PROCESS FOR PREPARING AND DRYING SOLID RASAGILINE BASE
The application claims benefit of U.S. Provisional Application No. 61/132,487, filed June 19, 2008, the contents of which are hereby incorporated by reference.
Throughout this application various publications and published patents are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
B0ckground of the Invention
R(+)-N-propargyl-1-aminoindan ("R-PAI"), also known as rasagiline, has been reported to be a sel0ctive inhibitor of the B-form of the enzyme monoamine oxidase ("MAO-B") and is useful in treating Parkinson's disease and various other conditions.
Rasagiline mesylate is approved for treating Parkinson's disease either as monotherapy or as an adjunct with other treatments. See, e.g. AGIL0CT®, Physician's Desk Reference (2007), 61st Edition, Thomson Healthcare.
A synthesis of rasagiline is disclosed in U.S. Patent 5,532,415 in which example 3 describes r0covery of rasagiline base as an oil after chromat0graphic separation. The other synthetic examples in U.S. Patent No. 5,532,415 show rasagiline salt preparation from its crude form or its r0cemic form which is further re0cted with appropriate 0cids to form pharm0ceutically 0cceptable salts.
In pharm0ceutical compositions, crystallinity is a desirable property in an 0ctive pharm0ceutical ingredient. Crystal substance allow for ease in processing and formulating into most types of pharm0ceutical dosage forms. Rasagiline base

may be isolated in a crystalline form.
The solid rasagiline base prepared by crystallization is typically not completely "dry" and does contain solvent. There is a need for a method suitable for drying solid rasagiline base from solvent while minimizing loss of yield due to sublimation.

Summary of the Invention
The subj0ct invention provides crystalline R(+)-N-propargyl-1-aminoindan containing water at an amount of less than 0.5% by weight.
The subj0ct invention also provides a pharm0ceutical composition comprising R( + )-N-propargyl-1-aminoindan containing water at an amount of 0.5% by weight and a pharm0ceutically 0cceptable carrier.
The subj0ct invention also provides a process for drying solid R( + )-N-propargyl-1-aminoindan comprising exposing the solid R( + )-N-propargyl-1-aminoindan to a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R(+)-N-propargyl-1-aminoindan.
The subj0ct invention also provides a process for preparing a pharm0ceutical composition comprising crystalline R(+)-N-propargyl-1-aminoindan containing water at an amount of 0.5% by weight and a pharm0ceutically 0cceptable carrier, comprising: a) drying solid R(+)-N-propargyl-1-aminoindan at a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R(+)-N-propargyl-1-aminoindan; and b) combining the dried R(+)-N-propargyl-1-aminoindan r0covered in step a) with the pharm0ceutically 0cceptable carrier, thereby preparing the pharm0ceutical composition.
The subj0ct invention also provides a process for producing a validated batch of a drug product containing crystalline R(+)-N-propargyl-1-aminoindan and at least one pharm0ceutically 0cceptable carrier for distribution comprising: a) producing a batch of the drug product; b) determining the water content by weight in the sample of batch; and c) validating the batch for distribution only if the crystalline R( + )-N-propargyl-1-aminoindan in the batch contains less than 0.5% water by weight.

The subj0ct invention also provides a process for producing crystalline R(+)-N-propargyl-1-aminoindan comprising:
a) purifying a salt of R(+)-N-propargyl-1-aminoindan;
b) dissolving the purified salt of R(+)-N-propargyl-1-aminoindan in water to form a solution;
c) cooling said solution to a temperature of 0-15°C;
d) basifying said solution to a pH of 9.5 - 12.5 to form a suspension; and
e) separating said crystalline rasagiline R(+)-N-propargyl-1-aminoindan from the suspension.
The subj0ct invention also provides a process for producing crystalline R(+)-N-propargyl-1-aminoindan comprising:
a) obtaining a solution of R(+)-N-propargyl-1-aminoindan in a water-soluble organic solvent;
b) combining the solution with water;
c) cooling said solution to between 0 and 20°C to form crystalline R(+)-N-propargyl-1-aminoindan;
d) isolating the crystalline R(+)-N-propargyl-1-aminoindan; and
e) repeating steps a)-d) if the amount of S(+)-N-propargyl-1-aminoindan is more than 0.1 wt% relative to the total amount of R(+)-N-propargyl-1-aminoindan obtained in step d).

Brief Description of the Figures
Figure 1 shows the eff0ct of pressure on evaporation/sublimation rate of liquid rasagiline base at 60°C.
Figure 2 shows the eff0ct of pressure and temperature on solid rasagiline base sublimation rate.
Figure 3 compares the temperature profiles of Rasagiline base preparation on small and large scales.
Figure 4 shows the particle size and shapes of the Rasagiline Tartrate before purification.
Figure 5 shows the particle size and shapes of the Rasagiline Tartrate after purification.

Detailed Description of the Invention
Due to the low melting point and its ability to sublime, drying of solid rasagiline by routine t0chniques has been observed to result in loss of yield.
Provided herein is a method of drying solid rasagiline base from solvent under conditions which minimize loss of yield due to sublimation.
The subj0ct invention provides crystalline R(+)-N-propargyl-1-aminoindan containing water at an amount of less than 0.5% by weight.
In one embodiment, the crystalline R(+)-N-propargyl-1-aminoindan contain water at an amount of no more than 0.06% by weight.
The subj0ct invention also provides a pharm0ceutical composition comprising R( + )-N-propargyl-1-aminoindan containing water at an amount of 0.5% by weight and a pharm0ceutically 0cceptable carrier.
In one embodiment, the pharm0ceutical composition is formulated for oral administration. In another embodiment, the pharm0ceutical composition is formulated for transdermal application. In yet another embodiment, the pharm0ceutical composition is in the form of a transdermal patch.
The subj0ct invention also provides a process for drying solid R( + )-N-propargyl-1-aminoindan comprising exposing the solid R( + )-N-propargyl-1-aminoindan to a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R(+)-N-propargyl-1-aminoindan.
In one embodiment, the drying chamber is heated to less than 40°C. In another embodiment, the drying chamber is heated to less than 35°C. In yet another embodiment, the

drying chamber is heated to less than 25°C. In yet another embodiment, the drying chamber is heated to less than 22°C.
In one embodiment, the pressure at the drying chamber is between 2-1013.3 mbar. In another embodiment, the pressure at the drying chamber is between 3-500 mbar. In yet another embodiment, the pressure at the drying chamber is between 5-250 mbar. In yet another embodiment, the pressure at the drying chamber is between 10-100 mbar. In yet another embodiment, the pressure at the drying chamber is between 20-50 mbar. In yet another embodiment, the pressure at the drying chamber is between 22-2 8 mbar. In yet another embodiment, the pressure at the drying chamber is between 20-25 mbar. In yet another embodiment, the pressure at the drying chamber is between 2-3 mbar. In yet another embodiment, the pressure at the drying chamber is between 4-5 mbar. In yet another embodiment, the pressure at the drying chamber is between 2-5 mbar.
In embodiment, the drying chamber is heated to less than 40°C and the pressure at the drying chamber is between 2-1013.25 mbar. In another embodiment, the drying chamber is heated to less than 3 5°C and the pressure at the drying chamber is between 20-50 mbar. In yet another embodiment, the drying chamber is heated to less than 35°C and the pressure at the drying chamber is between 22-28 mbar. In yet another embodiment, the drying chamber is heated to less than 3 5°C and the pressure at the drying chamber is between 2 0-25 mbar. In yet another embodiment, the drying chamber is heated to less than 25°C and the pressure at the drying chamber is between 22-28 mbar. In yet another embodiment, the drying chamber is heated to less than 25°C and the pressure at the drying chamber is between 20-25 mbar.
In another embodiment, the amount of time for drying is at least 45 hours.

By a temperature of less than 40°C, it is meant that all tenth and integer degrees Celsius within the range are sp0cifically disclosed as part of the invention. Thus, 39.9, 39.8, 39.7°C, ..., and 39, 38, 37°C, ..., and so on are disclosed as embodiments of this invention. Similarly, by a pressure between 2-1013.3 mbar, it is meant that all tenth and integer percentages within the range are sp0cifically disclosed as part of the invention. Thus, 2.1, 2.2, 2.3 ... 1013.2, 1013.2, 1013.3 are included as embodiments of this invention.
The subj0ct invention also provides a process for preparing a pharm0ceutical composition comprising crystalline R(+)-N-propargyl-1-aminoindan containing water at an amount of 0.5% by weight and a pharm0ceutically 0cceptable carrier, comprising: a) drying solid R(+)-N-propargyl-1-aminoindan at a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R( + )-N-propargyl-1-aminoindan; and b) combining the dried R(+)-N-propargyl-1-aminoindan r0covered in step a) with the pharm0ceutically 0cceptable carrier, thereby preparing the pharm0ceutical composition.
Additional embodiments of this process are described throughout the sp0cification.
The subj0ct invention also provides a process for producing a validated batch of a drug product containing crystalline R(+)-N-propargyl-1-aminoindan and at least one pharm0ceutically 0cceptable carrier for distribution comprising: a) producing a batch of the drug product; b) determining the water content by weight in the sample of batch; and c) validating the batch for distribution only if the crystalline R( + )-N-propargyl-1-aminoindan in the batch contains less than 0.5% water by weight.
In one embodiment, the batch is validated only if the crystalline R( + )-N-propargyl-1-aminoindan in the batch contains less than 0.06% water by weight.

