WO2011095985A2

WO2011095985A2 - Rasagiline salts and processes for the preparation thereof

Info

Publication number: WO2011095985A2
Application number: PCT/IN2011/000059
Authority: WO
Inventors: Sunil Sudhakar Zope; Colony Deshmukh; Laxmikant Madhukar Kelkar; Joseph Prabahar Koilpillai; Milind Moreshwar Gharpure
Original assignee: Glenmark Generics Limited
Priority date: 2010-02-02
Filing date: 2011-01-28
Publication date: 2011-08-11
Also published as: WO2011095985A3

Abstract

The present invention relates to crystalline salts of rasagiline and processes for the preparation thereof. The invention also relates to pharmaceutical compositions comprising the same.

Description

RASAGILINE SALTS AND PROCESSES FOR THE PREPARATION THEREOF

PRIORITY

[0001] This application claims the benefit of IN 242/MUM/2010 filed on February

2, 2010, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] . The present invention relates to salts of rasagiline and processes thereof. More particularly the present invention relates to crystalline salts of rasagiline and pharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION

[0003] Rasagiline, the R (+) enantiomer of n-propargyl-l -aminoindane, is an irreversible inhibitor of monoamine oxidase (MAO), which is approved as mesylate salt for the treatment of idiopathic Parkinson's disease. Rasagiline mesylate salt is administered X either as a monotherapy or as an adjunct with other treatments for various other conditions by inhibition of MAO-B in the brain. Rasagiline mesylate salt is available in the market in tablet form in dosage strengths of 0.5mg and l mg. Rasagiline mesylate is chemically described as 5-N-propargyl-l -(R)-aminoindan mesylate and is represented by the structural formula

[0004] U.S. Patent No. 3,51 3,244 describes propargylated aminoindans including racemic rasagiline and their pharmaceutically acceptable salts thereof.

• [0005] U.S. Patent No. 5,532,415 (US^'415) describes optically pure rasagiline and its pharmaceutically acceptable salts thereof. US^'415 describes specifically mesylate, esylate and sulfate salts of R (+) rasagiline.

[0006] U.S. Patent No. 6,956,060 describes tartrate salt of R(+) rasagiline. [0007] U.S. Patent. No. 7,547,806 describes tannate salt of R(+) rasagiline.

[0008] European publication application EP2054048 describes generically carboxylic acid and sulfonic acid salts of R(+) rasagiline such as edisilate, oxalate salts.

[0009] There are several concerns associated with the commercially available form of rasagiline mesylate. One of them is the potential for formation of genotoxic alkyl mesylates when rasagiline is treated with methanesulfonic acid in alcohol while preparing the rasagiline mesylate. One of the ways to solve this problem is to prepare alternate salts of rasagiline. There is a need in the art for the preparation of additional salt forms of rasagiline.

SUMMARY OF THE INVENTION

[0010] The present invention relates to crystalline salts of rasagiline and processes for the preparation thereof. The invention also relates to pharmaceutical compositions comprising the same.

[0011] The present invention provides a process for the preparation of the phosphate salt of rasagiline comprising:

(a) combining rasagiline and phosphoric acid in a solvent or mixture of solvents or

aqueous mixtures thereof; and

(b) isolating the rasagiline phosphate salt in crystalline form.

[0012] The present invention provides a phosphate salt of rasagiline characterized by data selected from the group consisting of an^' X-ray powder diffraction (XRPD) pattern, which is substantially in accordance with Fig. l ; a solid state ^{l 3}C nuclear magnetic resonance (¹³CNMR) spectr-unv which is substantially in accordance with Fig. 2; a Fourier transform infrared (FTIR) spectrum, . which is substantially in accordance with Fig.3; a differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Fig. 4; a thermogravimetric analysis (TGA) endotherm curve, which is substantially in accordance with Fig. 5; and a combination thereof.

[0013] The present invention provides a benzoate salt of rasagiline characterized by data selected from the group consisting of an X-ray powder diffraction(XRPD) pattern, which is substantially in accordance with Fig.8; a Fourier transform infrared (FTIR) spectrum, which is substantially in accordance with Fig.9; a differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Fig. 10; a thermogravimetric analysis (TGA) endotherm curve, which is substantially in accordance with Fig. l l .

[0014] The present invention provides a mandelate salt of rasagiline characterized by data selected from the group consisting of an X-ray powder diffraction (XRPD) pattern, which is substantially in accordance with Fig.12; a Fourier transform infrared ( FTIR) spectrum, which is substantially in accordance with Fig.13; a differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Fig. 14; a thermogravimetric analysis (TGA) endotherm curve, which is substantially in accordance with Fig. 15.

[0015] The present invention provides oxalate salt of rasagiline characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.3, 1 1 .4, 13.1 , 15.9, 16.2, 17.3, 18.7, 19.9, 21.9, 23.1 , 23.6, 24.0, 26.5 and 29. 1 ± 0.2 degree 2 theta .

[0016] The present invention provides a process for the preparation of salts of rasagiline comprising:

(a) combining rasagiline and acid in a solvent or mixture of solvents or aqueous mixtures thereof; and

(b) isolating the rasagiline salt in crystalline form.

[0017] The present invention provides crystalline rasagiline phosphate, rasagiline benzoate, rasagiline oxalate and rasagiline mandelate having a chemical purity of greater than about 99%, as measured by high performance liquid chromatography (HPLC).

[0018] The present invention advantageously provides a process for the preparation of salts of rasagiline in relatively high purity, of greater than about 98 %; and preferably greater than about 99%, as determined by chiral HPLC.

BRIEF DESCRIPTION OF THE FIGURES

[0021] Fig. 1 : is an X-ray powder diffraction pattern of crystalline rasagiline phosphate of the present invention.

[0022] Fig. 2: is ¹³C NMR spectrum of crystalline rasagiline phosphate of the present invention.

[0023] Fig. 3 is a FT Infrared spectrum of crystalline rasagiline phosphate of the present invention. [0024] Fig. 4: is a Differential scanning calorimetry endotherm of crystalline rasagiline phosphate of the present invention.

[0025] Fig. 5: is a Thermogravimetric analysis curve of crystalline rasagiline phosphate of the present invention.

[0026] Figure 6 is a particle size distribution histogram of crystalline rasagiline phosphate

[0027] Figure 7 is Scanning electron micrograph (SEM) of of crystalline rasagiline phosphate

[0028] Fig. 8: is an X-ray powder diffraction pattern of crystalline rasagiline benzoate of the present invention.

