogen carbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose, and the like.

Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like. Absorption accelerators used include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like.

Wetting agents may include, but are not limited to, glycerin, starch, and the like. Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like. Lubricants used include, but are not limited to, purified talc, stearates, boric acid powder, polyethylene glycol, and the like.

Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi- layered tablets.

When shaping the pharmaceutical composition into pill form, any commonly known excipient used in the art can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the like. Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like. Disintegrating agents used include, but are not limited to, agar, laminalia, and the like. For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known excipient used in the art can be used. For example, excipients include, but are hot limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, and semi synthesized glycerides.

When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic.

Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added. If necessary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations.

The amount of rasagiline salt contained in a pharmaceutical composition for treating Parkinson's disease, Alzheimer disease and various types of dementia should be sufficient to treat, ameliorate, or reduce the symptoms associated with it. For example, rasagiline may be present in an amount of about 1 % to about 60% by weight of the dose.

The pharmaceutical compositions of the invention may be administered in a variety of methods depending on the age, sex, and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules may be orally administered. Injection preparations may be administered individually or mixed with injection transfusions such as glucose solutions and amino acid solutions intravenously.

If necessary, the injection preparations may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered into the rectum The dosage of a pharmaceutical composition for treating Parkinson's disease, Alzheimer disease and various types of dementia according to the invention will depend on the method of use, the age, sex, and condition of the patient. The rasagiline acid addition salts and process for its preparation described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.

Example-1:

Preparation of (R)-rasagiline hydrobromide Form-I

5 g or (R)-(+)-iasagiline base and 15 mL methanol were taken in round bottom flask at 25°C. 7.5 g of cone, hydrobromic acid was added and heated at 65°C with stirring for 30 min.60 mL methyl tert-butyl ether was added and stirred for 1 hour at 55°C. The reaction mixture was cooled to 35°C and filtered. The wet-cake was washed with mixture of methanol and methyl tert-butyl ether and dried for 12 hours at 55°C under vacuum to obtain crystalline Form-I of (R)-rasagiline hydrobromide. The product is characterized by XRD (FIG.l) and IR (FIG.2). The water content is less than 0.5%, which shows it is anhydrous. TGA (FIG.3)

ExampIe-2:

Preparation of amorphous rasagiline hydrobromide

25.0 g of rasagiline hydrobromide is dissolved in 250.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through hyflosupercel, and the hyflosupercel pad is washed with 50.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 50 mL acetone was added and stirred to get clear solution. 2.2 mL liquor ammonia solution was added into, the reaction mixture followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C±5°C under vacuum for 16 hours to get 19.0 g of amorphous rasagiline hydrobromide.

h) Hot air supply 2 Kg/cn?

The spray-dried rasagiline hydrobromide is amorphous in nature. The obtained product contains residual solvent well within ICH limit. The product is characterized by XRD (FIG.4)

Example-3:

Preparation of (R)-Rasagiline hydrogen phosphate

3 g of (R)-(+)-rasagiline base and 20 mL isopropanol were taken in round bottom flask at 25°C. 0.5 g of phosphoric acid was added and heated at 40°C with stirring for 1 hours. The reaction mixture was cooled to 25°C and stirred for 1 hours. The product was filtered and washed with isopropanol. The product was dried for 12 hours at 55°C under vacuum to obtain crystalline Form-I of (R)-rasagiline phosphate. The product is characterized by XRD (FIG.5) and IR (FIG.6)

Example-5:

Preparation of (R)-rasagiline Mesylate

15.0 g rasagiline hydrobromide Form-I and 150 ml ethyl acetate were taken in round bottom flask. 10% NaOH 20 g in ethyl acetate was added to the reaction mixture and heated to 65°C. The reaction mixture was stirred for 4 hours at same temperature. After the completion of the reaction, the reaction mixture was distilled to remove ethyl acetate completely. The residue was suspended in isopropanol 150 mL followed by dropwise addition of methanesulfonic acid 6 g and stirred at 40°C for 30 minutes. The reaction was cooled to room temperature and resulting crystals were isolated by suction filtration to give the title compound with m.p. 157°C.

