WO2012153349A9

WO2012153349A9 - Rasagiline and its pharmaceutically acceptable salts

Info

Publication number: WO2012153349A9
Application number: PCT/IN2012/000329
Authority: WO
Inventors: Shriprakash Dhar Dwivedi; Ashok Prasad; Mayur Ramnikbhai Patel
Original assignee: Cadila Healthcare Limited
Priority date: 2011-05-04
Filing date: 2012-05-04
Publication date: 2014-02-13
Also published as: WO2012153349A2; EP2705021A2; WO2012153349A3

Abstract

The present invention relates to Rasagiline acid addition salts having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate. The invention also discloses a process for the preparation of such Rasagiline acid addition salts.

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 rasagiline and its pharmaceutically acceptable salts having larger particle size. 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 adj .

) BACKGROUND OF THE INVENTION

Rasagiline mesylate is an active pharmaceutical substance with an empirical formula of Ci2H₁₃NCH₄0₃S 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 (lR)-2,3-dihydro-N-2- propynyl-lH-inden-l-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). EP 0436492 ΒΪ discloses rasagiline base and its salts, such as hydrochloride and di-rasagiline L-tartrate which are characterized by their melting points.

EP 0812190 Bl discloses preparation of rasagiline hydrochloride and mesylate salts. It also discloses comparative stability and solubility of rasagiline mesylate with other salts like tartrate, maleate, sulphate, hydrochloride, tosylate, fumarate, phosphate, esylate, tannate and acetate.

Different polymorphic forms of certain rasagiline salts are disclosed for example, EP 2054048 Bl 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 Al discloses rasagiline base in crystalline form and International (PCT) publication No. WO 2009/118657 Al discloses rasagiline mesylate crystalline Form-I.

International (PCT) Publication No. WO 2006/091657 Al discloses a mixture of particles of a pharmaceutically acceptable salt of (R)-(+)-N-propargyl-l -amino indan, wherein more than 90% of the total amount by volume of (R)-(+)-N-propargyl-l- aminoindan salt particles have a size of less than 250 microns.

International (PCT) Publication No. WO 2010/0007181 A2 discloses rasagiline mesylate Form-I, benzoate Form-I, galactarate Form-I, gluconate amorphous Form, tosylate Form-I, phosphate amorphous Form, maleate Form-I, 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 2011/003938 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 Application No. 2010/0010098 A 1 discloses three crystalline forms of rasagiline hydrochloride i.e., Form-I, Form-II and Form-Ill.

International (PCT) Publication No. WO2010/111264 A2 discloses formulations comprising rasagiline mesylate having particle size distributions wherein about 90% of the particles have particle sizes from about 0.1 um to about 1000 um, or about 1 μπι to about 500 um, or about 10 um to about 250 um, or about 100 .um to about 150 um. International (PCT) Publication No. WO 2011/095985 A2 discloses crystal particle size of rasagiline salts have D90 less than about 2000 μηι wherein rasagiline phosphate particles having particle size distribution by 250 μ <d(0.9)<1000 μ, 10 μ <d(0.5) <50μ and 2 μ ^(0.1)<10μ and which is bimodal as determined by volume by laser-diffraction method.

International (PCT) Publication No. WO 2011/092717 A2 discloses rasagiline mesylate having large particle size in the range of about 255 microns to about 590 microns by crystallization and devoid of comminution techniques to control particle size.

International (PCT) Publication No. WO 2011/080589 A2 discloses the solid state forms of rasagiline salts like maleate, mandelate and salicylate for use in the pharmaceutical compositions having a D90 particle size of less than or equal to about 500 microns, specifically about 1 micron to about 495 microns, and most specifically about 255 microns to about 490 microns.

European Patent Application No. 2364967 Al provides rasagiline or pharmaceutically acceptable salt thereof having particle size distribution such that 90% of particles have particle size less than or equal to 9 μ and/or 50% of particles having particle size less than or equal to 4 μ.

International (PCT) Publication No. WO 2011/121607 A2 discloses various acid additions salts of rasagiline and process for preparation thereof.

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.

In general, the product of small particle size is easier to process in forming pharmaceutical compositions than a large particle size. The particle size reduction is common phenomenon for achieving finer particle size. In contrast, it would be desirable to prepare and characterize new rasagiline salt forms with larger particle size which are having ease of preparation and avoid comminution techniques to control particle size. Further, it would be desirable to provide reliable processes for producing rasagiline salts forms with larger particle size which doesn't affect the bioequivalence. There is still a need to provide suitable pharmaceutically acceptable salts of rasagiline with better purity and improved stability with larger particle size distribution.

SUMMARY OF THE INVENTION

In one general aspect it has been found that particle size distributions have a beneficial effect on the uniformity of the solid pharmaceutical composition of rasagiline. In contrast to the finer particle size of rasagiline and its pharmaceutically acceptable salts, the larger particle size i.e. coarser particle size still provide the better uniformity, flowability and suitable for pharmaceutical formulations.

In one general asepct, there is provided rasagiline acid addition salts having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate.