[0029] Fig. 9: is an Infrared spectrum of crystalline rasagiline benzoate of the present invention.

[0030] Fig. 10: is a Differential scanning calorimetry endotherm of crystalline rasagiline benzoate of the present invention.

[0031] Fig. 1 1 : is a Thermogravimetric analysis curve of crystalline rasagiline benzoate of the present invention.

[0032] Fig. 12: is an X-ray powder diffraction pattern of crystalline rasagiline mandelate of the present invention.

[0033] Fig. 13: is an Infrared spectrum of crystalline rasagiline mandelate of the present invention.

[0034] Fig. 14: is a Differential scanning calorimetry endotherm of crystalline rasagiline mandelate of the present invention.

[0035] Fig. 15: is a Thermogravimetric analysis curve of crystalline rasagiline mandelate of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention relates to crystalline salts of rasagiline and processes thereof. The invention also relates to pharmaceutical compositions comprising these crystalline salts.

[0037] In the pharmaceutical realm, there are often major hurdles to overcome before an active pharmaceutical ingredient (API) can be formulated into a composition that can be marketed. For example, the rate of dissolution of an API that has poor aqueous solubility poses manufacturing and bioavailability challenges. The aqueous solubility may be a major influence on the bioavailability of the API, where a poorly soluble API may affect the bioavailability of the API. Additionally, flowability, compactability and stickiness are factors likewise affected by the solid state properties of an API.

[0038] It has thus always been an aim of the pharmaceutical industry to provide many forms of an API in order to mitigate the hurdles described above. The forms of an API that can have different physicochemical and biological characteristics include different salts, crystalline forms or polymorphs, amorphous forms, solvates and hydrates. It would therefore be advantageous for the medicinal chemist to have a wide repertoire of alternative salts and crystalline forms of these and other known salts to aid in the preparation of products that are both efficacious and safe.

[0039] The preparation of various salts and morphs of a pharmaceutically useful compound, like rasagiline, provides a new opportunity to improve the performance characteristics of the ensuing pharmaceutical product. It widens the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

[0040] It would be beneficial to improve the thermodynamic properties of rasagiline by providing other salt forms of rasagiline, which have consistent physical and chemical properties. The invention seeks to provide these and other benefits, which will become apparent as the description progresses.

[0041] Beneficially, salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug without modifying its chemical structure. A salt form can have a dramatic influence on the properties of the drug. The selection of a suitable salt is partially dictated by yield, rate and quantity of the crystalline structure. In addition, hygroscopicity, stability, solubility and the process profile of the salt form are important considerations. The identification of a salt form that exhibits a suitable combination of properties can be difficult.

[0042] Solubility is one important characteristic of a salt form that can affect its suitability for use as a drug. Where aqueous solubility is low, i.e. less than 10 mg/ml, the dissolution rate at in vivo administration can be rate limiting in the absorption process leading to poor bioavailability. Hygroscopicity is also an important characteristic. Compounds having low hygroscopicity tend to have better stability and easier processing.

[0043] On the other hand, polymorphism can be characterized as the ability of a compound to crystallize into different crystal forms, while maintaining the same chemical formula. A crystalline polymorph of a given drug substance is chemically identical to any other crystalline polymorph of that drug substance in containing the same atoms bonded to one another in the same way, but differs in its crystal forms, which can affect one or more physical properties, such as stability, solubility, melting point, bulk density, flow properties, bioavailability, etc.

[0044] Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.

[0045] The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability. These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance.

[0046] Thus, an API's properties may be enhanced by its form or state; consequently manifesting said properties into the pharmaceutical product into which it is made.

[0047] In one embodiment, the present invention provides a phosphate salt of rasagiline characterized by data selected from the group consisting of an X-ray powder diffraction (XRPD) pattern, which is substantially in accordance with Fig. l ; ¹³C nuclear magnetic resonance ( CNMR) spectrum, which is substantially in accordance with Fig. 2; a Fourier transform infrared (FTIR) spectrum, which is. substantially in accordance with Fig.3; a differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Fig. 4; a thermogravimetric analysis (TGA) endotherm curve, which is substantially in accordance with Fig. 5; and a combination thereof.

[0048] In one embodiment, the present invention provides a phosphate salt of rasagiline characterized by data selected from the group consisting of an X-ray powder diffraction pattern having characteristic peaks at about 5.4, 7.1 , 7.9, 9.9, 10.8, 16.5, 19.9, 21.6, 22.2, 23.9 and 27.2 + 0.2 degree 2 theta, which is substantially in accordance with Fig. 1.

[0049] In one embodiment, the present invention provides a phosphate salt of rasagiline that exhibits a ¹³C NMR spectrum with signals at about 30.38, 32.07, 35.47,61.42, 75.49, 81.75,125.02, 125.08, 126.55, 128.14, 143.57, 144.20 ppm.

[0050] In yet another embodiment of the present invention the rasagiline phosphate described herein is a hemiphosphate.

[0051] In yet another embodiment of the rasagiline phosphate described herein the rasagiline content in the rasagiline phosphate is in the range of about 75% to about 80% by weight based on the total weight of rasagiline phosphate.

[0052] In another embodiment, the present invention provides a process for the preparation of phosphate salt of rasagiline comprising:

aqueous mixtures thereof; and

(b) isolating the rasagiline phosphate salt in crystalline form.

[0053] As used herein, a solvent is any liquid substance capable of dissolving rasagiline or salt thereof.

[0054] As used herein a mixture of solvents refers to a composition comprising more than one solvent.

[0055] In (a) above, the solution of rasagiline can be obtained by dissolving rasagiline in a solvent or mixture of solvents or their aqueous mixtures.

[0056] The solvent may be selected from the group consisting of C₃-Ci o aliphatic ketones; C i -C₆ chlorinated hydrocarbons; C i -C₆ aliphatic alcohols; C3-C 10 aliphatic esters; C₂-C₅ aliphatic nitriles; ethers; and mixtures thereof or aqueous mixtures aprotic polar solvents may include N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N- dimethylacetamide (DMA) and the like.

[0057] In an embodiment the solvents that can be used include, but are not limited to ; Ci -C₆ aliphatic alcohols selected form the group consisting of methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; C3-C 10 aliphatic ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; C₂-C₅ aliphatic nitriles such as acetonitrile, propionitrile and the like; C₃-C i₀ aliphatic esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions or their aqueous mixtures.