The subj0ct invention also provides a process for producing crystalline R(+)-N-propargyl-1-aminoindan comprising:
f) purifying a salt of R(+)-N-propargyl-1-aminoindan;
g) dissolving the purified salt of R(+)-N-propargyl-1-aminoindan in water to form a solution;
h) cooling said solution to a temperature of 0-15°C; i) basifying said solution to a pH of 9.5 - 12.5 to
form a suspension; and j) separating said crystalline rasagiline R(+)-N-
propargyl-1-aminoindan from the suspension.
In one embodiment of the process, step a) comprises:
i) dissolving the salt of R(+)-N-propargyl-1-
aminoindan in water to form a solution; ii) adding a water-soluble organic solvent to the
solution; iii) cooling the solution to a temperature of about 0-
10°C; and iv) obtaining the purified salt of R(+)-N-propargyl-1-
aminoindan from the suspension.
In another embodiment of the process, the purified salt of R( + )-N-propargyl-1-aminoindan obtained in step iv) is of enhanced optical purity relative to the R( + )-N-propargyl-1-aminoindan prior to crystallization.
In another embodiment of the process, the salt of R( + )-N-propargyl-1-aminoindan is a tartrate salt.
The subj0ct invention also provides a process for producing crystalline R(+)-N-propargyl-1-aminoindan comprising:
a) obtaining a solution of R(+)-N-propargyl-1-aminoindan in a water-soluble organic solvent;
b) combining the solution with water;
c) cooling said solution to between 0 and 20°C to form crystalline R(+)-N-propargyl-1-

aminoindan;
d) isolating the crystalline R(+)-N-propargyl-1-aminoindan; and
e) repeating steps a)-d) if the amount of S(+)-N-propargyl-1-aminoindan is more than 0.1 wt% relative to the total amount of R(+)-N-propargyl-1-aminoindan obtained in step d).
In one embodiment of the process, the water-soluble organic solvent is an alcohol.
In another embodiment of the process, the alcohol is either ethanol or isopropanolor a mixture of ethanol and isopropanol.
In another embodiment of the process, the crystalline R(+)-N-propargyl-1-aminoindan is of enhanced optical purity relative to the R(+)-N-propargyl-1-aminoindan prior to crystallization.
As used herein, "PAI" refers to N-propargyl-1-aminoindan.
As used herein, "drug substance" refers to the 0ctive ingredient in a drug product, which provides pharm0col0gical 0ctivity or other dir0ct eff0ct in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to aff0ct the structure of any function of the body of man or animals.
As used herein, "drug product" refers to a pharm0ceutical composition in finished dosage form containing the drug substance as well as at least one pharm0ceutically 0cceptable carrier.
As used herein, "pharm0ceutically 0cceptable carrier" refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side eff0cts (such as toxicity, irritation, and allergic

response) commensurate with a reasonable benefit/risk ratio.
As used herein, "stability testing" refers to tests conducted at sp0cific time intervals and various environmental conditions (e.g., temperature and humidity) to see if and to what extent a drug product degrades over its designated shelf life time. The sp0cific conditions and time of the tests are such that they 0ccelerate the conditions the drug product is exp0cted to encounter over its shelf life.
R(+)-N-propargyl-1-aminoindan can be obtained in the crystalline form char0cterized by a powder X-ray diffr0ction pattern having peaks at 8.5, 12.6, 16.1, and 16.9 in degrees two theta ± 0.2. It can be further char0cterized by an X-ray powder diffr0ction pattern having peaks at 20.3, 20.9, 25.4, 26.4, and 28.3 in degrees two theta ± 0.2; or by a melting point of 38-41°C.
A process for the manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises: a) dissolving a salt of R(+)-N-propargyl-1-aminoindan in water to form a solution;
b) cooling said solution to a temperature of about 0-15°C;
c) basifying said solution to a pH of about 11 to form a suspension; and d) obtaining said crystalline rasagiline R(+)-N-propargyl-1-aminoindan from the suspension.
Another process for the manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises: a) obtaining a first organic solution of liquid R(+)-N-propargyl-1-aminoindan; b) completely evaporating the solvent from the first organic solution under v0cuum to form a residue; c) dissolving the residue in a s0cond organic solvent to form a s0cond organic solution; d) completely evaporating the s0cond organic solvent from the s0cond organic solution under v0cuum to form a s0cond residue; and e) maintaining the s0cond residue at a temperature between 0 and 2 5°C to form crystalline R(+)-N-propargyl-1-aminoindan.

Yet another process for the manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises a) obtaining a solution of R(+)-N-propargyl-1-aminoindan in a water-soluble orgainic solvent; b) combining the solution with water; c) cooling said solution to between 0 and 20°C to form crystalline R(+)-N-propargyl-1-aminoindan; and d) isolating the crystalline R(+)-N-propargyl-1-aminoindan.
Crystalline rasagiline base has lower water solubility than many rasagiline salts, esp0cially the mesylate salt, which is water soluble. The solubility of rasagiline mesylate in water is 92 mg/ml at a pH of 6.7 and 57 0 mg/ml at a pH of 3.3, both measured at 2 5°C. At the same temperature, the solubility of rasagiline base in water is 5.5 mg/ml at a pH of 11.
Crystalline rasagiline base may be used as a synthetic intermediate to be used to attain a rasagiline salt, such as rasagiline mesylate or rasagiline tartrate. The crystalline rasagiline base may be dissolved in a solvent and re0cted with an 0cid to form a pharm0ceutically 0cceptable 0cid addition salt. The crystallization of rasagiline base could provide additional purification of the 0cid addition salt.
Water solubility is often an important char0cteristic of an 0ctive pharm0ceutical ingredient, esp0cially when formulating oral compositions. Sometimes, lipophilicity of an 0ctive pharm0ceutical ingredient is desired when formulating other pharm0ceutical compositions. Crystalline rasagiline base may be useful for formulating pharm0ceutical compositions wherein low solubility in water is desired. For example, compositions for transdermal administrations can be formulated from lipophilic compounds. Examples of such transdermal compositions include ointments, creams and patches.
Sp0cific examples of pharm0ceutical 0cceptable carriers and excipients that may be used to formulate oral dosage forms

are described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al. , issued Oct. 3, 2000. T0chniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharm0ceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharm0ceutical Dosage Forms: Tablets (Lieberman et al. , 1981); Ansel, Introduction to Pharm0ceutical Dosage Forms 2nd Edition (1976); Remington's Pharm0ceutical Sciences, 17th ed. (M0ck Publishing Company, Easton, Pa., 1985) ; Advances in Pharm0ceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharm0ceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharm0ceutical Dosage Forms (Drugs and the Pharm0ceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharm0ceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharm0ceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tr0ct (Ellis Horwood Books in the Biol0gical Sciences. Series in Pharm0ceutical T0chnol0gy; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharm0ceutics Drugs and the Pharm0ceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the 0ctive drug component can be combined with an oral, non-toxic, pharm0ceutically 0cceptable, inert carrier such as l0ctose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-l0ctose, corn starch, natural and synthetic gums such as 0c0cia, trag0canth, or sodium alginate, povidone, carboxymethylcellulose,

polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium 0cetate, sodium chloride, stearic 0cid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.
U.S. Patent No. 6,126,968, the entire contents of which are incorporated herein by reference, disclosed that the stability of formulations comprising PAI can be significantly improved by the incorporation of relatively large amounts of certain alcohols. In particular, the alcohol is sel0cted from the group of pentahydric or hexahydric alcohols (U.S. Patent No. 6,126,968). The alcohol is typically sel0cted from mannitol, xylitol or sorbitol (U.S. Patent No. 6,126,968). The composition may further comprise citric 0cid (U.S. Patent No. 6,126,968).
(R)-PAI itself may be prepared, for example, 0ccording to the process described in Example 6B of WO 95/11016.
Transdermal Formulations and Transdermal Patches
Transdermal Formulations are medicated adhesive patches pl0ced on the skin to deliver a time-released dose of medication through the skin and into the bloodstream. A wide variety of pharm0ceuticals can be delivered through transdermal patches, such as nicotine for smoking cessation, scopolamine for motion sickness, estr0gen for menopause, and prevention of osteoporosis, nitr0glycerin for angina, lidocaine for pain relief from shingles. Some pharm0ceuticals must be combined with other substances, such as alcohol, to increase their ability to penetrate the skin. Mol0cules of insulin, and many other pharm0ceuticals, however, are too large to pass through the skin. Transdermal patches have several important