In another general asepct, there is provided rasagiline acid addition salts having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, wherein acid addition salt is selected from hydrobromide, hydrogen phosphate, 1,5- dinapsylate, 1-napsylate, 1,2-diesylate, 2-napsylate, besylate and ascorbate.

In another general aspect, there is provided rasagiline besylate having larger particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

In another general aspect, there is provided of crystalline rasagiline hydrobromide having larger particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

In another general aspect, there is provided processes for the preparation of acid addition salts of rasagiline with larger particle size distribution. In particular, the acid addition salts of rasagiline are having purity greater than 99% by area percentage of HPLC.

In general, the invention provides crystalline Forra-I of rasagiline besylate, which show better purity and physiochemical properties. The besylate salt 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.

In another general aspect, there is provided pharmaceutical composition which includes a therapeutically effective amount of the crystalline Form-I of rasagiline besylate; and one or more pharmaceutically acceptable carriers, excipients or diluents. In another general aspect, there is also provided a stable rasagiline besylate Form-I which does not show any discoloration and remains as crystalline white to off- white free flowing powder upon storage for 3 months at 25°C/60%RH and 40°C/75%RH.

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 besylate Form-I.

FIG.2 illustrates representative IR spectra for rasagiline besylate Form-I.

FIG.3 illustrates a differential scanning calorimetry (DSC) pattern for rasagiline besylate Form-I.

FIG.4 illustrates representative PSD histogram of rasagiline besylate Form-I having larger particle size.

FIG.5 illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline hydrobromide Form-I.

FIG.6 illustrates representative IR spectra for rasagiline hydrobromide Form-I.

FIG.7 illustrates a representative TGA pattern for rasagiline hydrobromide Form-I. FIG.8 illustrates a representative powder X-ray diffraction (PXRD) pattern for amorphous rasagiline hydrobromide.

FIG.9 illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline hydrogen phosphate Form-I.

FIG.10 illustrates representative IR spectra for rasagiline hydrogen phosphate Form-I. FIG.11 illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline mesylate Form-I.

FIG.12 illustrates representative IR spectra for rasagiline mesylate Form-I.

FIG.13 illustrates representative PSD histogram of rasagiline hydrobromide Form-I having larger particle size.

FIG.14 illustrates a differential scanning calorimetry (DSC) pattern for rasagiline besylate Form-I as per reference example- 1.

FIG.15 illustrates a representative powder X-ray diffraction (PXRD) pattern for rasagiline besylate Form-I as per reference example- 1. DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that by preparing rasagiline acid addition salts 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 with higher particle size distribution.

In general, the reduction of particle size is achieved by mechanical process of reducing the size of particles which includes any one or more of grinding, milling, micronizing, and trituration and any conventional method known. The most common motivation for decreasing particle size is to increase dissolution. The rate of dissolution of small particles is usually faster than that of large particles because a greater surface area of the drug substance is in contact with the liquid medium. This effect has been highlighted by the superior dissolution rate observed after micronization of sparingly soluble drugs.

But, in contrast to such an approach, the inventors of the present invention provides rasagiline acid addition salts with larger particle size which are having ease of preparation and avoid comminution techniques to control particle size. Further, it would be desirable to provide reliable processes for producing rasagiline salts forms with larger particle size which doesn't affect the bioequivalence. There is provided suitable pharmaceutically acceptable salts of rasagiline with better purity and improved stability with larger particle size distribution.

As used herein the term "obtaining" 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, may 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 may 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 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.

The rasagiline free base used for the preparation of acid addition salts may be prepared by known methods in the art e.g. process disclosed in EP 0436492 Bl and U.S. Patent No. 5,519,061, which are incorporated herein as reference in their entirety. The rasagiline acid addition salts in crystalline and amorphous form may also be prepared by methods disclosed in our own international (PCT) Publication WO 201 1/0121307 A2 and which are described herein after.

In another general aspect, there is provided rasagiline besylate having size D(90) greater than 250 microns and D(50) greater than 100 microns. In particular, the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns. In general, the particle size distribution may be measured by Malvern Laser diffraction method and rasagiline besylate is crystalline Form-I.

In another general aspect, there is provided crystalline Form-I of rasagiline besylate having size D(90) greater than 250 microns and D(50) greater than 100 microns. In particular, the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns.

The crystalline Form-I of rasagiline besylate may be characterized by X-ray powder diffraction (PXRD) pattern having characteristic peaks at about 5.2°, 10.4°, 13.6°, 18.1°, 19.6°, 24.1°, and 27.7° (2Θ). The crystalline Form-I of rasagiline besylate may be characterized by IR spectra having characteristic peaks at _^2985, 2812, 2360, 1479, 1444, 1182, 1124, 1016, 756 and 613 cm^"1.