[0058] In an embodiment the solvents that can be used include C ] -C₆ aliphatic alcohols selected form the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; preferably, isopropanol is used.

[0059] There is no specific order in which the rasagiline base and the phosphoric acid must be combined in the solvent to form the solution. Generally the conditions are such that all of the rasagiline (and all of the acid) is dissolved in the solvent, though strictly speaking such is not required; i.e., some amount of solid or immiscible rasagiline may be present in the solution. The dissolution of rasagiline base in the solvent is advantageously performed at an enhanced temperature, which includes the reflux temperature of the solvent. The contacting or combining of the rasagiline-containing solvent with the acid is advantageously performed at an ambient or higher than ambient temperature, including the reflux temperature of the solvent. In other embodiments, the acid can be added, e.g., substantially at the same time as the base, before the base, etc. ,

[0060] The temperature for obtaining a clear and homogenous solution can range from about 25°C to about 75°C or at the boiling point of the solvent/s used. Preferably from about 25°C to about 40°C.

[0061] The rasagiline base or salt thereof used in forming the rasagiline salt of present invention can be any form or morph, including rasagiline hydrate, in any degree of purity. The starting rasagiline base can also be crude rasagiline that is present in the reaction mixtures obtained after the chemical synthesis of rasagiline.

[0062] The phosphoric acid used is preferably an 85% phosphoric acid. The molar ratio of rasagiline to phosphoric acid is in the range of about 1 : 0.3 to about 1 :0.5.

[0063] The solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.

[0064] The isolation of the rasagiline salt in crystalline form can be accomplished in various ways. For example, the precipitation can occur spontaneously upon contacting of the rasagiline with the acid in the organic solvent. Precipitating of the rasagiline acid addition salt can also be induced by seeding the solution, cooling the solution, stirring at the same temperatures for longer time period evaporating at least part of the solvent, adding an antisolvent, and by combining one or more of these techniques. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.

[0065] The antisolvents include, but are not limited to, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene and the like or mixtures thereof in various proportions without limitation. Preferably, n-hexane.

[0066] Advantageously the volume of solvent and antisolvent used to precipitate the solid can range from about 5 volumes to about 100 volumes with reference to starting compound taken. Preferably, from about 40 volumes to about 60 volumes with reference to starting compound are taken.

[0067] In one embodiment, the range of solvent to antisolvent is from about 1 :7.

Preferably, about 1 :4.

[0068] The order of addition is immaterial, where the solution of rasagiline or salt thereof may be added to the antisolvent or the antisolvent may be added to the solution of rasagiline or salt thereof to precipitate the solid.

[0069] The temperature for precipitation of solid can range from about -10°C to about 35°C. Preferably, from about 25°C to about 35°C.

[0070] The precipitated rasagiline acid addition salt can be isolated from the solution by conventional techniques, e.g. filtering or centrifugation, and can be washed and dried.

[0071] In an embodiment of the process of the present invention rasagiline base is reacted with 85% phosphoric acid in mole ratio of about 1 :0.4 in a C]-C₆ aliphatic alcoholic solvent like, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol at ambient temperatures. The phosphoric acid can be added to rasagiline base directly or predissolved into an organic solvent and added. The resultant reaction mass is maintained at ambient temperatures for about 2-3 hours optionally under stirring. The resultant solid rasagiline phosphate can be isolated by filtration or centrifugation.

[0072] The crystalline rasagiline phosphate salt prepared in an embodiment as described above has phosphate content in the range of about 22% to about 23%. [0073] The crystalline rasagiline phosphate salt prepared in an embodiment as described above has rasagiline content in the rasagiline phosphate between 77% to 78%. by weight based on the total weight of rasagiline phosphate.

[0074] The isolated rasagiline salt can, however, be purified if desired. For example, the isolated salt is recrystallized or reprecipitated by dissolving (at least partially, e.g., suspending) the isolated salt in a solvent, such as any of the above defined polar organic solvents, at an enhanced temperature (which includes a reflux temperature of the solvent), and then crystallizing or precipitating the salt from the solvent or by washing the isolated salt with a solvent. The recrystallization (reprecipitation) process may be repeated until a desired purity of the isolated rasagiline acid addition salt is obtained. For clarity, the terms "purify", "purification", "purified" and variations thereof are used herein to indicate an improvement in the quality or purity of the substance and are not meant in the narrow sense of obtaining near absolute purity. The crystalline salts of rasagiline obtained by the above processes may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents. When implemented, the preferred instrument is a vacuum tray dryer. Preferably, vacuum tray dryer.

[0075] The substantially pure solid crystalline salt of rasagiline phosphate, can be dried at temperatures from about 25°C to about 75° C, preferably from about 25° C to about 50°C and at reduced pressure of about 5 mbar to about 20 mbar, preferably, about 5 mbar to about 10 mbar, for about 1 hour to about 48 hours, preferably about 10 hours to about 15hours. Preferably, at about 50°C and at reduced pressure of about 5 mbar for about 30 minutes to about 2 hours.

[0076] Generally the crystalline salts of rasagiline of the present invention can be obtained in a stable solid state form making them useful for purification, bulk storage, or use in pharmaceutical compositions and methods of treatment.

[0077] In one embodiment, the present invention provides a benzoate salt of rasagiline characterized by data selected from the group consisting of a powder X-ray diffraction pattern, which is substantially in accordance with Fig.8; an IR spectrum, which is substantially in accordance with Fig.9; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Fig. 10; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Fig. 1 1 . [0078] In a still further embodiment, the present invention provides benzoate salt of rasagiline characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.1 , 12.3, 16.7, 17.6, and 18.9 + 0.2 degree 2 theta, which is substantially in accordance with Fig.6.

[0079] In yet another embodiment, the present invention provides mandelate salt of rasagiline characterized by data selected from the group consisting of a powder X-ray diffraction pattern, which is substantially in accordance with Fig.12; an IR spectrum, which is substantially in accordance with Fig.13; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Fig. 14; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Fig. 15.

[0080] In a still further embodiment, the present invention provides mandelate salt of rasagiline characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 10.7, 1 1.1 , 17.2, 19.4 and 19.6 ± 0.2 degree 2 theta, which is substantially in accordance with Fig.12.

[0081] In another embodiment, the present invention provides oxalate salt of rasagiline characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.3, 1 1.4, 13.1 , 15.9, 16.2, 17.3, 18.7, 19.9, 21 .9, 23.1 , 23.6, 24.0, 26.5 and 29.1 ± 0.2 degree 2 theta .