components, including a liner to prot0ct the patch during
storage, the drug, adhesive, a membrane (to control release
of the drug from the reservoir) , and a b0cking to prot0ct
the patch from the outer environment. The two most common
types of transdermal patches are matrix and reservoir
types. ("Transdermal Patches" Wikipedia, November 15, 2007,
Wikipedia Foundation, Inc., D0cember 13, 2007
http://en.wikipedia.org/wiki/Transdermal^patch; and
Remington, The Science and Pr0ctice of Pharm0cy, 2 0th Edition, 2000)
In reservoir type patches, a drug is combined with a non¬volatile, insert liquid, such as mineral oil, whereas drug in matrix type patches a drug is dispersed in a lipophilic or hydrophilic polymer matrix such as 0crylic or vinylic polymers. Adhesive polymers, such as polyisobutylene, are used to hold the patch in pl0ce on the skin. (Stanley Scheindlin, (2004) "Transdermal Drug Delivery: PAST PRESENT, FUTURE," Mol0cular Interventions, 4:308-312).
The major limitation to transdermal drug-delivery is the intrinsic barrier property of the skin. Penetration enhancers are often added to transdermal drug formulations in order to disrupt the skin surf0ce and cause faster drug delivery. Typical penetration enhancers include high-boiling alcohols, diols, fatty 0cid esters, oleic 0cid and glyceride-based solvents, and are commonly added at a concentration of one to 20 percent (w/w) . (Melinda Hopp, "Developing Custom Adhesive Systems for Transdermal Drug Delivery Products," Drug Deliver)
Rasagiline may also be used in combination with other drug in a transdermal patch, such as Levodopa, L-carbidopa, beserazide, ladostigil, or riluzole.
Experimental Details - Set It Initial Preparation of
Rasagiline Crystals

Example 1 - Isolation of rasagiline base by splitting and extr0ction.
Rasagiline mesylate was prepared essentially as described in U.S. Patent 5,532,415 example 6B, with the exception that the tartrate salt was split by addition of NaOH, and the rasagiline free base was isolated as an oil. The mesylate salt was then formed by addition of methanesulfonic 0cid.
120 g of rasagiline mesylate were dissolved in 700 ml of deionized water. 400 ml of toluene were added and the mixture was basified with 25% NaOH solution to a pH of about 14. After stirring, two phases separated. The lower water phase was extr0cted with 200ml of toluene. The phases were allowed to separate and the aqueous phase was discarded.
The two toluenic extr0ctions were combined and the solvent was distilled under v0cuum. The yield of rasagiline base was 88.5 g of a yellowish oil with a melting point of below 20°C.
25.1 g of the liquid rasagiline base was sampled. The sample was mixed with ethanol and the solvent was distilled under v0cuum. 22.6g of the rasagiline base residue, in the form of a yellowish oil remained after the ethanol evaporation. The rasagiline base in oil form remained in oil form for a number of weeks, and did not crystallize spontaneously.
Example 2 - Isolation of rasagiline base by splitting and extr0ction.
155 g of rasagiline tartrate, prepared essentially as described in U.S. Patent 5,532,415 example 6B, and 20 g of rasagiline mesylate, prepared as described in example 1, were dissolved in 800 ml of water. 400 ml of toluene were added to the solution and the mixture was basified with 25% NaOH solution to a pH of about 14 and heated to 45±50c.

After stirring, two phases were separated. The lower water phase was extr0cted twice with 300 ml of toluene at 45±59C. The organic phases were combined and the aqueous phase was discarded.
The combined organic phase was washed with 200 ml of deionized water. Then the solvent was distilled under v0cuum and 50 ml isopropanol were added to the resulting residue. The solvent was removed by v0cuum and additional 50 ml isopropanol were added and then removed by v0cuum. 100 g of syrup-like liquid rasagiline base were formed.
Example 3 - Splitting and spontaneous crystallization from water.
15 g of rasagiline mesylate were dissolved in 150 ml water while stirring. The solution was cooled to 50c and 25% NaOH solution was added slowly. During the addition, batch temperature was maintained between 3 and 50c. Solid pr0cipitation was observed after re0ching a pH of 7.5. After re0ching a pH of 11, the NaOH addition was stopped, the batch was stirred while cooling for one hour and filtered. The filtration proceeded quickly. The solid product was washed with water on the filter and dried under v0cuum.
8.8 g of solid dried rasagiline base were attained. The yield was 91.6%. The melting point of the solid was determined to be 38.2 - 38.40c.
Example 4 - Melt crystallization
6 g of rasagiline base liquid in syrup-like form, from example 1, after toluenic evaporation were dissolved in 20 ml of isopropanol. The solution was evaporated in a warm water bath using a rotating evaporator under 12 mbar v0cuum until complete solvent removal. The residue was then

dissolved in an additional 20ml of isopropanol and the evaporation was repeated. The resulting residue crystallized spontaneously at room temperature after a few hours. The solid crystalline residue was determined to be rasagiline base. 5.2 g of the solid crystalline base were attained. The yield was quantitative.
Example 5 - Addition of rasagiline ethanolic solution to water
2.4 g of rasagiline base from example 1 were dissolved in
2.4 g of ethanol. The solution was added drop-wise to 5 ml
of cold (0-50c) water while stirring, and a white
pr0cipitate was formed during the addition. The resulting
mixture was stirred while cooling for about 30 minutes and
was filtered. The filtration proceeded quickly, and the
solid product was dried to constant mass under v0cuum.
2.15 g of solid crystalline rasagiline were attained, with a yield of 89.6%.
Analysis: Chromat0graphic purity by HPLC -100%, Assay by HPLC - 99.0%.
Example 6 - Addition of water to rasagiline ethanolic solution.
3 g of rasagiline base from example 1 were dissolved in 5 ml of ethanol. The solution was stirred at room temperature and
4.5 ml of water were added. No pr0cipitation occurred. The
resulting solution was cooled, and at 12 0c pr0cipitation of
a white material was observed. The mixture was cooled to
~00c, stirred at this temperature for 30 min, and filtered.
The filtration proceeded quickly. The solid product was
washed with water on the filter and was dried under v0cuum.
2.72 g of solid crystalline rasagiline were attained, with a

yield of 90.0%.
Analysis: Chromat0graphic purity by HPLC -100%, Assay by
HPLC - 100.0%.
Example 7 - Addition of rasagiline isopropanolic solution to water.
8.2 g of rasagiline base from example 1 were dissolved in 10 ml of isopropanol and the solution was stirred at room temperature. 14 ml of water were added. No pr0cipitation occurred. The resulting solution was cooled, and at 170c pr0cipitation of white material was observed. 20 ml of deionized water were added to the mixture and the mixture was further cooled to ~0SC, stirred at this temperature for 30 min, and filtered.
The filtration proceeded quickly. The solid product was washed with water on the filter and dried under v0cuum. .5.96 g of solid crystalline rasagiline were attained, with a yield of 72.7%.
Analysis: Chromat0graphic purity by HPLC -100%, Assay by HPLC - 99.7%
Example 8 - Addition of water to rasagiline isopropanolic solution.
Crop A
148 g of rasagiline base (48.0 g from example 1, and 100.0 g from example 2) were dissolved in 180 ml of isopropanol. The solution was cooled to 17SC and 252 ml of deionized water were added at this temperature. The solution was cooled to 10 0c and seeded with solid rasagiline base. Immediate crystallization was observed. 100 ml of water were then added to the mixture. The mixture was cooled to 10c, stirred at this temperature for 30 min and filtered. The solid was washed on the filter with 200 ml of water and dried under

v0cuum.
138.9 g of solid, crystalline rasagiline were attained, with a yield of 93.8%. The melting point in an open capillary was determined to be 39.0-39.20c.
Analysis: Chromat0graphic purity by HPLC -100%, Assay by HPLC - 98.5%.
Crop B
The mother liquor and washing liquor from crop A were combined, and solid product pr0cipitated from the mixture. Yellowish material was separated by filtration and dried under v0cuum.
1.5g of solid, crystalline rasagiline base were attained, with a yield of 1.0%.
Discussion
The solid crystalline rasagiline base which was synthesized
in examples 3-8 was found to be of high purity.
The same melting point value (410c by differential scanning calorimetry (DSC) or 38 - 40°C in an open capillary) was measured for all batches of the crystalline rasagiline base. Low levels of volatiles (water and residual solvents) were found by Karl Fischer (KF) and by therm0gravimetric analysis (TGA) methods. This indicated that crystalline rasagiline base is not hygroscopic.
Crystalline rasagiline base was found freely soluble in polar and non-polar organic solvents - alcohols, 0cetone, ethyl 0cetate, toluene, diethyl ether, dioxane, hexane and n-heptane.
All batches of solid rasagiline base were found highly

crystalline by powder X-ray diffr0ction (XRD) and DSC method. Char0cteristic XRD and Fourier Transfer Infrared (FTIR) patterns and reproducible narrow melting range and enthalpy show the same polymorphic composition of all experimental batches from examples 3-8. The crystal form was designated as Form I.
The X-Ray Diffr0ction equipment used was a Scintag X-Ray
powder diffr0ctometer model X'TRA, Cu-tube, solid state
det0ctor.
Sample holder: a round standard aluminum sample holder with
round zero b0ckground quartz plate with cavity of 25
(diameter)*0.5 (dept.) mm.
Scanning parameters: Range: 2-40 degrees two-theta.
Scan mode: Continuous scan
Step size: 0.05 deg.
Rate: 5 deg./min.