The crystalline Form-I of rasagiline besylate may be further characterized by X- ray powder diffraction (PXRD) pattern with peaks at about 5.2°, 10.4°, 12.3°, 13.6°, 14.3, 15.5, 16.9, 18.1°, 18.7, 19.6°, 20.8°, 22.2°, 22.6°, 24.Γ, 25.4°, 25.7°, 26.2°, 26.9°, 27.7°, 28.1°, 28.7° and 29.6° (2Θ).

The crystalline Form-I of rasagiline besylate may be further characterized by a PXRD pattern substantially as depicted in FIG. 1.

The crystalline Form-I of rasagiline besylate may also be characterized by IR spectra 3226, 2985, 2812, 2360, 1479, 1444, 1213, 1182, 1124, 1068, 1053, 1016, 997, 756, 729, 692, 648, 613 and 567 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 2.

The crystalline Form-I of rasagiline besylate may also be characterized by DSC having endothermic peak at about 79.40°C. It may also be characterized by DSC endotherm substantially as depicted in FIG. 3.

In another general aspect, there is provided a process for the preparation of crystalline Form-I of rasagiline besylate having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, the process comprising:

(a) providing solution of rasagiline free base in one or more suitable organic solvent; (b) adding benzene sulfonic acid solution in one or more of suitable organic solvent to obtain the solution;

(c) obtaining rasagiline besylate by filtering the solution;

(d) dissolving rasagiline besylate in one or more of suitable organic solvent at elevated temperature to obtain reaction mixture;

(e) optionally stirring the reaction mixture with slow stirring rate;

(f) cooling the reaction mixture with the slow cooling rate; and

(g) obtaining the crystalline Form-I of rasagiline besylate.

In general, the process includes contacting rasagiline free base with benzene sulfonic 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- I of rasagiline besylate. The stirring RPM (rotation per minute) should be with slow stirring rate, in particular in the range of 60 to 100. The cooling should be at the rate of 20°C hour i.e. within one hour, reaction mixture may be cooled to 25°C and gradually to 10°C thereafter. The rasagiline besylate may be obtained as ^"crystalline solid by conventional technique.

The suitable solvents comprise one or more of C1-C5 alcohol solvents, esters, ketones, aromatic hydrocarbons, polar aprotic solvents, water or mixtures thereof. In particular, the Q-C5 alcohols comprises one or more of methanol, ethanol, isopropanol, butanol and the like₄ esters comprises one or more of ethyl acetate, isopropyl acetate, n- propyl acetate, butyl acetate and the like, ketones comprises one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, aromatic hydrocarbon includes toluene, xylene, ethylbenzene and the like, polar aprotic solvent includes dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl- sulfoxide and the like. More particularly esters like ethyl acetate or isopropyl acetate or alcohols like methanol or isopropanol may be used.

The embodiments of the process may optionally include addition of an anti- solvent. The suitable anti-solvent may 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 rasagiline besylate obtained may be crystallized in one or more of suitable solvents comprises of C1-C5 alcohols like methanol, ethanol, isopropanol, butanol and the like, esters like ethyl acetate, isopropyl acetate, n-propyl acetate, butyl acetate and the like, ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like to achieve the higher particle size. The recrystallization may include heating crystalline Form-I of rasagiline besylate at about 50°C while maintaining the stirring rate from 60 to 100 RPM followed by cooling within 1 hour to 25°C. The particles thus obtained upon filtration were washed with suitable solvent of recrystallization and dried for 6-8 hours at atmospherically. The product thus obtained may be sieved from 60 Mesh to achieve higher particle size.

The embodiments of the process comprises treating rasagiline free base in one or more esters solvents with benzene sulfonic acid at about 25°C to 80°C, for example, at about 10°C to about 35°C.

The crystalline Form-I of rasagiline besylate may have particle size distributions, wherein 90^th volume percentile particle size (D90) is greater than about 250 um, or any combination thereof. In particular, the crystalline Form-I of rasagiline besylate may have particle size distribution, wherein 10^th volume percentile particle size (D₁₀) is greater than about 20 m, the 50th volume percentile'particle size (D50) is greater than about 100 um and D(90) is greater than about 250 μm.

In one general aspect, the mother liquor from the process as disclosed herein above may be subjected to the recovery of crystalline Form-I of rasagiline besylate having particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

The process embodiments includes providing mother liquor containing rasagiline besylate; treating mother liquor with suitable base and water to obtain rasagiline base; dissolving the rasagiline free base in one or more suitable organic solvent; adding benzene sulfonic acid solution in one or more of suitable organic solvent to obtain the solution; obtaining rasagiline besylate by filtering the solution; dissolving rasagiline besylate in one or more of suitable organic solvent at elevated temperature to obtain reaction mixture; optionally stirring the reaction mixture with slow stirring rate; cooling the reaction mixture with the slow cooling rate; and obtaining the crystalline Form-I of rasagiline besylate.

In general, the suitable base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia and the like.

The suitable organic solvent comprises one or more of Q-C₅ alcohols selected from methanol, ethanol, isopropanol, butanol and the like, esters selected from ethyl acetate, isopropyl acetate, n-propyl acetate, butyl acetate and the like, ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, aromatic hydrocarbon selected from toluene, xylene, ethylbenzene and the like, polar aprotic solvent includes dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like. In particular, the suitable organic solvent may be ethyl acetate, isopropyl acetate, methanol, isopropanol and the like.