[0082] In another embodiment, the present invention provides a process for the preparation of salts of rasagiline comprising:

(b) isolating the rasagiline salt in crystalline form.

[0083] The acid used can be selected from mandelic acid, benzoic acid and oxalic acid and the process and isolation of the respective salts is similar to that of phosphate salt of rasagiline which is described herein.

[0084] The present invention provides the process of preparation of purified rasagiline comprising obtaining solid crystalline salts of rasagiline, prepared in the process herein described and converting said salts back to purified rasagiline. Crude rasagiline may be purified by converting it initially to a rasagiline salt, by the process as described above and then converting the rasagiline salt back into rasagiline base. [0085] The present invention provides the process of preparation of purified rasagiline base comprising (a) combining crude rasagiline and an acid in a first solvent, preferably a polar organic solvent, to obtain an acid addition salt of rasagiline; (b) isolating the acid addition salt of rasagiline in solid state from the first solvent; (c) converting the rasagiline acid addition salt into rasagiline base in a second solvent, preferably an aqueous solvent; and (d) isolating the rasagiline base from said second solvent.

[0086] Structurally related impurities present in the crude rasagiline are generally soluble in the organic solvents used to form the acid addition salt, and thus these impurities may generally remain in the first solution during the isolation of the solid rasagiline acid addition salt; subsequently, these impurities will be separated from the rasagiline moiety. The conversion to rasagiline base, especially in an aqueous-based solvent, can likewise provide a further purification effect with respect to water-soluble impurities.

[0087] "Crude rasagiline" means a rasagiline base or salt having insufficient purity and includes reaction mixtures obtained after the chemical synthesis of rasagiline. From a practical standpoint, the crude rasagiline is typically a rasagiline base including hydrates and solvates thereof. Likewise, the produced "rasagiline base," which has an enhanced purity or quality relative to the crude rasagiline, includes hydrates and solvates of rasagiline base and specifically includes rasagiline monohydrate. The above recited process guidelines are not exhaustive; additional steps may also be included. For example, the acid addition salt of rasagiline can itself be purified, such as by (re)crystallization as described above, before being converted to rasagiline base.

[0088] The isolated solid crystalline salts of rasagiline can be converted into rasagiline base by any suitable or convenient technique. Generally, the solid salt is dissolved and/or suspended in the second solvent and converted to the rasagiline base, optionally via the use of an inorganic or organic base.

[0089] The second solvent is preferably more polar than the first solvent.

Advantageously, the second solvent is an aqueous-based solvent in which rasagiline base is insoluble. Such solvents include water as well as water-miscible solvents and combinations thereof.

[0090] The organic or inorganic base used to convert the salt of rasagiline to rasagiline base is preferably a base that binds the acid present in the second solvent to form a salt that is soluble in the second solvent. Suitable bases include sodium and potassium hydroxide. Upon addition of the base to the salt-containing second solvent, rasagiline generally precipitates in a solid form. The precipitated and purified rasagiline can then be isolated from the reaction mixture, e.g., by filtration or centrifugation, and is optionally washed and dried.

[0091] In one embodiment, the present invention provides a process for a conversion of crystalline salts of rasagiline described herein to rasagiline mesylate salt comprising a) treating the salt of rasagiline with an organic or inorganic base in a solvent or mixture of solvents to form pure rasagiline base; b) reacting the obtained pure rasagiline base with methane sulfonic acid in a solvent or mixture of solvents; c) obtaining highly pure rasagiline mesylate.

[0092] In a), the base that can be used include but not limited to any inorganic or organic base. Preferably potassium carbonate.

[0093] In b), the solvent for extraction of rasagiline base is preferably water and any inert aprotic solvent, such as methylene chloride.

[0094] The present invention provides a rasagiline base prepared by the process directly described herein having a purity greater than about 98 % area, as measured by high performance liquid chromatography (HPLC), more preferably greater than about 99% area as measured by HPLC.

[0095] The present invention provides a rasagiline mesylate prepared by the process directly herein described having purity greater than about 98 % area, as measured by HPLC, more preferably greater than about 99% area as measured by HPLC.

[0096] The present invention provides crystalline rasagiline phosphate, rasagiline benzoate, rasagiline oxalate and rasagiline mandelate having a chemical purity of greater than about 99%, as measured by high performance liquid chromatography (HPLC).

[0097] The present invention provides rasagiline crystalline salts containing less than about 0.5%, of corresponding impurities as characterized by HPLC. Preferably, less than about 0.1 %. The percentage, as used herein, refers to weight percent obtained from the area % of the peaks representing the impurities, as measured by HPLC. The crystalline salts of rasagiline of present invention are substantially free of other process-related impurities.

[0098] The present invention provides crystalline rasagiline phosphate, having a chemical purity of greater than about 99.9% (as measured by HPLC). [0099] The present invention provides crystalline rasagiline phosphate, rasagiline benzoate, rasagiline oxalate and rasagiline mandelate having a polymorphic purity of greater than 99% (as measured by XRPD or DSC).

[00100] The present invention advantageously provides a process for the preparation of salts of rasagiline in relatively high purity, of greater than about 98 %; and preferably greater than about 99%, as determined by chiral HPLC.

[00101] The present invention provides crystalline rasagiline phosphate, having enantiomeric purity greater than about 99.9 percent by weight, as measured by high performance liquid chromatography.

[00102] Advantageously, the crystalline salt forms of rasagiline of the present invention exhibit an excellent flowability, which might enhance their pharmaceutical properties as compared with the rasagiline mesylate salt that is currently marketed. Thus, the selected group of rasagiline salts of the present invention are better handled and processed during milling and formulating, as compared with the rasagiline mesylate salt that is currently marketed. Consequently, the crystalline salt forms of rasagiline of the present invention are more suitable for pharmaceutical formulation use.

[00103] Further, the crystalline salt forms of rasagiline of the present invention exhibit a high solubility profile in water, and hence also show enhanced pharmaceutical properties regarding the dissolution rate and bioavailability.

[00104] in addition, the crystalline salt forms of rasagiline of the present invention have been found to be stable. This stability is manifested visually, and by analytical determination of chemical purity and of polymorphic form, either at normal storage conditions or at accelerated stability conditions of temperature and relative humidity (40 C and 75% RH) for at least about 10 months to about 24 months. The stable attribute of the crystalline salts of the present invention makes them viably suitable for pharmaceutical formulation use.