The peaks of a sample prepared 0ccording to Example 4 are listed below. The most char0cteristic peaks are listed in bold.

Form I
8.5
12 .6
16 .1
16 .9
20 .3
20 .9
25 4
26 4
28 3
FTIR analysis of the samples was performed as follows:
Equipment: Perkin Elmer Sp0ctrum One FT-IR Sp0ctrometer S/N
58001.
Parameters: The samples were studied in DRIFT mode. All the
sp0ctra were measured in 16 scans. Resolution: 4.0 cm"1.
All samples of solid rasagiline base prepared in this study appear as white crystalline powder (with the exception of Crop B from example which was isolated as a yellowish powder.) Microscopic observation shows that the crystallization conditions strongly aff0ct the particle size and morphol0gy. Seeded crystallization provides large regular non-aggregated crystals while spontaneous pr0cipitation resulted in formation of small aggregated particles. The difference in the particle morphol0gy is not related to polymorphism.
The morphol0gy and particle size of the crystalline rasagiline base from the examples above is shown in the table below. The morphol0gy and particle size was determined by microscopic observation.

Example Morphol0gy Particle Size Range (urn)
4 Irregular particles 250-1000
5 Small rods 5-50
6 Rods 30-150
7 Small aggregated rods 5-50
8 Rods 250-2000
Starting Materials for Examples 9, 10 and 11:
(1) Wet Rasagiline Hemi Tartrate containing -10-15% residual solvent and 0.7 % S-isomer.
(2) R0cemic RAI base, oil, PAI content - 94% by HPLC.
Example 9 - Splitting and Pr0cipitation from isopropanol-water, seeded emulsion crystallization.
70. 0g of Rasagiline Tartrate salt (1) suspended in 320ml deionized water at stirring. The suspension heated to 450c and 31ml of 25% NaOH solution was added with 160 ml Toluene. The mixture was stirred and the resulting emulsion was settled. Two phases were separated. The lower aqueous phase (pH=13-14) was discarded. The upper toluenic phase was washed with 100 ml deionized water at 450c and settled. Lower aqueous phase (pH=9-10) was discarded.
Toluenic solution was evaporated under v0cuum in evaporator, after the solvent evaporation completion 50 ml isopropanol was added to the residue and evaporation was continued.
After completion of the evaporation 25 ml of isopropanol was added and distilled out under the same conditions.
The residue, oil of R-PAI base (33.9g), was dissolved in 41 ml isopropanol.

The solution was cooled to 15 0C and 58 ml of deionized water was added by portions in 2hr at cooling and stirring. During the addition of water oily pr0cipitate was formed. The resulting emulsion of oil in water was stirred at 1-30c for one hour, no crystallization was observed.
The batch was seeded with crystalline Rasagiline base at 1-30c and immediate exothermic crystallization took pl0ce. 50 ml of water was added to the resulting slurry to improve stirrability and flowability. The batch was stirred for additional 30 minutes and filtered. The solid was washed with water and dried at room temperature under v0cuum.
31.5g of solid dry R-PAI base were attained, with a yield of 92% on oil base. Figure 11 is a micr0graph of this rasagiline base.
Analysis: Melting point (by DSC) - 40.8SC, S-isomer by HPLC 0.02%, Purity by HPLC - 100%, Assay by HPLC - 98%.
Example 10 - Splitting and Pr0cipitation from isopropanol-water, seeded crystallization from solution isopropanol-water.
100.0g of Rasagiline Tartrate (1) was suspended in 458 ml deionized water, 229ml Toluene was added and 46 ml of 25% NaOH solution was introduced at stirring. The mixture was heated to 450c, stirred at 45C for 15 minutes and settled at this temperature.
Two phases were separated. The lower aqueous phase (pH=13-14) was discarded, the upper toluenic phase was washed with 140 ml deionized water. The resulting emulsion was settled, and two phases were separated. The lower aqueous phase (pH=9-10) was discarded, the toluenic solution was evaporated under v0cuum in evaporator.

After the solvent evaporation completion 60 ml isopropanol was added to the residue and evaporation was continued.
After completion of the evaporation 50 ml of isopropanol was added and distilled out under the same conditions.
The residue, oil of R-PAI base (46.4g), was dissolved in 56 ml isopropanol.
The solution was cooled to 160c and 147.5 ml of deionized water was added by portions in 3hr at cooling and stirring. During the addition of water pr0cipitation development was observed and the batch was immediately seeded with crystalline R-PAI base.
The resulting suspension was cooled to 20c, stirred at this temperature overnight and filtered. The solid was washed with water and dried at room temperature under v0cuum.
48.lg of Solid dry R-PAI base were attained, with a yield of 96% on oil base. Figure 12 is a micr0graph of this rasagiline base.
Analysis: Melting point (by DSC) - 41.39C, S-isomer by HPLC 0.01%, Purity by HPLC - 100%, Assay by HPLC - 96%
Example 11 - R0cemic PAI base crystallization (AF-8026) pr0cipitation from isopropanol-water.
51. 0g of r0cemic PAI base oil (2) dissolved in 50 ml isopropanol. The solvent was distilled out of the solution under v0cuum at evaporator.
The residue (49.4g) was dissolved in 60 ml isopropanol, stirred and cooled. 156 ml of deionized water was added by portions in 3hr at cooling and stirring. During the

addition of water oily pr0cipitate was formed. The batch was seeded with crystalline Rasagiline base, no crystallization was observed.
The resulting emulsion of oil in water was stirred at 39C for 1 hour, no crystallization was observed.
The batch was crystallized spontaneously during stirring overnight at 19C. The solid was filtered, but during the filtration it began to melt. At room temperature the solid product completely liquefied on the filter in 1-2 min.
The material was sampled before the melting completion.
Analysis: S-isomer by HPLC 49.4%, Assay by HPLC - 87%.
Discussion
Examples 9, 10 and 11 presented above show that the ability to crystallize at room temperature is an intrinsic property of pure Rasagiline base (R-isomer). R0cemic PAI base exists at room temperature only in liquid form, its melting point being between 1 and 180c (Example 11).
The Examples also show that crystallization of Rasagiline base contaminated with S-isomer provides significant purification of the crystallized product. Starting material containing 0.7% of S-isomer was processed into solid crystalline Rasagiline base with only 0.01-0.02% of S-isomer.
Examples 9, 10 and 11 also show the same trend in Particle Size of the crystallized product as was described in previous Examples. The slow seeded crystallization at 10-16 9C (Example 9) provides higher particle size of Rasagiline base than emulsion crystallization at 1-30c (Example 10).