Example-6:

Preparation of (R)-rasagiline Mesylate Form-I

3.4 g of (R)-(+)-rasagiline base and 27 mL acetone were taken in round bottom flask at 25°C. 8.7 g of methane sulphonic acid was added and maintain for 1 hour at 35°C. The reaction mixture was filtered and wet-cake was washed with acetone and dried for 12 hours at 55°C under vacuum to obtain crystalline Form-I of (R)-rasagiline Mesylate. The product is characterized by XRD (FIG.7) and IR (FIG.8). The water content is less than 0.5%, which shows it is anhydrous.

Example-7:

Preparation of (R)-rasagiline 1,2-edisylate Form-II 10 g of (R)-(+)-rasagiline base and 100 mL acetone were taken in round bottom flask at 25°C. 1 1.08 g of ethane- 1,2-disulphonic acid was added and heated at 55°C with stirring for 30 mins. The reaction mixture was cooled to 25°C-35°C and stirred for 1 hours. The product was filtered and washed with acetone. The product was dried for 12 hours at 45°C under vacuum to obtain crystalline Form-II of (R)-rasagiline 1 ,2- edisylate. The product is characterized by XRD (FIG.9) and DSC (FIG.10).

Example-8:

Preparation of crystalline (R)-rasagiline 2-napsylate

10 g of (R)-(+)-rasagiline base and 100 mL acetone were taken in round bottom flask at 25°C. 12.14 g of naphthalene-2-sulphonic acid was added and heated at 55°C with stirring for 30 mins. The reaction mixture was cooled to 25°C-35°C and stirred for 1 hour. The product was filtered and washed with acetone. The product was dried for 12 hours at 45°C under vacuum to obtain crystalline (R)-rasagiline 2-napsylate. The product is characterized by XRD (FIG.l 1 ) and DSC (FIG.12).

Example-9:

Preparation of (R)-rasagiline 1,5-dinapsylate Form-I

10 g of (R)-(+)-rasagiline base and 100 mL acetone were taken in round bottom flask at 25°C. 16.8 g of naphthalene- 1,5-disulphonic acid was added and heated at 55°C with stirring for 30 mins. The reaction mixture was cooled to 25°C-35°C and stirred for 1 hour. The product was filtered and washed with acetone. The product was dried for 12 hours at 45°C under vacuum to obtain crystalline Form-I of (R)-rasagiline 1,5- dinapsylate. The product is characterized by XRD (FIG.13) and DSC (FIG.14).

Example-10:

Preparation of (R)-rasagiline 1,5-dinapsylate Form-II

10 g of (R)-(+)-rasagiline base and 100 mL acetone were taken in round bottom flask at 25°C. 8.4 g of naphthalene- 1 ,5-disulphonic acid was added and heated at 55°C with stirring for 30 mins. The reaction mixture was cooled to 25°C-35°C and stirred for 1 hour. The product was filtered and washed with acetone. The product was dried for 12 hours at 45°C under vacuum to obtain crystalline Form-II of (R)-rasagiline 1,5- dinapsylate. The product is characterized by XRD (FIG.15) and DSC (FIG.16).

Example-11:

Preparation of crystalline (R)-rasagiline l-napsylatate

10 g of (R)-(+)-rasagiline base and 100 mL acetone were taken in round bottom flask at 25°C. 12.14 g of naphthalene- l -sulphonic acid was added and heated at 55°C with stirring for 30 mins. The reaction mixture was cooled to 0°C-5°C and stirred for 1 hour. The product was filtered and washed with chilled acetone. The product was dried for 12 hours at 45°C under vacuum to obtain crystalline (R)-rasagiline 1 -napsylate. The product is characterized by XRD (FIG.17) and DSC (FIG.18).

Example-12:

Preparation of crystalline (R)-rasagiline ascorbate

10 g or (R)-(+)-rasagiline freebase and 20 mL methanol were taken in round bottom flask at 25°C. 10.3 g ascorbic acid was added and heated at 65°C with stirring for 30 min. 60 mL methyl tert-butyl ether was added and stirred for 1 hour at 55°C. The reaction mixture was cooled to 35°C and filtered. The wet-cake was washed with mixture of methanol and methyl tert-butyl ether and dried for 12 hours at 55°C under vacuum to obtain 15 g crystalline (R)-rasagiline ascorbate.