[00105] The characterization techniques employed for solid salt forms of rasagiline of the present invention utilized, but not limited to, determinations using powder X-ray diffraction pattern (XRD), ^{l 3}C NMR spectrum and Fourier Transform Infrared (FTIR) spectra.

[00106] The physical attributes of salts are established to correlate with the pharmaceutical product in which they will be utilized. Herein, the crystalline rasagiline salts' attributes include the measurement done via DSC, TGA, XRPD, IR. These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which define a particular polymorphic form of a substance. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x- ray crystallography, solid state ¹³C NMR spectrometry, and infrared spectrometry.

[00107] The crystalline salts of rasagiline of the present invention are characterized by X-ray powder diffraction, which were performed on a Philips X'pert PRO Diffractometer using Cu K radiation (Cu Κα1 = 1 .54060A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded at start angle from 2° to 50° 2Θ, a step size 0.0167° with a time per step of 1000 seconds.

[00108] ^{l 3}C NMR spectrum was recorded in DMSO d₆ using 100 MHz

Bruker 400 NMR spectrometer.

[00109] TGA analysis was recorded on TGA Q500 V6.5. Thermogram was recorded at 30-350°C at the rate of 10°C/min. Nitrogen flow was l OOml/min.

[00110] The crystalline salts of rasagiline of the present invention are characterized by differential scanning calorimetry as follows:

[00111] Approximately l -5mg of sample was accurately weighed into an aluminum

DSC pan with lid. The sample was placed then into a Mettler Toledo DSC822^C equipped with a liquid nitrogen cooling unit and allowed to equilibrate at 30°C until stable heat flow response was seen. A dry nitrogen purge gas at a flow rate of 50ml/min was used to produce the inert atmosphere and prevent oxidation of the sample during heating. The sample was scanned from 50-250°C at rate of 10°C/min and resulting heat flow response was measured against temperature.

[00112] Infrared Spectra (IR) Fourier transform IR spectra were acquired on a

Perkin Elmer, and samples were characterized in potassium bromide pellets.

[00113] The purity of the above described crystalline salts of rasagiline have been analysed by following method:

[00114] Related substances by HPLC for final:

Reagents, Solvents and Standards: Water (MilliQ or equivalent)

Octane sulfonic acid sodium salt (GR grade)

Triethylamine (For synthesis)

70%Perchloric acid (GR Grade)

Methanol (HPLC grade)

Acetonitrile (HPLC grade)

Chromatographic Conditions:

Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.

Column: C₈ Zorbax SB, 250 X 4.6mm, 5μ (Part No: 880975-906)

Column temperature: 25°C

Mobile Phase:

Mobile phase A = Buffer

Buffer : 1 ml of Triethylamine and 1 gm of Octane sulfonic acid sodium salt in 1000ml of water. Adjust pH to 2.5 with diluted Perchloric acid.

Mobile Phase B = Methanol

Time (min.) % Mobile Phase A % Mobile Phase B

0.0 60 40 15 55 45

25 55 45

40 35 65

50 35 65

53 60 40 60 60 40

Diluent: Buffer : Acetonitrile (90 : 10, v/v) ; Flow Rate : 1.OmL/minute; Detection : UV 210nm;

Injection Volume: Ι Ομί

[00115] Preparation of Reference solution (a) Transfer about 75.0mg of R-

Rasagiline mesylate in-house reference standard, accurately weighed into a 50mL volumetric flask. Add about 25-30 mL of diluent and sonicate to dissolve. Make up to the mark with diluent and mix. Dilute 5ml of this solution to 100ml with diluent and mix. Further dilute 2ml of this solution to 100ml with diluent and mix.

[00116] Preparation of Reference solution (b) Transfer about 1 5.0mg of 1 - aminoindane impurity standard, accurately weighed into a l OOmL volumetric flask. Add about 50-60 mL of diluent and sonicate to dissolve. Make up to the mark with diluent and mix.

[00117] Preparation of Reference solution (c) Transfer about 15.0mg of Dimer impurity standard, accurately weighed into a 1 OOmL volumetric flask. Add about 50-60 mL of diluent and sonicate to dissolve. Make up to the mark with diluent and mix.

[00118] Preparation of reference solution (d) Transfer about 1 50.0mg of R- Rasagiline mesylate in-house reference standard, accurately weighed into a l OOmL volumetric flask. Add about 50-60mL of diluent and sonicate to dissolve. Add 1 .5ml of reference solution (b) and reference solution (c). Make up to the mark with diluent and mix.

[00119] Preparation of Test solution. Transfer about 75.0 mg of sample, accurately weighed into a 50 mL volumetric flask. Add about 25-30 mL of diluent and sonicate to dissolve. Make up to the mark with diluent & mix.

[00120] Separately inject the equal volumes of blank (diluent), reference solution (d) and six replicate injections of reference solution (a). Then inject test solution in duplicate and record the chromatogram for all injections eliminating the peaks due to blank. Identify the peaks corresponding to 1 -aminoindane impurity & Dimer impurity from reference solution (d) chromatogram. The retention time of main peak is about 19.4 minutes, retention time of 1 -aminoindane impurity is about 16.9 minutes and retention time of Dimer impurity is about 23.0 minutes under these conditions.

[00121] System suitability test

The relative standard deviation determined from the six replicate injections of reference solution (a) is not more than 5.0%. Resolution between 1 -aminoindane and main peak is not less than 2.0 and resolution between main peak and dimer impurity is not less than 3.0 from reference solution (d).

[00122] The chiral purity of the above described crystalline salts of rasagiline have been analyzed by following method

Stereochemical purity by HPLC Reagents, Solvents and Standards: n-Hexane (HPLC Grade, Merck); Ethanol 99.9% (Analysis reagent); Diethylamine (GR Grade)

Chromatographic Conditions:

Column: Chiralpak AD-H, 250 X 4.6mm

Column temperature: 30°C ; Mobile Phase : n-Hexane : Ethanol : Diethylamine (94 : 06 : 0.02, v/v)

Diluent : Mobile phase; Flow Rate : 0.5mL / minute ; Detection: UV 210nm ; Injection Volume: 20μΤ ; Run time: 35 minutes

Preparation of Blank solution

Transfer about 2 ml of ethanol into a 100ml volumetric flask. Make up to the mark with diluent and mix.

Preparation of Test solution

Transfer about 50.0 mg of sample, accurately weighed into a 100ml volumetric flask. Add

2 ml of ethanol and sonicate to dissolve. Add about 50-60 ml of diluent and mix. Make up to the mark with diluent and mix.