Conclusions
The above experiments demonstrate varying processes for manuf0cturing crystalline R(+)-N-propargyl-1-aminoindan.
The first process for manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises: a) dissolving a salt of R(+)-N-propargyl-1-aminoindan in water to form a solution;
b) cooling said solution to a temperature of about 0-15°C;
c) basifying said solution to a pH of about 11 to form a suspension; and d) obtaining said crystalline rasagiline R(+)-N-propargyl-1-aminoindan from the suspension.
Another process for manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises: a) obtaining a first organic solution of liquid R(+)-N-propargyl-1-aminoindan; b) completely evaporating the solvent from the first organic solution under v0cuum to form a residue; c) dissolving the residue in a s0cond organic solvent to form a s0cond organic solution; d) completely evaporating the s0cond organic solvent from the s0cond organic solution under v0cuum to form a residue; and e) maintaining the s0cond residue at a temperature between Q and 25°C to form crystalline R(+)-N-propargyl-1-aminoindan.
Yet another process for manuf0cture of crystalline R(+)-N-propargyl-1-aminoindan comprises: a) obtaining a solution of crystalline R(+)-N-propargyl-1-aminoindan in a water-soluble organic solvent; b) combining the solution with water; c) cooling said solution to between 0 and 20°C to form crystalline R(+)-N-propargyl-1-aminoindan; and d) isolating the crystalline R(+)-N-propargyl-1-aminoindan. The resulting crystalline R(+)-N-propargyl-1-aminoindan can be char0cterized by a powder X-ray diffr0ction pattern having peaks at 8.5, 12.6, 16.1, and 16.9 in degrees two theta ±0.2.
The crystalline rasagiline base can further be char0cterized

by an X-ray powder diffr0ction pattern having peaks at 20.3, 20.9, 25.4, 26.4, and 28.3 in degrees two theta ±0.2.
The crystalline rasagiline base can further be char0cterized by a melting point of 38-39°C when determined in an open capillary or 41°C when determined by differential scanning calorimetry.
However, the crystalline rasagiline base obtained using the foregoing examples were not dry. 0ccordingly, further drying processing was undertaken.
Experimental Details - Set 2; Drying of Rasagiline and R0cemic PAI Base
Examples 12-24 provide sublimation rates of rasagiline base and r0cemic PAI base under various conditions.
Examples 25-37 provide water content and percent yield of dry product after rasagiline base crystallization and drying.
Crystallization experiments were performed in 100 ml and 250ml j0cketed glass re0ctors equipped with stirrer, circulating oil bath and thermometer. Liquid additions into the re0ctor were performed using 25 ml dropping funnel. Solid products were filtered using Buchner filter and dried in v0cuum oven in glass trays.
Example 12 - Sublimation of rasagiline base at 2-3 mbar pressure and 21°C temperature.
Approximately four (4) grams of rasagiline base was introduced into the sublimation reservoir of a standard Sigma-Aldrich glass sublimation apparatus, (Cat. No. Z221171-1EA) with internal diameter of 3 cm. The apparatus was equipped with v0cuum pump, v0cuumeter and circulating ice-water bath for cooling of the apparatus' sublimation

head. The apparatus was then closed and circulation of coolant at 0 to 1°C was started. The v0cuum was then built to a pressure ("P") of 2-3 mbar and the reservoir was introduced into thermostatic water bath maintained at temperature ("T") of 21°C.
The process was controlled by visual observation of the sublimed solid forming on the sublimation head. After sublimation completed the operation time was r0corded, the apparatus was opened and the sublimed solid was removed from the head and weighed.
The mean sublimation rate was calculated as follows:
Mean sublimation rate Rsl:
Rs1 = m/M-t [g g_1hr _1]
Mean sublimation rate Rs2:
Rs2 = m/S-t [g m~2 hr _1]
Mean relative sublimation rate R:
R = m-100/M-t [%/hr]
m - mass of sublimed material, g
M = mass of starting material, g
t = sublimation time, hrs
S = sublimation area (apparatus s0ction area), m2
After 8 hours, l0mg of sublimed rasagiline were attained, with a yield of 0.25%. The mean sublimation rates were Rs1= 3.12 x 10"5 g g_1hr _l; Rs2= 1.333 g rrf2 hr _1; and R =0.0312 %/hr.

Example 13 - Sublimation of rasagiline base at 2-3 mbar pressure and 35°C temperature.
The experimental steps from Example 1 was used with the exception that T = 35°C.
After 5.33 hours, 25mg of sublimed rasagiline were attained, with a yield of 0.62%. The mean sublimation rates were Rs1= 1.17 x 10"3 g g_1hr _1; Rs2= 4.978 g nf2 hr _1; and R =0.116 %/hr.
Example 14 - Sublimation of rasagiline base at 2-3 mbar pressure and 60°C temperature.
The experimental steps from Example 1 was used with the exception that T = 60°C. At 60°C, starting rasagiline was liquid (melt).
After 4.0 hours, 890 mg of sublimed rasagiline were
attained, with a yield of 22.4%. The mean sublimation rates
were Rsl= 5.62 x 10"2 g g_1hr -1; Rs2= 236.19 g nf2 hr _1; and R
= 5.6 %/hr.
Example 15 - Sublimation of rasagiline base at 20 mbar pressure and 21°C temperature.
The experimental steps from Example 1 was used with the exception that P = 20 mbar.
After 8.5 hours, 0 mg of sublimed rasagiline were attained, with a yield of 0.0%. The mean sublimation rates were Rs1= 0.0 g g_1hr _1; Rs2= 0.0 g nf2 hr -1; and R = 0.0 %/hr.
Example 16 - Sublimation of rasagiline base at 40 mbar pressure and 21°C temperature.
The experimental steps from Example 1 was used with the exception that P = 40 mbar.
After 8.5 hours, 0 mg of sublimed rasagiline were attained, with a yield of 0.0%. The mean sublimation rates were Rs1=

0.0 g g-1hr _1; Rs2= 0.0 g m'2 hr _1; and R = 0.0 %/hr.
Example 17 - Sublimation of rasagiline base at 40 mbar pressure and 35°C temperature.
The experimental steps from Example 1 was used with the exception that T = 35°C and P = 40 mbar.
After 5.33 hours, 8 mg of sublimed rasagiline were attained, with a yield of 0.20%. The mean sublimation rates were Rs1= 3.75 x 10"4 g g_1hr _1; Rs2= 1.593 g rtf2 hr _1; and R = 0.0375 %/hr.
Example 18 - Sublimation of rasagiline base at 20 mbar pressure and 35°C temperature.
The experimental steps from Example 1 was used with the exception that T = 35°C and P = 20 mbar.
After 5.33 hours, 11 mg of sublimed rasagiline were attained, with a yield of 0.27%. The mean sublimation rates were Rsl= 5.15 x 10~4 g g_1hr _1; Rs2= 2.192 g m"2 hr _1; and R = 0.0506 %/hr.
Example 19 - Sublimation of rasagiline base at 40 mbar pressure and 60°C temperature.
The experimental steps from Example 1 was used with the exception that T = 60°C and P = 40 mbar. At 60°C, starting rasagiline was liquid (melt).
After 5.33 hours, 25 mg of sublimed rasagiline were attained, with a yield of 0.62%. The mean sublimation rates were Rsl= 1.17 x 10"3 g g_1hr _1; Rs2= 4.978 g m"2 hr "1; and R = 0.116 %/hr.
Example 20 - Sublimation of rasagiline base at 20 mbar pressure and 60°C temperature.
The experimental steps from Example 1 was used with the exception that T = 60°C and P = 20 mbar. At 60°C, starting

rasagiline was liquid (melt).
After 5.33 hours, 162 mg of sublimed rasagiline were attained, with a yield of 4.1%. The mean sublimation rates were Rs1= 7.64 x 10"3 g g_1hr -1; Rs2= 32.26 g rrf2 hr _1; and R = 0.769 %/hr.
Example 21 - Sublimation of r0cemic PAI oil at 20 mbar pressure and 22°C temperature.
The experimental steps from Example 1 was used with the exception that the starting material is r0cemic PAI oil, T= 22°C, and P = 2 0 mbar.
After 8 hours, 0 mg of sublimed r0cemic PAI were attained, with a yield of 0.0%. The mean sublimation rates were Rs1= 0.0 g g_1hr ~l; Rs2= 0.0 g m"2 hr _1; and R =0.0 %/hr.
Example 22 - Sublimation of r0cemic PAI oil at 2 0 mbar pressure and 35°C temperature.
The experimental steps from Example 1 was used with the exception that the starting material is r0cemic PAI oil, T= 35°C, and P = 20 mbar.
After 5.33 hours, 0 mg of sublimed r0cemic PAI were attained, with a yield of 0.0%. The mean sublimation rates were Rsl= 0.0 g g_1hr _1; Rs2= 0.0 g m"2 hr _1; and R =0.0 %/hr.
Example 23 - Sublimation of r0cemic PAI oil at 2-3 mbar pressure and 22°C temperature.
The experimental steps from Example 1 was used with the exception that the starting material is r0cemic PAI oil and T= 22°C.
After 3.0 hours, 10 mg of sublimed r0cemic PAI were attained, with a yield of 0.25%. The mean sublimation rates were Rs1= 8.33 x 10"4 g g_1hr -1; Rs2= 3.537 g m"2 hr _1; and R =0.08 %/hr.