Example-13:

Preparation of amorphous rasagiline ascorbate

10.0 g of. rasagiline ascorbate is dissolved in 250.0 mL of acetone at 25°C to

30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added arid stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 50.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 50 mL acetone was added and stirred to get clear solution, the solution was subjected to spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C±5°C under vacuum for 16 hours to get 7.0 g of amorphous rasagiline ascorbate.

Example-14:

Calculation of pH of 1 % aqueous solution of rasagiline acid addition salts.

Weigh accurately about 1 g of the sample, transfer to a glass beaker of suitable capacity. Add 100 ml of deionized water and dissolve the sample using a glass rod. Immerse the pH electrode in the sample solution, allow a sufficient time for stabilization, giving occational shaking. Check the temperature displayed by the pH meter or measure the temperature using a calibrated thermometer. The pH measurements are made at 25°C±2°C. Record the pH value and the temperature at which the pH value was measured.

While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

We Claim:

1. Rasagiline hydrobromide.

2. An isolated rasagiline hydrobromide.

3. The rasagiline hydrobromide as claimed in claim 1 or 2, which is crystalline.

4. The rasagiline hydrobromide as claimed in claim 1 or 2, which is amorphous.

5. The rasagiline hydrobromide as claimed in claim 3, which is anhydrous.

6. The anhydrous crystalline rasagiline hydrobromide as claimed in claim 5, wherein the rasagiline hydrobromide has a water content of less than about 0.5% wt/wt.

7. Crystalline rasagiline hydrobromide Form I characterized by one or both of X-ray powder diffraction having characteristic peaks at about 9.3°, 1 1.6°, 16.8°, 20.3°,

23.5°, 23.7° and 25.1° (2Θ), or X-ray powder diffraction substantially as depicted in FIG. l .

8. The amorphous rasagiline hydrobromide as claimed in claim 4 characterized by X- ray powder diffraction^' substantially as depicted in FIG.4.

9. The crystalline rasagiline hydrobromide Form I as claimed in claim 7, which is further characterized by one or both of IR spectra having characteristic peaks at 3219, 2347, 2123, 1840, 1564, 1477, 1460, 1435, 1313, 1091 , 1024, 894 and 765 cm^"1, or IR spectra substantially as depicted in FIG.2.

10. Crystalline rasagiline hydrobromide having particle size distributions wherein the 10^th volume percentile particle size (Dio) is less than about 50 μιη, the 50^th volume percentile particle size (D50) is less than about 250 μ^ηι, or the 90^th volume percentile particle size (D90) is less than about 500 μιη, or any combination thereof.

11. A process for the preparation of crystalline rasagiline hydrobromide, the process comprising:

(b) adding hydrobromic acid;

(c) heating reaction mixture;

(d) adding one or more suitable anti-solvents; and

(e) isolating the crystalline rasagiline hydrobromide.

12. The process as claimed in claim 1 1 , wherein the suitable organic solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol, and mixtures thereof.

13. The process as claimed in claim 1 1 , wherein the suitable anti-solvent comprises one or more of toluene, xylene, ethylbenzene, n-hexane, heptane, cyclohexane, diisopropylether, methyltert-butyl ether, tetrahydrofuran, ethyl acetate, butyl acetate, isopropyl acetate, and mixtures thereof.

14. A process for the preparation of amorphous rasagiline hydrobromide, the process comprising:

(a) providing a solution of rasagiline hydrobromide in one or more suitable solvents; and

(b) isolating the rasagiline hydrobromide in the amorphous form.

15. The process as claimed in claim 14, wherein isolating the rasagiline hydrobromide comprises using one or more of suitable techniques including rotational distillation device, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like.

16. The process as claimed in claim 14, wherein isolating the rasagiline hydrobromide comprises adding one or more anti-solvents.

17. A crystalline rasagiline hydrogen phosphate.

18. Crystalline form of rasagiline hydrogen phosphate characterized by one or both of X-ray powder diffraction peaks at about 5.3°, 7.7°, 10.7°, 14.1°, 16.3°, 19.8°, 21.1°, 21.6°, 23.7°, 27.Γ; and 28.8° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.5.