In another general aspect, there is provided a process for the preparation of rasagiline acid addition salts comprising reacting racemic 1-aminoindane with propargyl chloride in presence of atleast two bases in one or more of suitable organic solvent to obtain rasagiline base and converting rasagiline base to rasagiline acid addition salts.

In another general aspect, there is provided a process for the preparation of rasagiline besylate comprising reacting racemic 1-aminoindane with propargyl chloride in presence of atleast two bases in one or more of suitable orgafi¼ solvent to obtain rasagiline base and converting rasagiline base to rasagiline besylate, wherein rasagiline besylate obtained is having particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

In general, the suitable bases comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia and the like. In particular, the bases comprises of potassium carbonate and sodium hydroxide.

International (PCT) Publication No. WO 2010/0007181 A2 in example-66 and example-67 discloses preparation of rasagiline besylate Form-I by use of toluene. It discloses the isolation of white powder. However, upon repetition of the experiments as per example-66 and example-67, the resulted compound obtained was yellow powder with melting point of 63.7°C by DSC (FIG.14) and XRD (FIG.15) resembles Form-I.

The rasagiline besylate Form-I (yellow powder) with melting point 63.7°C when subjected to heat tends to become sticky and gummy mass. Hence, it may not be suitable for formulations.

In another general aspect, there is also provided a stable rasagiline besylate Form-I which does not show any discoloration and remains as crystalline white to off- white free flowing powder upon storage for 3 months at 25°C/60%RH.

In another general aspect, there is also provided stable rasagiline besylate Form-

I which does not show any discoloration and remains as crystalline white to off-white free flowing powder upon storage for 3 months at 40°C/75%RH.

In another general aspect, there is also provided a stable rasagiline besylate Form-I having a melting point in the range of 79-84°C when measured by differential scanning calorimetry.

In general, the rasagiline besylate Form-I with larger particles size prepared by the process of present invention is white to off-white free flowing powder with a melting point 79.40°C (FIG.3) and doesn't change its color under heating conditions.

Stability Data of crystalline rasagiline besylate Form-I

Interval Initial 1 Month 2 Months 3 Months

40°C±2°C/ 40°C±2°C/ 40°C±2°C/ 25°C±2°C/

Station

RH 75%±5% RH 75%±5% RH 75%±5% RH 60%±5% Test

Off-white Off-white Off-white Off-white Off-white

Description

powder powder powder powder powder

Related Substances

. Dimer ND ND ND ND ND. Amino Indane BQL BQL BQL BQL BQL. Total Impurities 0.06 0.07 0.06 0.06 0.06

Polymorphism Crystalline Crystalline Crystalline Crystalline Crystalline

ND = Not Detected

BQL = Below Quantification Limit

In another general aspect, there is also provided stable rasagiline besylate Form- 5 I which does not show increase by more than 0.5% of related impurities upon storage for 3 months at 25°C/60%RH.

In another general aspect, there is also provided stable rasagiline besylate Form- I which does not show increase by more than 0.5% of related impurities upon storage for 3 months at 40°C/75%RH.

10 In another general aspect, there is provided a crystalline rasagiline hydrobromide having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns. In particular, the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns.

In general, the particle size distribution may be measured by Malvern Laser 15 diffraction method rasagiline hydrobromide is crystalline.

In general, the crystalline rasagiline hydrobromide 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).

20 The crystalline rasagiline hydrobromide may be further characterized by X-ray powder diffraction (PXRD) pattern with peaks at about 9.3°, 11.6°, 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. 5. The crystalline rasagiline hydrobromide 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. 6.

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. 7. Thus, crystalline rasagiline hydrobromide is anhydrous.

In another general aspect, there is provided a process for the preparation of crystalline rasagiline hydrobromide having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, 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;

(e) optionally stirring the reaction mixture with slow stirring rate;

(f) cooling the reaction mixture with the slow cooling rate; and

(g) obtaining the crystalline rasagiline hydrobromide by the removal of the solvent.

In general, the suitable organic solvent comprises one or more alcoholic solvents like methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol, and the like. In particular, methanol may be used as a solvent.

The suitable anti-solvent comprises 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 to obtain reaction mixture and the 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 60°C to about 65°C. The reaction mixture is may be treated with one or more suitable anti-solvents. The stirring RPM (rotation per minute) should be with slow stirring rate, in particular in the range of 60 to 100. The rate of cooling may be at about 5°C/hour. The reaction mixture was maintained overnight and filtered. The rasagiline hydrobromide may be obtained as crystalline solid by conventional technique.

In general, 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 can be isolated by known techniques reported in the art. The crystalline rasagiline hydrobromide may be further dried.