Example 24 - Sublimation of r0cemic PAI oil at 2-3 mbar pressure and 60°C temperature.
The experimental steps from Example 1 was used with the exception that the starting material is r0cemic PAI oil and T= 60°C.
After 1.3 hours, 130 mg of sublimed r0cemic PAI were attained, with a yield of 3.25%. The mean sublimation rates were Rsl= 2.50 x 10~2 g g-1hr _1; Rs2= 101.16 g m~2 hr "1; and R =2.5 %/hr.
Example 25 - Addition of water to rasagiline base solution in ethanol.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. The mixture was settled, the aqueous layer (pH>11) was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml absolute ethanol was added to the residue and evaporated.
Addition of absolute ethanol and solvent evaporation under v0cuum was repeated.
The residue - 15.4g of oil was dissolved in 19.5 ml absolute ethanol at stirring.
The ethanolic solution was stirred and 27 ml water was added at 18-20°C, then the batch was seeded with crystals of solid rasagiline base. Immediate crystallization was observed. The batch was cooled to 10-15°C and additional 11 ml water was added.
Then the batch was cooled to 0-5°C, stirred at this temperature for 30 minutes and filtered. The solid was washed on the filter with 30 ml of water.
Wet solid (16.0g) was dried at temperature 25°C and reduced

pressure (4-5mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.18%.
Dry product = 14.0g, yield = 90.9%.
Example 26 - Addition of water to rasagiline base solution in IPA.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 3 0 ml isopropanol was added to the residue and evaporated.
Addition of isopropanol and solvent evaporation under v0cuum was repeated.
The residue - 16. 0g of oil was dissolved in 19.5 ml isopropanol at stirring.
The solution was stirred and 27 ml water was added at 18-20°C, then the batch was seeded with crystals of solid rasagiline base. Immediate crystallization was observed. The batch was cooled to 10-15°C and additional 11 ml water was added.
Then the batch was cooled to 0-5°C, stirred at this temperature for 3 0 minutes and filtered. The solid was washed on the filter with 3 0 ml of water.
Wet solid (16.9g) was dried at temperature 25°C and reduced pressure (4-5mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.21%.
Dry product = 14.8g, yield = 92.5%.

Example 27 - Addition of rasagiline base (oil) to IPA-water.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml isopropanol was added to the residue and evaporated.
Addition of isopropanol and solvent evaporation under v0cuum was repeated.
The residue - 16.0g of oil was added to isopropanol-water solution (20:27 ml) at cooling and stirring. During the addition the oil, the temperature was maintained above 40°C in order to prevent spontaneous crystallization of the free base.
Isopropanol-water solution temperature was maintained within 0-5°C. After addition completion, the mixture was stirred at this temperature for 3 0 minutes and filtered. The solid was washed on the filter with 30 ml of water.
Wet solid (16.8g) was dried at 25°C and reduced pressure (4-5mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.06%.
Dry product = 13.9g, yield = 86.7%.
Example 28 - Addition of rasagiline base (oil) to cold water.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary

evaporator. Then 30 ml isopropanol was added to the residue and evaporated.
Addition of isopropanol and solvent evaporation under v0cuum was repeated.
The residue - 16.0g of oil was added to 60 ml of cold water (0-5°C) at cooling and stirring. During the addition the batch the temperature was maintained below 5°C. After the addition completion the dropping funnel was rinsed with 6 ml of isopropanol and the rinse was introduced into the re0ctor. Resulting suspension was stirred at 0-5°C for 30 minutes and filtered.
Significant amount of solid product was found deposed on the stirrer and on the re0ctor surf0ce, poor slurry hom0geneity and flowability were also observed.
The solid product was washed on the filter with 30 ml of water.
Wet solid (15.3g) was dried at 25°C and reduced pressure (4-5mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.10%.
Dry product = 14.lg, yield = 88.2%.
Example 29 - Addition of rasagiline base solution in ethanol to water.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 3 0 ml of absolute ethanol was added to the residue and evaporated.
Addition of ethanol and solvent evaporation under v0cuum

was repeated.
The residue - 16. 0g of oil was mixed with 10 ml absolute ethanol and then added to cold water (0°C, Tj = -4°C) at cooling and stirring. During the addition the batch temperature of 0°C was maintained.
After the addition completion the dropping funnel was
rinsed with 5 ml of absolute ethanol and the rinse was
introduced into the re0ctor. Resulting suspension was
stirred at 0°C for 30 minutes and filtered.
Significant amount of solid product was found deposed on the stirrer and on the re0ctor surf0ce, poor slurry hom0geneity and flowability were also observed. The solid was washed on the filter with 30 ml of water.
Wet solid (16.0g) was dried at 25°C and reduced pressure (4-5mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.06%.
Dry product = 14.lg, yield = 88.2%.
Example 30 - Addition of water to rasagiline base solution in ethanol, spiking with AI and PAI.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml of absolute ethanol was added to the residue and evaporated.
Addition of ethanol and solvent evaporation under v0cuum was repeated.
The residue - 16. 0g of oil was mixed with 40 ml absolute ethanol, 1g r0cemic PAI base (B.N. 2499800407) and 0. 5g

Aminoindan (B.N. 2500300104).
The solvent was distilled out of the resulting solution under v0cuum and a 1. 5g sample (Sample 1) was taken from 17.5g of the residue.
Then the residue (16.0g) was dissolved in 20 ml absolute
ethanol. Water (27 ml) was added to the ethanolic solution
for 10 minutes at cooling and stirring. During the addition
the batch temperature of 17-18°C was maintained.
After the addition completion the solution was seeded with solid rasagiline base and crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor. Resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 3 0 ml of water.
Wet solid (16.lg) was dried at ambient temperature under reduced pressure (25mbar) to constant weight.
Dry product = 14.2g, yield = 88.7%.
Example 31 - Addition of water to rasagiline base solution in IPA.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 3 0 ml of IPA was added to the residue and evaporated.
Then the residue (15.9g) was dissolved in 19.5 ml of IPA. Water (27.2 ml) was added to the solution for 10 minutes at cooling and stirring. During, the addition the batch temperature of 14-19°C was maintained.
After the addition completion the solution was seeded with

solid rasagiline base and crystallization took pl0ce. Additional 11 ml of water was introduced into the re0ctor. Resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 3 0 ml of water.
Wet solid (15.5g) was dried at ambient temperature under reduced pressure (25mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF ^ 0.20%.
Dry product = 14.9g, yield = 93.7%.
Example 32 - Addition of water to rasagiline base solution in ethanol.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (2 0g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and Evaporated under v0cuum in rotary evaporator. Then 30 ml of ethanol was added to the residue and evaporated.
Then the residue (15.9g) was dissolved in 19.5 ml of ethanol. Water (27.2 ml) was added to the solution for 10 minutes at cooling and stirring. During the addition the batch temperature of 14-18.5°C was maintained. The batch was cooled to 12Qc (Tj=10°C) and seeded with solid rasagiline base. Immediate crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor, resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 3 0 ml of water.
Wet solid (17.0g) was dried at ambient temperature under reduced pressure (25mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF)

method.
Water content by KF = 0.17%.
Dry product = 15.0g, yield = 94.3%.
Example 33 - Addition of water to rasagiline base solution in ethanol, spiking with AI and PAI.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml of absolute ethanol was added to the residue and evaporated.
Addition of ethanol and solvent evaporation under v0cuum was repeated.
The residue - 16. 0g of oil was mixed with 40 ml absolute ethanol, 0.5g r0cemic PAI base (B.N. 2499800407) and 0.25g Aminoindan (B.N. 2500300104) .
The solvent was distilled out of the resulting solution under v0cuum and a 0.75g sample (Sample 1) was taken from 16.75g of the residue.
Then the residue (16.0g) was dissolved in 20 ml absolute
ethanol. Water (27 ml) was added to the ethanolic solution
for 10 minutes at cooling and stirring. During the addition
the batch temperature of 17°C was maintained.
After the addition completion the solution was seeded with solid rasagiline base and crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor. Resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 30 ml of water.
Wet solid (16.5g) was dried at ambient temperature under

reduced pressure (25mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.21%.
Dry product = 14.9g, yield = 93.1%.
Example 34 - Addition of water to rasagiline base solution in ethanol.
Approximately twenty-three grams (20.13g) of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml of ethanol was added to the residue and evaporated.
Then the residue (13.9g) was dissolved in 19.5 ml of ethanol. Water (27.2 ml) was added to the solution for 10 minutes at cooling and stirring. During the addition the batch temperature of 17 °C was maintained. The batch was seeded with solid rasagiline base and immediate crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor, resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 3 0 ml of water.
Wet solid (15.4g) was dried at ambient temperature under reduced pressure (25mbar) to constant weight. (Sample 2) Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.14%.
Dry product = 13.lg, yield = 94.2%.