Preparation of Reference solution (a) :

Transfer about 50.0 mg of R-Rasagiline Mesylate in-house reference standard, accurately weighed into a lOOmL volumetric flask. Add 2 ml of ethanol and sonicate to dissolve. Add about 50-60mlof diluent and mix. Make up to the mark with diluent and mix. Dilute 5ml of this solution to 100ml with diluent and mix. Further dilute 2 ml of this solution to 100ml with diluent and mix.

Preparation of Reference solution (b) :

Transfer about 5.0mg of racemic mixture of R-Rasagiline Mesylate standard into a l OOmL volumetric flask. Add 2mL of ethanol and sonicate to dissolve. Add about 50-60mlof diluent and mix: Make up to the mark with diluent and mix.

Preparation of Reference solution (c)

Transfer about 50.0mg of Rasagiline Mesylate standard into a l OOmL volumetric flask.

Add 2mL of ethanol and sonicate to dissolve. Add 5ml of reference solution (b) and mix.

Make up to the mark with diluent and mix. Procedure

Separately inject the equal volumes of blank (diluent), reference solution (c) and six replicate injections of reference solution (a). Then inject test solution in duplicate and record the chromatogram for all injections eliminating the peaks due to blank. The retention time of main peak i.e. R-isomer is about 14.9 minutes and retention time of other isomer i.e. S-isomer peak is about 12.9 minutes under these conditions.

System suitability test

The relative standard deviation determined from the reference solution (c) in six replicate injections should not more than 5.0% and resolution between the S-isomer peak and R-isomer peak from reference solution (c) chromatogram should not be less than 2.0 and theoretical plate of the main peak should not be less than 3000.

[00123] The crystalline salts of rasagiline of the present invention have residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia; the recommended amount is less than 5000 ppm for ethanol, isopropanol, methanol, ethyl acetate and acetone; less than 800ppm for toluene, dichloromethane, dimethyl formamide and diisopropyl ether. Preferably, the amount is less than about 3000 ppm residual organic solvent, more preferably less than about 2000 ppm residual organic solvent, most preferably, less than about 1000 ppm.

(00124] The present invention provides that the crystalline salts of rasagiline may exist as enantiomers and may include racemic mixtures and stereo-isomerically pure forms of the same.

[00125] The term "about", as used herein for example relative to residual organic solvent, generally means within 10%, preferably within 5%, and more preferably within 1 % of a given value or range. Alternatively, the term "about", means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art.

[00126] The present invention advantageously provides crystalline salts of rasagiline, obtained by the processes herein described, having high stability at any given temperature and relative humidity for any given time period.

[00127] It is generally known that drug particles from a crystallization process may have large and irregular shapes. Although a drug substance is normally measured by weight, volume also plays an important role during the tablet formation process. As such, large and irregularly-shaped particles can easily decrease content uniformity.

[00128] Particle sizes of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle size and size distribution. This will be even more critical for low-dose drugs and satisfactory dosage units of low doses cannot be manufactured from a drug that does not meet certain particle size and size distribution specifications. Also particle sizes play an important role in dissolution of active ingredient form of the final dosage form.

[00129] Hence, these physicochemical properties not only affect the processes of the preparing the pharmaceutical formulations but also affect the performance of the pharmaceutical product both in vitro and in vivo.

[00130] In order to have uniformity of the crystal particles size, drug product, and to have better solubility, bioavailability in aqueous medium generally the size of the drug particles will be reduced.

[00131] 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.

[00132] In one embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 2000μιη.

[00133] In another embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 1000 μπι.

[00134] In a yet another embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 700 μιη.

[00135] In a still further embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 500 μηι.

[00136] In a yet further embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 250 μηι. [00137] In another embodiment of the present invention, the crystal particle size of rasagiline salts have D90 less than about 100 μιη.

|00138] In an embodiment of the present invention, the crystal particle size of rasagiline base has D90 less than about 100 μιτι.

[00139] In an embodiment, the crystal particle size of rasagiline mesylate has D90 less than about 250 μπι.

[00140] In another embodiment, the crystal particle size of rasagiline mesylate has D90 less than about 100 μπι.

[00141] Many analytical tools are available to determine particle size distribution (PSD). In the early development stage, the analysis of PSD was performed through microscopic and sieve analysis. Laser diffraction was chosen as the 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(0.1 ), which is the size, in microns, below which 10% of the particles by volume are found.

[00142] The D 10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is a size value where at least 90 percent of the particles have a size smaller than the stated value. Likewise D10 refers to 10 percent of the particles having a size smaller than the stated value. D50 refers to at least 50 percent of the particles having a size smaller than the stated value and D[4,3] value refers to a mean particle size. Methods for determining D10, D50, D90 and D [4,3] include those using laser light diffraction with equipment sold by Malvern Instruments ltd.

[00143] Samples for measurement using the Malvern Mastersizer 2000 can be prepared by transferring the sample on sample tray and spreading it uniformly and measuring the particle size.

[00144] In one embodiment the present invention provides rasagiline phosphate particles having a bimodal size distribution. Bimodal distribution refers to a distribution of particles where two maxima are present.

[00145] In one embodiment the invention provides rasagiline phosphate particles having at least one of the following particle size distribution and which is bimodal as determined by volume by laser-diffraction method. Ia)250 μ <d(0.9)

lb) 250 μ «Ι(0.9)<1000 μ

Ila) 10 μ <ά(0.5) <100μ

lib) 10 μ <d(0.5) <50μ

Πο) 50 μ <(1(0.5) <100μ

ΙΠ) 2 μ <ά(0.1 )<10μ

The present invention provides the following combination of size distributions:

[00146] In one embodiment the present invention provides rasagiline phosphate particles having a particle size distribution which is a combination of lb ,11b and III represented by 250 μ <d(0.9)<1000 μ, 10 μ <d(0.5) <50μ and 2 μ <ά(0. Ί )<10μ and which is bimodal as determined by volume by laser-diffraction method

[00147] In one aspect, the present invention provides rasagiline phosphate having rod shaped crystals, as characterized by Scanning Electron Micrograph (SEM), which is substantially in accordance with Fig. 7.

[00148] In yet another aspect, the present invention relates to pharmaceutical composition comprising crystalline salts of rasagiline of present invention and at least one pharmaceutically acceptable carrier as an active ingredient, in association with a pharmaceutically acceptable carrier.

[00149] In yet another embodiment, the present invention provides a pharmaceutical composition comprising crystalline salts of rasagiline of present invention and at least one pharmaceutically acceptable excipient.