The crystalline rasagiline hydrobromide may have particle size distributions, wherein 90^th volume percentile particle size (D₉₀) is greater than about 250 μπι, or any combination thereof. In particular, the crystalline rasagiline hydrobromide may have particle size distribution, wherein 10^th volume percentile particle size (D₁₀) is greater than about 50 um, the 50th volume percentile particle size (D50) is greater than about 100 urn.

Stability Data of crystalline rasagiline hydrobromide

ND = Not Detected

In another aspect, the present invention provides amorphous form of rasagiline 20 hydrobromide characterized by X-ray powder diffraction substantially as depicted in FIG.8 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, l,4_^dioxane, 2-methoxyethanol, and the like. In general, 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, may be used for the preparation of feed stock, for example, the crystalline rasagiline hydrobromide described herein above may 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, C_2-6 acetates, acetonitrile, methylene dichloride, water or mixtures thereof.

In another general aspect, there is provided crystalline rasagiline hydrogen phosphate having size D(90) greater than 250 microns and D(50) greater than 100 microns when measured by Malvern Laser diffraction method. In particular, the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns.

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 27.1° (2Θ) and IR spectra having characteristic peaks at S271, 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: 1°, 21.6°, 23.7°, 27.1°, and 28.8° (2Θ). The crystalline Form of rasagiline hydrogen phosphate may be further characterized by a PXRD pattern substantially as depicted in FIG. 9.

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. 10.

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 stirring RPM (rotation per minute) should be with slow stirring rate, in particular in the range of 60 to 100. The cooling should be at the rate of 5°C/hour. The reaction mixture was maintained overnight and filtered. The rasagiline hydrogen phosphate can be isolated as crystalline solid by conventional technique.

The suitable solvents comprise one or more of Q-C5 alcohol solvents, water and mixtures thereof. In particular, the C_\-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 90^th volume percentile particle size (D90) is greater than about 250 um, or any combination thereof. In particular, the crystalline rasagiline hydrogen phosphate may have particle size distribution, wherein 10^th volume percentile particle size (D|o) is greater than about 20 um, the 50th volume percentile particle size (D₅₀) is greater than about 100 urn.

Stability Data of crystalline rasagiline hydrogen phosphate

5

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 10 characterized by X-ray powder diffraction pattern having characteristic peaks at about 8.8°, 13.4°, 18.0° and 22.6° (2Θ) 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°, 15 17.3°, 24.2° and 27.2° (2Θ). The Form-I may be further characterized by a PXRD pattern substantially as depicted in FIG. 11.

The crystalline Form I of rasagiline mesylate can also be characterized by IR spectra 3277, 3221, 2667, 2588, 2351, 2127, 1627, 1481, 1207, 1155, 1047, 765, 646, 559 and 540 cm^"1. The Form-I may also be characterized by IR spectra substantially as 20 depicted in FIG. 12.

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-I. The reaction can be carried out at 25°C to about 40°C.

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'

The IR spectrum was measured by the KBr method.

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

Flow Character Hausner Ratio

Excellent 1.00-1.11

Good 1.12-1.18

Fair 1.19-1.25

Passable 1.26-1.34

Poor 1.35-1.45 Very poor 1.46-1.59

Very, very poor > 1.60

Accordingly, in one of the aspect, there is provided crystalline rasagiline hydrogen phosphate having bulk density of about 0.458 gm/rrtl 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.

In another general aspect, there is provided pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-I of rasagiline besylate having particle size D(90) greater than 250 microns and D(50) greater than 100 microns; and one or more pharmaceutically acceptable carriers, excipients or diluents.

The amount of rasagiline besylate 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.

There are various techniques available for determination of PSD. The PSD can be obtained through hot stage microscopic and sieve analysis, through laser diffraction using Malvern Mastersizer instrument using dry method as well as wet methods. In particular, laser diffraction can be chosen as final analytical method for measuring the PSD. Because the large particles were of major concern, the important characteristics of the PSD were the d(0.9), which is the size, in microns, below which 90% of the particles by volume are found, and the d (0.5), which is the size^ n microns, below which 50% of the particles by volume are found.

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form-I of rasagiline besylate having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the crystalline rasagiline hydrobromide having particle size D(90) greater than 250 microns and D(50) greater than 100 microns, and one or more pharmaceutically acceptable carriers, excipients or diluents.

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 may 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, carboxymethyl 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 not 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 may 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 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.

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.

Exam pie- 1:

Preparation of (R)-rasagiline besylate Form-I with larger particle size.