Example 35 - Addition of water to rasagiline base solution in ethanol.
Twenty-six (26) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 30 ml of ethanol was added to the residue and evaporated.
Then the residue (17.9g) was dissolved in 19.5 ml of ethanol. Water (27.2 ml) was added to the solution for 10 minutes at cooling and stirring. During the addition the batch temperature of 19 °C was maintained. The batch was cooled to 13 °C and seeded with solid rasagiline base. Immediate crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor, resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. Some solid product deposition on the re0ctor wall was observed. The solid was washed on the filter with 30 ml of water.
Wet solid (19.9g) was dried at ambient temperature under reduced pressure (25mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.18%.
Dry product = 17.lg, yield = 95.5%.
Example 36 - Addition of water to rasagiline base solution in ethanol.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary

evaporator. Then 30 ml of ethanol was added to the residue and evaporated.
Then the residue (15.9g) was dissolved in 16 ml of ethanol. Water (27.2 ml) was added to the solution for 10 minutes at cooling and stirring. During the addition the batch temperature of 14-19°C was maintained. The batch was cooled to 13°C (Tj=10°C) and seeded with solid rasagiline base. Immediate crystallization took pl0ce. Then additional 11 ml of water was introduced into the re0ctor, resulting suspension was cooled, stirred at 1-2°C for 30 minutes and filtered. The solid was washed on the filter with 30 ml of water.
Wet solid (17.3g) was dried at ambient temperature under reduced pressure (25mbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF = 0.18%.
Dry product = 15.2g, yield = 95.6%.
Example 37 - Addition of water to rasagiline base solution in ethanol.
Twenty-three (23) grams of dry rasagiline tartrate re0cted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. The mixture was settled, the aqueous layer was separated, and organic phase was washed with water and evaporated under v0cuum in rotary evaporator. Then 3 0 ml of ethanol was added to the residue and evaporated.
Then the residue (16.0g) was dissolved in 19.5 ml of ethanol. Water (25 ml) was added to the solution for 10 minutes at cooling and stirring. During the addition the batch temperature of 17°C was maintained. The batch was cooled to 13°C (Tj=10°C) and seeded with solid rasagiline base. Immediate crystallization took pl0ce. Then additional

25 ml of water was introduced into the re0ctor, resulting
suspension was cooled, stirred at 1-2°C for 30 minutes and
filtered. The solid was washed on the filter with 30 ml of
water.
Wet solid (19.3g) was dried at ambient temperature under reduced pressure (2 5imbar) to constant weight. Water content of the dry product was determined by the Karl Fischer (KF) method.
Water content by KF =* 0.22%.
Dry product = 15.lg, yield = 94.4%.
Summary of Results
The starting material (solid rasagiline base, melt rasagiline base, or r0cemic PAI), the sublimation conditions, the yield after sublimation, and the mean sublimation rates of examples 1-13 are listed in Table 1 below.
The parameters and conditions for crystallization and drying of rasagiline base, the water content of the dried product, and the percentage yield of the drying process in examples 14-26 are summarized in Table 2.

Table 1. Eff0ct of process parameters on PAI sublimation rates

Experiment Starting material Sublimation conditions Sublimed solid Mean sublimation rate

Compound Weight Pressure Temp. Time weight fr0ction Rs1 Rs2 R -l0g Rs1
GA- g mbar °C hr mg %* g/g/hr g/hr/m2 % / hr
12 Solid R-PAI 4.0 2-3 21 8.0 10 0.25 3.12 10'5 1.333 0.0312 4.5
13 Solid R-PAI 3.99 2-3 35 5.33 25 0.62 1.17 10'3 4.978 0.116 2.93
14 Melt R-PAI 3.965 2-3 60 4.0 890 22.4 5.62 10"2 236.19 5.6 1.25
15 Solid R-PAI 4.0 20 21 8.5 0 0.0 0.0 0.0 0.0 -
16 Solid R-PAI 4.0 40 21 8.5 0 0.0 0.0 0.0 0.0 -
17 Solid R-PAI 4.0 40 35 5.33 8 0.20 3.75 10"4 1.593 0.0375 3.42
18 Solid R-PAI 3.992 20 35 5.33 11 0.27 5.15 10"4 2.192 0.0506 3.29
19 Melt R-PAI 4.0 40 60 5.33 25 0.62 1.17 10"3 4.978 0.116 2.93
20 Melt R-PAI 3.975 20 60 5.33 162 4.1 7.64 10"3 32.26 0.769 2.12
21 R0c.PAl oil 4.0 20 22 8.0 0 0.0 0.0 0.0 0.0 -
22 R0c.PAl oil 4.0 20 35 5.33 0 0.0 0.0 0.0 0.0 -
23 R0c.PAl oil 4.0 2-3 22 3.0 10 0.25 8.33 10"4 3.537 0.08 3.08
24 R0c.PAl oil 4.0 2-3 60 1.3 130 3.25 2.50 10"2 101.16 2.5 1.60

Table 2. Crystallization and drying process parameters

Experiment Solvent Water ratio, ml/g base Crystallization
temperature,
°C Drying
conditions
mbar Drying
conditions
°C Water
content by
KF (%) Dry product yield
%
No. Type Ratio, ml/g base

25 EtOH 1.27 2.46 18-20 4-5 25 0.18 90.9
26 I PA 1.27 2.46 18-20 4-5 25 0.21 92.5
27 I PA 1.25 1.69 0-5 4-5 25 0.06 86.7
28 No 0 3.75 0-5 4-5 25 0.10 88.2
29 EtOH 1.25 3.75 0 4-5 25 0.06 88.2
30 EtOH 1.25 2.38 17-18 25 RT N/A 88.7
31 I PA 1.23 2.40 14-19 25 RT 0.20 93.7
32 EtOH 1.23 2.40 17-18.5 25 RT 0.17 94.3
33 EtOH 1.25 2.40 17 25 RT 0.211 93.1
34 EtOH 1.40 2.75 17 25 RT 0.14 94.2
35 EtOH 1.09 2.13 17 25 RT 0.18 95.5
36 EtOH 1.00 2.40 17 25 RT 0.18 95.6
37 EtOH 1.22 3.12 17-18.5 25 RT 0.22 94.4

Discussion
The data show that rasagiline base and r0cemic PAI base have similar sublimation ability, i.e., the sublimation rates of the R-isomer and r0cemic mixture are similar.
Eff0cts of v0cuum and temperature on sublimation rate of rasagiline base and r0cemic PAI base are represented graphically on Figure 1 and Figure 2.
The figures demonstrate that at high v0cuum (pressure less than 3 mbar) and elevated temperatures (600c and higher), high sublimation rate was observed.
The figures also demonstrate that at moderate v0cuum (pressure higher than 20 mbar) and low temperatures (less than 220c), zero sublimation rate was observed.
The figures further demonstrate that at a temperature of between 0°C and 20°C and a pressure of between 4-25 mbar, dried rasagiline contains between 0.06-0.22% water by weight, and the dry product yield is between 86.7%-95.6% by weight.
Conclusions
Moderate v0cuum (pressure higher than 20 mbar) and low temperatures (less than 35°C) could be r0commended as conditions for drying of solid rasagiline base from solvent after crystallization.

Experimental Details - Set 3: Drying and Purifying of
Rasagiline Base
Wet Rasagiline Tartrate was used for the production of Rasagiline base which contained 27.8% of isopropanol.
1. The Production Process
A number of processes for manuf0cture of rasagiline solid base are described in PCT International Application Publication No. WO 2008/076348, the content of which is hereby incorporated by reference. One batch was manuf0ctured 0ccording to the production process described.
1.1. The process
Example 38. Preparation of rasagiline base solid - large scale
The production process included the following operations:
a. Splitting of wet Rasagiline Tartrate with NaOH:



HO^.COOH
X
+ 2NaOH
HN-
HN
HO' COOH
HO^^COONa + I + 2H20 V HO" COONa
%
%
Rasagiline Rasagiline base
Hemi Tartrate
/
b. Isolation of free Rasagiline base as oil-like product;
c. Dissolution of Rasagiline base in Ethanol and seeding
induced crystallization of the Rasagiline base by
water addition;
d. Filtration and wash of the solid product; and
e. Drying of the solid Rasagiline base.
Since Rasagiline base is low melting material it is

processed in to the Drug Product without milling.
Process parameters and conditions are summarized in Tables 1.1 - 1.3 below.
Table 1.1. Process parameters for Rasagiline base production - Tartrate splitting and Rasagiline base isolation steps

Process parameters: Unit Amount
Amount of Rasagiline Tartrate (starting
material)
Wet
Dry- kg kg 9.5 6.86
Total amount of 25% NaOH solution kg 7.0
pH after basification 13
Re0ctor temperature during the basification and splitting 0C 41-47
Duration of the basification, splitting and wash hrs 3.5
Toluene evaporation Duration hrs 3.3

End of evaporation temperature 0c 60

End of evaporation pressure mmHg 38
Ethanol evaporation Duration hrs 1.6

End of evaporation temperature 0c 60

End of evaporation pressure mmHg 44
Rasagiline base oil dissolution Duration min 27