19. The crystalline form of rasagiline hydrogen phosphate as claimed in claim 18, which is further characterized by one or both of IR spectra having characteristic peaks at about 3271 , 2123, 2584, 2349, 1433, 1027, 948, 765, 744, 696 and 503 cm^" or IR spectra substantially as depicted in FIG.6.

20. Crystalline rasagiline hydrogen phosphate having particle size distributions wherein the 10^th volume percentile particle size (Dio) is less than about 20 μιη or the 50^th volume percentile particle size (D₅₀) is less than about 50 μιη or the 90^th volume percentile particle size (D90) is less than about 250 μπι.

21. A process for the preparation of crystalline form of rasagiline hydrogen phosphate, the process comprising:

(a) contacting rasagiline free base with phosphoric acid in the presence of one or more suitable solvents;

(b) removing the solvents;

(c) optionally, adding one or more anti-solvents; and

(d) isolating the crystalline form of rasagiline hydrogen phosphate.

22. The process as claimed in claim 21 , wherein the suitable solvent comprises one or more of C1-C5 alcohol solvent, water, and mixtures thereof.

23. The process as claimed in claim 21 , wherein the suitable anti-solvent comprises one or more of methyl tert-butyl ether, diisopropyl ether, cyclohexane, hexane, heptane, toluene, xylene, and the like.

24. Chemically stable rasagiline acid addition salts, wherein the rasagiline acid addition salts contain less than about 0.1% (wt/wt) (R)-N,N-di(prop-2-ynyl)-2,3-dihydro- lH-inden-1 -amine after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

25. Chemically stable rasagiline acid addition salts, wherein the rasagiline acid addition salts contain less than about 0.1 % (wt/wt) 2,3-dihydro-lH-inden-l-one oxime after storage for three months at 40°C and 75% relative humidity and at 25°C and 60% relative humidity.

26. Rasagiline acid addition salts having enantiomeric purity greater than about 99.75%.

27. Rasagiline acid addition salts, wherein 1 % aqueous solution of the salts has a pH of from about 3.5 to about 7.0.

28. The rasagiline acid addition salt according to any of the proceeding claims, which is a hydrobromide, hydrogen phosphate, 1 ,5-dinapsylate, 1 -napsylate, 1 ,2-diesylate, 2- napsylate, or ascorbate.

29. The rasagiline acid addition salts as claimed in claim 28, which are crystalline.

30. Crystalline Form-II of rasagiline 1 ,2-edisylate characterized by one or both of X-ray powder diffraction peaks at about 6.6°, 8.1°, 1 1.9°, 12.3°, 13.0°, 13.5°, 19.5°, 20.5°, 21.7°, 22.2°, 23.2°, 24.2°, 25.2°, 27.3° and 29.5° (20), or X-ray powder diffraction substantially as depicted in F1G.9.

31. The crystalline Form-II of rasagiline 1 ,2-edisylate as claimed in claim 32, which is further characterized by endothermic peak at about 99.5°C in differential scanning calorimetry analysis substantially as depicted in FIG.10.

32. A crystalline rasagiline 2-napsylate.

33. The crystalline rasagiline 2-napsylate as claimed in claim 32 is characterized by one or both of X-ray powder diffraction peaks at about 9.3°, 1 1.3°, 13.9°, 17.5°, 17.8°, 18.4°, 20.1°, 21.3°, 22.8°, 23.8°, 25.8°, 27.1° and 35.0° (20), or X-ray powder diffraction substantially as depicted in FIG.1 1.

34. The crystalline rasagiline 2-napsylate as claimed in claim 32, which is further characterized by endothermic peak at about 148.9°C in differential scanning calorimetry analysis substantially as depicted in FIG.12.

35. A crystalline Form-I of rasagiline 1 ,5-dinapsylate characterized by one or both of X-ray powder diffraction peaks at about 8.7°, 1 1.0°, 1 1.8°, 15.3°, 16.6°, 17.7°, 18.3°,

20.5°, 21.9°, 23.0°, 23.9°, 24.5°, 26. Γ, 27.1° and 31. Γ (2Θ), or X-ray powder diffraction substantially as depicted in FIG.l 3.