[00150] The pharmaceutical dosage may be in any form, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracistemal, intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray. The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.

[00151] Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Capsule dosages will contain the solid composition within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating.

[00152] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The examples which follow will further illustrate the preparation of the compound of the invention. These examples are not intended to limit the scope of the invention as defined herein above. EXAMPLES

EXAMPLE-1 : PREPARATION OF RASAGILINE PHOSPHATE

R-(+) rasagiline base (20. Og) was dissolved in isopropanol (200ml) at about 25- 30°C and thereafter, a solution of phosphoric acid (5.72g, 0.5mole) in isopropanol (100ml) was added at about 25-30°C in about 30 min. The content was stirred at about 25-30°C for about 2.0 hr. The product was filtered and dried at about 50-55°C. HPLC purity: 99.93%, Chiral purity: 99.92%.

EXAMPLE-2: PREPARATION OF RASAGILINE PHOSPHATE

R-(+) Rasagiline Tartrate (130.0 g) was neutralized by 25% aqueous ammonia solution (~ 75 ml) to alkaline pH 9-10 in demineralized water 1.3 liters and extracted in cyclohexane solvent (2X520 ml). The cyclohexane layer was distilled under reduced pressure at about 40-45°C to obtain R-(+)-rasagiline base as a oily product ( 100.0 g). The R-(+) rasagiline base (85.0 g, 0.496 moles) was dissolved in isopropyl alcohol (680 ml) at about 25-30°C and thereafter, 85% phosphoric acid ( 19.46 g, 0.198 mole) was dissolved in about 85 ml isopropyl alcohol and added to the solution at about 25-30°C.The contents were stirred at about 25-30°C for about 2.0 hr. The obtained salt was filtered and washed with isopropyl alcohol and dried in vacuum tray dryer at about 50 -55°C.

Yield: 70.0 g,

HPLC Purity: 99.96%

Chiral Purity: 'R' isomer: 100.0 %

Particle size d (0.9): 334.78 μηι.

Phosphate content: 22.46% w /w

Rasagiline content : 77.9 %

X-ray powder diffraction pattern

Pos. [°2Th.] d-spacing Rel. Int. [%] Height [cts] Area

[A] [cts*°2Th.]

5.4389 16.24889 82.23 18630.01 1537.10

7.1905 12.29406 81.02 18355.49 1817.34 7.9288 1 1.15087 100.00 22654.94 2243.02

9.9612 8.87986 33.26 7536.14 746.14

10.8507 8.15384 50.55 1 1451 .98 1 133.84

12.3128 7.18869 0.78 176.68 29.16

14.1223 6.27142 3.65 827.42 54,61

14.3594 6.16842 15.40 3489.94 403.12

15.8621 5.58725 22.07 4999.00 494.94

16.5156 5.36761 84.51 19145.67 221 1 .50

16.9031 5.24544 2.84 642.60 74.23

18.0710 4.90898 1.44 325.31 37.58

18.7923 4.72216 1.83 414.14 41.00

19.0464 4.65972 6.57 1487.83 98.20

19.3017 4.59866 14.78 3348.83 386.82

19.9730 4.44560 27.55 6240.93 720.89

20.8853 4.25342 9.00 2039.37 201 .91

21 .2626 4.17879 28.97 6563.1 8 758.1 1

21.6065 4.1 1305 41.26 9348.15 925.54

21.7738 4.08182 44.84 10158.83 838.17

22.0603 4.02944 18.87 4275.00 493.80

22.2614 3.99351 21.40 4848.00 479.99

23.9101 3.72174 15.55 3522.15 464.96

24.2007 3.67770 3.76 851.09 70.22

24.8684 3.58046 8.44 1912.12 252.42

25.6884 3.46799 7.13 1615.00 159.90

25.9238 3.43704 2.53 572.20 47.21

26.9290 3.31097 12.28 2781.12 275.35

27.2926 3.26769 21 .01 4759.90 ■ 549.81

27.7350 3.21656 1.05 237.86 23.55

28.1954 3.16508 4.68 1059.74 139.90

28.4300 3.13949 1.76 397.88 26.26

28.9197 3.08487 4.60 1042.67 198.53

29.7515 3.00050 6.10 1382.08 300.74

30.4314 2.93499 2.07 469.39 51 .07

30.7166 2.90839 2.94 665.73 90.54

31.4913 2.83858 2.65 599.69 65.25

31.9653 2.79756 2.05 463.68 88.28

32.8569 2.72365 1.14 257.64 70.08

33.4167 2.67930 1.31 296.61 64.54

34.3572 2.60808 4.92 1 1 13.89 181.79

35.4322 2.53137 1.62 366.06 199.14

36.2597 2.47548 1.72 390.04 127.31

36.6177 2.45210 1.50 340.68 92.66

37.5027 2.39624 4.99 1 130.88 123.04

37.9031 2.37184 2.95 668.40 127.26

38.1516 2.35696 2.59 586.36 95.69

38.5475 2.33366 ^: 2.45 555.18 90.61 ₍

38.9985 2.30771 8.1 1 1 836.36 1 99.80¹

39.6848 2.26936 2.53 574.16 62.47 40.5504 2.22289 1 .60 362.08 49.24

43.6228 2.07319 2.45 555.06 150.98

45.6884 1.98415 1.56 352.81 57.58

47.3215 1.91941 0.41 92.50 60.38

48.0313 1.89269 0.27 61.45 20.06

48.7502 1.86645 0.97 219.55 95.55

49.5245 1.83906 1.14 257.47 56.03

EXAMPLE-3: PREPARATION OF RASAGILINE BENZOATE

R-(+) Rasagiline base (20. Og) was dissolved in isopropanol (80ml) at about 25- 30°C and thereafter, Benzoic acid ( 14g, 0.91 mole) was added to the solution at about 25- 30°C. The contents were stirred at about 20-30°C for about 1.0 hr. The mixture was concentrated at about 45-50°C under reduced pressure. Hexane (100ml) was added to the oily residue and stirred the contents at about 25-30°C for about 30 min. The precipitated salt was filtered and dried at about 50-55°C. Yield: 27g (78%), HPLC purity: 99.94%, Chiral purity: 99.96%.