50 g of rasagiline free base and 150 mL ethyl acetate were stirred at 25°C in a round bottom flask. 57.7 g of benzene sulfonic acid solution in 180 mL ethyl acetate was added and stirred for 3 hours at about 10°C. The product was filtered and washed with ethyl acetate. The rasagiline besylate thus obtained was dissolved in 315 mL ethyl acetate at about 50°C. The stirring should be at the rate of about 100 RPM (rotation per minute). The reaction mixture was cooled to 25°C with slow cooling rate and stirred for 18 hours. The reaction mixture was further cooled to about 10°C and stirred for 2 hours. The product was filtered and washed with ethyl acetate. The wet-cake was dried at 40°C to 45°C for 6 to 8 hours. The product was sieved with 60 Mesh to obtain the crystalline Form-I of rasagiline besylate with larger particle size. The particle size distribution (PSD) was measured by the following method. The product was characterized by XRD (FIG.l), IR (FIG.2) and DSC (FIG.3). The mother liquor obtained after filtration was used for recovery of rasagiline besylate. The product was sieved through a 60 Mesh. The particle size distribution of rasagiline besylate samples^{^} s measured using Malvern Laser diffraction, using the Malvern Mastersizer 2000 instrument. The laser diffraction relies on the fact that diffraction angle of light is inversely proportional to particle size. Properties of particles are measured and interpreted as measurements of a sphere (a sphere being the only shape that can be described by one unique number). In addition, the laser diffraction calculates a particle size distribution based around volume terms, thus eliminating particle count from the determination of particle size. The PSD histogram is depicted in FIG. 4.

Dispersant Light liquid Paraffin

Instrument Malvern Mastersizer S Ver. 2.19

Analysis Model Polydisperse

Presentation 3PAE

Particle Refractive Index 1.5

Dispersant Refractive Index 1.4

Range Lens 300 mm

Beam Length 2.35 mm

Sampler MSI

Speed 2000 rpm

Sweeps 5000

Obscuration 10% to 30%

Results:

The Particle Size distribution provided in FIG.4 is a representative histogram provided herein as reference.

Example-2:

Preparation of (R)-rasagiline hydrobromide Form-I: 5 g or (R)-(+)-rasagiline base and 15 mL methanol were^ataken in a 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.5) and IR (FIG.6). The water content is less than 0.5%, which shows it is anhydrous. TGA (FIG.7)

Example-3:

Preparation of (R)-rasagiline hydrobromide Form-I with larger particle size.

150 g of Rasagiline free base and 300 mL methanol were stirred at 25°C in round bottom flask. The reaction mixture was charcoalized and stirred for 1 hour at 50°C. The reaction mixture was filtered and washed with methanol. 148 g of hydrobromic acid was added and the reaction mixture was heated at 60°C to 65°C and cooled to 50°C. 2500 mL methyl-tertbutyl ether was added to the reaction mixture and stirred for 30 minute and gradually cooled to 0°C. The stirring RPM (rotation per minute) should be in the range of 60 to 100 and cooling rate should be 5°C hour. The reaction mixture was maintained overnight and filtered. The solid thus obtained was washed with methyl tert-butyl ether. The product was dried at 50°C for 12 hours in hot air oven. The crystalline rasagiline hydrobromide (195 g) thus obtained is having larger particle size. The particle size distribution (PSD) was measured using the following method.

Rasagiline hydrobromide samples PSD were measured using Malvern Laser diffraction, using the Malvern Mastersizer 2000 instrument. Laser diffraction relies on the fact that diffraction angle of light is inversely proportional to particle size. Properties of particles are measured and interpreted as measurements of a sphere (a sphere being the only shape that can be described by one unique number). In addition, laser diffraction calculates a particle size distribution based around volume terms, thus eliminating particle count from the determination of particle size. PSD histogram is depicted in FIG. 13.

Instrument : Malvern Mastersizer 2000

Particle RI : 1.5

Absorbance : 0.1 Disparasant RI 1.375

Measurement time 12 seconds

Background time 12 seconds

Mesurement snap 12000

Background snap 12000

Stirrer speed 2000 rpm

Obscuration 10% to 30%

Delay between two measurements 180 seconds

Diluent 1% Dioctyl sulfosuccinate sodium salt in n-hexane

Example-4:

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.

Sr. No Parameters Conditions a) Feed pump 30 rprrT

b) Inlet temperature 60°C

c) Outlet temperature 40°C

d) Aspirator rate 1300 rpm

e) Vacuum for conveying the dry product 80 mm ofHg

h) Hot air supply 2 Kg/cm²

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.8)

Example-5:

Preparation of (R)-Rasagiline hydrogen phosphate Form-I

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 hour. The stirring RPM (rotation per minute) should be in the range of 60 to 100 and cooling rate should be 5°C/hour. The reaction mixture was maintained overnight and filtered. 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 was characterized by XRD (FIG.9) and IR (FIG.10).

Rasagiline hydrogen phosphate samples PSD were measured using Malvern

Laser diffraction, using the Malvern Mastersizer 2000 instrument by the method disclosed in example-2. The crystalline rasagiline hydrogen phosphate may have particle size distributions, wherein the 10^th volume percentile particle size (D₁₀) is greater than about 20 um, the 50th volume percentile particle size (D₅o) is greater than about 100 μπι, or the 90^th volume percentile particle size (D90) is greater than about 250 um, or any combination thereof.

ExampIe-6:

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 l OmL 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-7:

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.11) and IR (FIG.12). The water content is less than 0.5%, which shows it is anhydrous.