36. The crystalline Form-I of rasagiline 1,5-dinapsylate as claimed in claim 35, which is further characterized by two endothermic peaks at about 197.2°C and at about 221.7°C in differential scanning calorimetry analysis substantially as depicted in FIG.14.

37. A crystalline Form-II of rasagiline 1 ,5-dinapsylate characterized by one or both of X-ray powder diffraction peaks, at about 8.3°, 9.5°, 12.2°, 14.2°, 14.8°, 16.3°, 16.6°, 17.0°, 21.9°, 22.1°, 22.8°, 24.4°, 25.8°, 27.4° and 29.8° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.15.

38. The crystalline Form-II of rasagiline 1 ,5-dinapsylate as claimed in claim 37, which is further characterized by endothermic peak at about 223.3°C in differential scanning calorimetry analysis substantially as depicted in FIG.16.

39. A crystalline rasagiline 1 -napsylate.

40. The crystalline rasagiline 1 -napsylate as claimed in claim 39 is characterized by one or both of X-ray powder diffraction peaks at about 6.2°, 8.6°, 8.9°, 12.6°, 14.6°, 15.8°, 16.5°, 20.2°, 21.2°, 22.5°, 23.2°, 25.3°, 28.8°, 30.4° and 31.8° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.l 7.

41. The crystalline rasagiline 1 -napsylate as claimed in claim 40, which is further characterized by endothermic peak at about 128.2°C in differential scanning calorimetry analysis substantially as depicted in FIG.18.

42. A process for the preparation of chemically stable acid addition salts of rasagiline, the process comprising:

(a) combining rasagiline free base with a acid selected from hydrobromic acid, phosphoric acid, 1,5 -naphthalene disulfonic acid, naphthalene 1 -sulfonic acid, 1 ,2- ethane disulfonic acid, naphthalene 2-sulfonic acid, and ascorbic acid in the presence of one or more solvents;

(b) removing the solvents;

(c) optionally, adding one or more suitable anti-solvents; and (d) isolating the chemically stable acid addition salts of rasagiline. .

43. The process as claimed in claim 42, wherein the solvent comprises one or more of methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone ethyl acetate, butyl acetate, isopropyl acetate, n-propyl acetate, toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, methyl-tert butyl ether, diisopropyl ether, diethyl ether, tetrahydrofuran, water, and mixtures thereof.

44. The process as claimed in claim 42, wherein the removal of solvent comprises one or more of distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation, and centrifugation.

45. The process as claimed in claim 42, wherein the suitable anti-solvent comprises one or more of methyl-tertbutyl ether, diisopropyl ether, cyclohexane, hexane, heptane, and xylene..

46. A process for the preparation of crystalline Form-I of rasagiline mesylate of the Formula (la),

the process comprising:

(c) adding methanesulphonic acid; and

(d) isolating the crystalline Form-I of rasagaline mesylate.

47. The process as claimed in claim 46, wherein the suitable base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal bicarbonates, sodium hydride, sodium methoxide, potassium t-butoxide, and ammonia.

48. The process as claimed in claim 46, wherein the suitable organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, methylisobutyl ketone, ethyl acetate, toluene, and acetonitrile.

49. Rasagiline ascorbate.

50. An isolated rasagiline ascorbate.

51. The rasagiline ascorbate as claimed in claim 49 or 50, which is crystalline.

52. The rasagiline ascorbate as claimed in claim 49 or 50, which is amorphous.

53. A process for the preparation of rasagiline ascorbate, the process comprising contacting rasagiline free base with ascorbic acid in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and isolating the rasagiline ascorbate.

54. A process for the preparation of rasagiline ascorbate in amorphous form, the process comprising:

(a) providing a solution of rasagiline ascorbate in one or more suitable solvents; and

(b) isolating the rasagiline ascorbate in the amorphous form.

55. The process as claimed in claim 55, wherein the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

56. A pharmaceutical composition comprising rasagiline acid addition salts selected from one or more of hydrobromide, hydrogen phosphate, 1 ,5-dinapsylate, 1 - napsylate, 1,2-diesylate, 2-napsylate, or ascorbate, and one or more pharmaceutical acceptable excipients.