EXAMPLE-4: PREPARATION OF RASAGILINE MANDELATE

R-(+) Rasagiline base (20. Og) was dissolved in isopropanol (200ml) at about 25- 30°C and thereafter, a solution of L-(+)-Mandelic acid ( 17.77g, l .Omole) in Isopropanol (100ml) was added at about 25-30°C. This mixture was stirred at about 25-30°C for about 2 hr. The precipitated salt was filtered and dried at about 50-55°C. Yield: 23 g (61 %), HPLC purity: 99.89%, Chiral purity: 99.95%.

EXAMPLE S: PREPARATION OF RASAGILINE OXALATE

R-(+) Rasagiline base (2.0g) was dissolved in isopropanol (10ml) at about 25-30°C and thereafter oxalic acid (1.47g, l .Omole) was added at about 25-30°C. The mixture was stirred at about 25-30°C for about 2 hr. The precipitated salt was filtered and dried at about 50-55°C. Yield: 2.5g.

The characteristic data of the above said crystalline salts are as follows:

methanol, soluble in methanol, in methanol, very ethanol, methanol, Soluble in slightly soluble in

Insoluble in ethanol, ethanol, acetone water, Insoluble in acetone and acetone and and water. ethanol and sparingly soluble soluble in acetone.

in water. water.

Purity by 99.98% 99.94% 99.94% 99.99%

HPLC

Related 1 -aminoindan: 1 - 1 -aminoindan: 1 -aminoindan: impurity 0.02%; aminoindan: 0.01 %; 0.04%;

Dimer: BDL 0.05%; Dimer: BDL Dimer: Not

Single Max Dimer: BDL Single Max detected; Single

Imp. : 0.01 % Single Max Imp. : 0.02% max. imp: 0.05%.

Imp. : 0.01 %

Acid 22.94% 41 .61 % 48.14%

content

SOR 17.7° 15.83°

S-isomer% 0.028% — 0.07% 0.07%

BDL: Below detection limit

Comparative Solubility Data

of the crystalline Benzoate, Phosphate, Mandelate, Oxalate salts of Rasagiline against Mesylate salt of Rasagiline:

Oxalate 9.0mL

COMPARATIVE EXAMPLEPREPARATION OF RASAGILINE PHOSPHATE

R-(+) Rasagiline base (10. Og, 0.058 mole) was dissolved in Isopropanol (80ml) at about 25-30°C and thereafter, 85% Phosphoric acid (5.72 g, 0.058 mole) was added to the solution at about 25-30°C. The contents were stirred at about 25-30°C for about 2.0 hr. The, reaction mass became sticky and the product could not be isolated.

Example 6

An exemplary formulation of crystalline rasagiline phosphate comprising a dose of l mg of rasagiline base is presented below.

Process:

All excipients except lubricants were mixed. Roll compact the blend followed by milling and sifting to the desired granule size. Blend these granules with lubricants. Compress this final lubricated blend in to tablets using suitable punches.

Claims

CLAIMS:

1. Phosphate salt of rasagiline characterized by an X-ray powder diffraction pattern, which is substantially in accordance with Fig.1 ; a ¹³C nuclear magnetic resonance spectrum, which is in accordance with Fig. 2; a Fourier transform infrared spectrum, which is substantially in accordance with Fig.3; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Fig. 4; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Fig. 5; and a combination thereof. 2. The phosphate salt of rasagiline that exhibits a X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 θ± 0.2°θ at about 5.4, 7.1 , 7.9, 9.9, 10.8, 16.5, 19.9, 21.6, 22.2, 23.9 and 27.

2 .

3. The phosphate salt of rasagiline that exhibits a ^!3C NMR spectrum with signals at about 30.38, 32.07, 35.47,61.42, 75.49, 81 .75, 125.02, 125.08, 126.55, 128.14, 143.57, 144.20 ppm.

4. The phosphate salt of rasagiline of claim 1 wherein the salt is a hemiphosphate.

5. The phosphate salt of rasagiline of claim 1 wherein the rasagiline content in the rasagiline phosphate is between 75% to 80% by weight based on the total weight of rasagiline phosphate.

6. A process for the preparation of the phosphate salt of rasagiline of claim 1

comprising:

aqueous mixtures thereof; and

(b) isolating the rasagiline phosphate salt in crystalline form.

7. The process of claim 6 wherein the molar ratio of rasagiline to phosphoric acid is in the range of 1 : 0.3 to 1 :0.5.

8. The process of claim 6, wherein said solvent is selected from the group consisting of C3- C io aliphatic ketones; C | -C₆ chlorinated hydrocarbons; C | -C₆ aliphatic alcohols; C3-C 10 aliphatic esters; C₂-C₅ aliphatic nitriles; ethers; and mixtures thereof or aqueous mixtures.

5 9. The process of claim 7, wherein said organic solvent is selected from the group consisting of, methanol, ethanol, isopropanol, n butanol, tertbutanol and mixtures thereof or aqueous mixtures.

10. The phosphate salt of rasagiline of claim 1 , having a chemical purity greater than about 10 99.9 percent by weight, as measured by high performance liquid chromatography.

1 1. The phosphate salt of rasagiline of claim 1 , having an enantiomeric purity greater than about 99.9 percent by weight, as measured by high performance liquid chromatography.

1 5 12. Rasagiline phosphate particles having a bimodal size distribution.

13. Rasagiline phosphate particles of claim 12 having at least one of the following particle

i

size distribution as determined by volume by laser-diffraction method.

la)250 μ <d(0.9)

0 lb) 250 μ <d(0.9)<1000 μ

Ila) 10 μ <ά(0.5) <100μ

lib) 10 μ <ά(0.5) <50μ

ΙΙο) 50 μ <(1(0.5) <100μ

III) 2 μ <ά(0. 1 )<10μ

5

14. Rasagiline phosphate particles of claim 13 having a particle size distribution of 250 μ <d(0.9)<1000 μ, 10 μ <d(0.5) <50μ and 2 μ <ά(0.1 )<10μ

15. A pharmaceutical composition comprising a crystalline phosphate salt of rasagiline of 0 claim 1 and at least one pharmaceutically acceptable excipient.

16. Benzoate salt of rasagiline characterized by a powder X-ray diffraction pattern, which is substantially in accordance with Fig.8; an IR spectrum, which is substantially in accordance with Fig.9; a differential scanning calorimetry endotherm curve, which is 5 substantially in accordance with Fig. 10; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Fig. 1 1.

17. Mandelate salt of rasagiline characterized by a powder X-ray diffraction pattern, which is substantially in accordance with Fig.12; an IR spectrum, which is substantially in accordance with Fig.13; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Fig. 14; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Fig. 15.