Example-8:

Preparation of (R)-Rasagiline freebase oil

(A) Preparation of 1-Indanone Oxime

In a 10 L four-necked flask fitted with a mechanical stirrer, a reflux condenser and a thermometer was placed 2500 mL of methanol, 500 g 1-indanone and 289 g hydroxylamine hydrochloride. A clear, colorless solution formed to which was added 151.2 g sodium hydroxide solution (1000 mL water). The reaction mixture was heated at 70°C to 75°C and cooled. The reaction mixture was diluted with 3000 mL water and cooled to obtain 1-indanone oxime. The product was isolated by filtration and drying. (B) Preparation of 1-Aminoindane racemic

1.5 Kg pressured ammonia gas purged into 2500 mL methanol to obtain 20 to 25% ammonia solution in 5.0 L autoclave at 10°C to 15°C. The oxime (300 g, 1.0 mole), Raney nickel catalyst (75 g) were added and the mixture hydrogenated at a constant pressure of 5 Kg pressure. A nearly theoretical amount of hydrogen had been absorbed after 24 to 30 hours at 40°C. The temperature range during hydrogenation was 40°C-42°C. The filtered methanol solution was concentrated on the rotary evaporator (maximum bath temperature, 40°C). The residue was extracted in 1000 mL methylene dichloride. The solution was cooled and acidified with cone. HC1 (10%) to adjust the pH 4 to 5. The separated aqueous layer washed with methylenedichloride was further basified with 40% sodium hydroxide to adjust the pH 9.5 to 10 at 15°C. The separated aqueous layer was further extracted with methylene dichloride. The separated organic layer was distilled and degassed to obtain racemic 1-aminoindan aS^'eil. HPLC purity > 95%.

(C) Preparation of racemic rasagiline free base

Dimethyl formamide 600 mL, 100 g of racemic 1-aminoindane, 124.2 g of potassium carbonate and 9 g sodium hydroxide were taken in round bottom flask and heated to get 40°C. 67 g of propargyl chloride was added gradually while maintaining the temperature at 40°C. The reaction mixture was heated at 65°C to 70°C stirred for 7 hours. After completion of the reaction on TLC, the reaction mixture was cooled to 25°C and acidified with 15% HC1 solution to adjust the pH 4. The separated aqueous layer was basified with 20% NaOH solution to adjust the pH 9-10. The reaction mixture was extracted with ethyl acetate 400 mL. The ethyl acetate layer was distilled under vacuum at 55°C to obtain racemic Rasagiline base as residue as yellow oil.

(D) Resolution of racemic rasagiline free base

The racemic rasagiline base 20.g and L-(+)-tartaric acid 17.5 g were taken in round bottom flask and stirred for 15 min at 25°C. The reaction mixture was heated at 65°C for 30 min and cooled to 25°C. Methyl tert-butyl ether 150 mL was added and stirred for 3 hours. The product di-(R-(+)-N-propargyl-l-aminoindan)-L-tartrate was filtered and washed with mixture of methanol and methyl tert-butyl ether. The product was dried at 55°C for 12 hours to get tartrate salt.

(E) Preparation of (R)-Rasagiline free base

50 g of di-(R-(+)-N-propargyl-l-aminoindan)-L-tartrate, 500 mL water and 16 g (40%) sodium hydroxide solution were taken in round bottom flask at room temperature. The reaction mixture was stirred and treated with 250 mL toluene to separate the layers. The separated aqueous layer was extracted with 125 mL toluene at 25°C. The combined toluene layer was dried over sodium sulfate and charcoalized with 5 g activated carbon. The reaction mixture was filtered and washed with toluene. The toluene layer was distilled completely under vacuum at 55°C to obtain R-(+)-rasagiline base as oil.

Reference Example-1: Preparation of (R)-rasagiline besylate Form-I (WO 2010/007181 A2)

Toluene (150 mL) and benzene sulfonic acid (48.95 g) were stirred for 10 minutes. The reaction mixture was heated to reflux to obtain clear solution. The reaction mixture was cooled to room temperature. Rasagiline base (50 g) in toluene (50 mL) was added to the reaction mixture at 25°C. The reaction mixnire> was stirred for 3 hours. The precipitated solid was filtered and washed with toluene (50 mL). The product was dried under vacuum in oven at 35° to 40°C to obtain 91 g pale yellow solid. DSC (FIG.14) and XRD (FIG.15).

Impurity profile

Rasagiline base = 0.23

Individual Impurity = 0.15%

Total impurities = 0.64%

HPLC Purity = 99.36%

The product upon subjecting to heat under normal stability conditions changes to sticky mass.

Reference Example-9: Preparation of (R)-rasagiline besylate Form-I (WO 2010/007181 A2 - Example-68)

Rasagiline base (0.5 g) was dissolved in 2-propanol (2 mL) at room 20 temperature. The solution obtained was light yellow. Benzenesulfonic acid (0.46 g) was added at room temperature. The solution was stirred for 3 h, but no precipitation was obtained; The solution was heated at 40°C to allow evaporation. A white wax was obtained. No solid powder isolation.

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 acid addition salts having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate.

2. Rasagijine acid addition salts having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, wherein the acid addition salt is selected from hydrobromide, hydrogen phosphate, 1,5-dinapsylate, 1-napsylate, 1,2-diesylate, 2- napsylate, besylate and ascorbate.

3. Rasagiline besylate having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

4. Rasagiline besylate as claimed in claim 3, wherein the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns.

5. Crystalline Form-I of rasagiline besylate having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

6. The crystalline Form-I of rasagiline besylate as claimed in claim 5 having an X-ray powder diffraction (PXRD) pattern comprising characteristic peaks at about 5.2°,

10.4°, 13.6°, 18.1°, 19.6°, 24. , and 27.7° (2Θ).

7. The crystalline Form-I of rasagiline besylate as claimed in claim 5 having a melting point in the range of 79-84°C when measured by differential scanning calorimetry.

8. A process for the preparation of crystalline Form-I of rasagiline besylate having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, the process comprising:

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

(b) adding benzene sulfonic acid solution in one or more suitable organic solvents;

(c) obtaining rasagiline besylate by the removal of the solvents;

(d) dissolving rasagiline besylate in one or more suitable organic solvents at an elevated temperature to get a solution;

(e) optionally stirring the solution at a slow stirring rate;

(f) cooling the solution at a slow cooling rate; and

(g) obtaining the crystalline Form-I of rasagiline besylate.

9. The process as claimed in claim 8, wherein the suitable organic solvent comprises one or more of Q-C5 alcohols selected from methanol, ethanol, isopropanol, and butanol; esters selected from ethyl acetate, isopropyl acetate, n-propyl acetate, and butyl acetate; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.

10. The process as claimed in claim 9, wherein the suitable organic solvent is ethyl acetate, isopropyl acetate, methanol, and isopropanol.

11. The process as claimed in claim 8, wherein the solution is stirred at a slow stirring rate of about 60 to 100 RPM.

12. The process as claimed in claim 8, wherein the obtained crystalline Form-I of rasagiline besylate is sieved through a 60 Mesh to obtain a particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

13. Stable rasagiline besylate crystalline Form-I which does not show any discoloration and remains as crystalline white to off-white free flowing powder upon storage for 3 months at 25°C/60%RH and/or at 40°C/75%RH.

14. Stable rasagiline besylate Form-I which does not show increase by more than 0.5% of related impurities upon storage for 3 months at 25°C/60%RH and/or at 40°C/75%RH.

15. Rasagiline hydrobromide having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

16. Rasagiline hydrobromide as claimed in claim 15, wherein the particle size D(90) is greater than 400 microns and D(50) is greater than 150 microns.

17. Rasagiline hydrobromide as claimed in claim 15 which is crystalline having an X- ray powder diffraction (PXRD) pattern comprising characteristic peaks at about 9.3°, 11.6°, 16.8°, 20.3°, 23.5°, 23.7° and 25.1° (2Θ).

18. A process for the preparation of crystalline rasagiline hydrobromide having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, the process comprising:

(b) adding hydrobromic acid to get a reaction mixture;

(c) heating the reaction mixture;

(d) adding one or more suitable anti-solvents; (e) optionally stirring at a slow stirring rate;

(f) cooling at a slow cooling rate; and

19. The process as claimed in claim 18, wherein the suitable organic solvent comprises one or more of alcoholic solvents like methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, and dodecanol.

20. The process as claimed in claim 18, wherein the suitable anti-solvent comprises one or more of hydrocarbons selected from toluene, xylene, ethylbenzene, n-hexane, heptane, and cyclohexane; ethers selected from diisopropylether, methyltert-butyl ether, and tetrahydrofuran; and esters selected from ethyl acetate, butyl acetate, and isopropyl acetate.

21. The process as claimed in claim 18, wherein the reaction mixture is stirred at a slow stirring rate of about 60 to 100 RPM.

22. A process for the preparation of rasagiline acid addition salts comprising reacting racemic 1-aminoindane with propargyl chloride in the presence of at least two bases in one or more of suitable organic solvents to obtain rasagiline base and converting the rasagiline base to rasagiline acid addition salts.

23. A process for the preparation of rasagiline besylate comprising reacting racemic 1- aminoindane with propargyl chloride in the presence of at least two bases in one or more of suitable organic solvent to obtain rasagiline base and converting the rasagiline base to rasagiline besylate, wherein the rasagiline besylate obtained is having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns.

24. The process as claimed in claim 29, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, and the like.

25. The process as claimed in claim 30, wherein the base comprises potassium carbonate and sodium hydroxide.

26. A pharmaceutical composition comprising a therapeutically effective amount of a rasagiline acid addition salt having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate; and one or more pharmaceutically acceptable carriers, excipients or diluents.

27. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form-I of rasagiline besylate having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns; and one or more pharmaceutically acceptable carriers, excipients or diluents.

28. A pharmaceutical composition comprising a therapeutically effective amount of crystalline rasagiline hydrobromide having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns; and one or more pharmaceutically acceptable carriers, excipients or diluents.