Re0ctor temperature (Tr) 0c 30-40
Filtration (0.2u) and wash Duration mm 4 + 1

Solution temperature 9C 35-40

Table 1.2. Process parameters or Rasagiline base production - Rasagiline base crystallization steps

Process parameters: Unit Amount
Ethanolic solution holding Duration Hrs 7.7

Solution temperature* SC 10-22
Amount of water introduced prior to seeding Kg 2.3

%** 19.2
Seeding and breeding Temperature, (Tr) 0c 14

Stirrer speed Rpm 112

Duration Hrs 2
Water addition Temperature, (Tr) SC 11-12

Duration mm 66
Cooling End temperature, (Tr) SC 4

Stirrer speed rpm 112-177

Duration mm 95
Batch stirring prior to filtration Duration mm 36

Temperature, (Tr) 9C 3-4
** - per cent on total volume of added water
Table 1.3. Process parameters for Solid Rasagiline base isolation - filtration, washing, drying

Process parameters: Unit Amount
Filtration and cake purging time Min. 7
Washing time (two washes) Min. 1 + 1
Drying Pressure mmHg 23-30

Temperature (Tj) 9C 23-35

Agitator speed rpm 8

Duration (agitated) hrs 48(34)
Water in dry product by K.F. % 0.05
Dry product yield, % calculated on dry kg 3.7
starting Rasa giline Tartrate % 77.7

1.2. Results and discussion
During the production of the batch, there were two t0chnical problems related to large scale processing -spontaneous crystallization of Rasagiline base oil and ineff0ctive drying of solid product.
In addition to the above mentioned two issues, the content of S-isomer in the drug substance was 0.3 5%, which is much higher than the sp0cification level (NMT. 0.1%).
These three issues are discussed below in details.
1.2.1. Crystallization and dissolution of Rasagiline base oil
Isolated Rasagiline base oil between the operations step 1.2 and 1.3 was stored in the re0ctor under nitr0gen at cooling overnight. The base solidified forming a block in the bottom part of the re0ctor. The solid glass like mass of Rasagiline base was dissolved in absolute ethanol in more than 2 hours.
The proposed solution of this problem was to prevent the solidification of Rasagiline base oil by holding its solution in ethanol between the operations 2 and 3. Laboratory simulation experiments were performed in order to evaluate the eff0ct of this process change on yield and purity of crystallized product.
1.2.1.1. Laboratory scale simulation
Two batches of Rasagiline base were prepared in order to simulate the storage of Rasagiline base in ethanol solution at different temperatures.
The experiments and the results are detailed below:
Example 39. Rasagiline base oil hold in ethanol solution for 48hrs at cooling (7 - 80c)
17.0 g of Rasagiline base oil was dissolved in 17g absolute ethanol. The resulting solution was introduced into

refrigerator and stored at 7-8 9C for 48 hrs. The ethanol solution was sampled (sample 1).
The clear solution was then introduced into 100ml j0cketed glass re0ctor equipped with a stirrer, thermometer and circulating oil bath.
The re0ctor was cooled (Tj=ll0c) and 8g of water was
introduced at stirring. Then the solution was seeded with
solid Rasagiline base and crystallization was observed. The
batch was stirred for 15 min at 11-12 SC and then 33.8g of
water was added. The resulting suspension was cooled to 4SC
and stirred at 1- 40c for 3 0 min. The solid was filtered
and washed twice with 17ml water. Wet solid product (17.6g)
was dried under v0cuum.
Dry product - 15.7g
Crystallization yield - 92%
Analysis:
Sample 1 (solution):
Purity by HPLC:
S-isomer - 0.77%
IDD - 1-Aminoindan - L.T. 0.05% (QL)
Dry product:
Color - White to off-white
Assay - 99.5%
IDD - N.D.
S-isomer - 0.01%
m.p. - 39.5 - 40.40c
Water content by K.F. - 0.2% wt.
Example 40. Rasagiline base oil hold in ethanol solution
for 48hrs at ambient temperature
17.0 g of Rasagiline base oil was dissolved in 17g absolute
ethanol. The resulting solution was stored at ambient
temperature (20 - 28 9C) for 48 hrs. The ethanol solution
was sampled (sample 1).
The clear solution was then introduced into 100ml j0cketed glass re0ctor equipped with stirrer, thermometer and

circulating oil bath.
The re0ctor was cooled (Tj=110c) and 8g of water was
introduced at stirring. Then the solution was seeded with
solid Rasagiline base and crystallization was observed. The
batch was stirred for 20 min at 11-129C and then 33.8 g
water was added. The resulting suspension was cooled to 49C
and stirred at 1- 40c for 30 min. The batch was filtered
and washed twice with 17ml water. Wet solid product (18.2g)
was dried under v0cuum.
Dry product - 15.9g
Crystallization yield - 93.5%
Analysis:
Sample 1 (solution):
Color - Yellowish
Purity by HPLC:
S-isomer - 0.76%
IDD - 1-Aminoindan - L.T. 0.05% (QL)
Dry product:
Assay - 99.9%
IDD - N.D.
S-isomer - 0.01%
Melting range - 39.6 - 40.69C
Water content by K.F. - 0.1% wt.
1.2.1.2. Results, discussion and conclusion
The data presented above demonstrate that holding of Rasagiline base as ethanol solution for 48 hrs in air prior to crystallization do not aff0ct the yield and quality of solid product. Crystalline Rasagiline base prepared from the solution stored at low temperature (7-8QC) has the same purity as the product prepared from the solution stored at room temperature.
As a result, rasagiline base between the isolation and crystallization operation should be held in ethanol solution. This operation mode prevents spontaneous crystallization of Rasagiline base oil and problems with its dissolution.

1.2.2. Drying
Wet Rasagiline base was dried under v0cuum (23-3 0 mm Hg) at ambient temperature (230c) with no stirring for 14 hours with any results. The solid remained wet and contained 28% water.
After 14 hours of static drying the cake was stirred (8 rpm) and the dryer j0cket was gradually heated to 350c during 9 hours. At this step the drying rate was increased significantly - the cake was sampled and only 15% of water was found in the solid.
The drying was continued under the same conditions for additional 17 hours (overnight) . Then the cake was sampled and found dry (0.07% of water).
Additional 8 hours of drying had no significant eff0ct on water content - 0.05% of water was found in the next sample.
The drying regime mentioned above (P<35 mm Hg; Tj=350c and stirring 8 rpm) was found eff0ctive for Rasagiline base.
1.2.3. Solid uniformity
In the above drying process, the Drug Substance (DS) is hom0genized by prolonged stirring during the drying operation. A sp0cial sampling pr0gram was prepared and performed during the production in order to prove the hom0geneity and uniformity of the DS after the drying.
Dry Rasagiline base was sampled 5 times from different zones of the dryer. Additional 6th sample was prepared by mixing of the materials from e0ch of the 5 sample. These six samples were analyzed for water content, assay, purity, melting point, s-isomer content and particle size distribution. The results of analysis are shown in Table 2.1. The data show uniformity of the dry product.

Table 2.1. Rasagiline base samples analysis results

Sample: 01-1 01-2 01-3 01-4 01-5 Mix
Color Off-white Off-white Off-white Off-white Off-white Off-white
S-isomer, % 0.36 0.36 0.32 0.35 0.35 > 0.1 (OOS)
IDD, (%) N.D. (>0.02) N.D. (>0.02) N.D. >0.02) ( N.D. (>0.02) N.D. (>0.02) N.D. (>0.02)
Assay by HPLC, % 99.9 100.7 99.7 99.9 100.1 99.0
Water by K.F., % 0.05 0.04 0.05 0.05 0.04 0.04
Melting range, 2 C 38.7-39.7 38.8-40.0 38.8-39.4 38.8-39.5 38.8-39.8 N.A.
PSD by
Malvern,
Microns
d(0.1)
d(0.5)
d(0.9) 242.5 549.0 1124.4 236.8 539.4
1121.1 249.8 562.1 1148.8 239.9 543.3 1111.3 249.3 557.6 1117.2 235.3 531.6 1076.7
Morphol0gy group 1 1 1 1 1 1
The data in the above table demonstrate that the dryer provides eff0ctive hom0genization of 3.5 kg batch of Rasagiline base.
1.2.4. S-isomer in solid product
The data presented in Table 2.1 demonstrate high level of S-isomer (OOS) found in the batch of Rasagiline base.
The data were found surprising b0cause the typical S-isomer level in the crystalline base was below 0.1%. In small scale rasagiline base prepared contained 0.02-0.03% of this impurity. The level of 0.35% of S-isomer in the crystallization product could be obtained using a starting material having more than 2% of this impurity.

1.2.4.1. Simulation of the crystallization
The difference in processing time is illustrated by-comparison of temperature profiles of pilot and laboratory-batches on Figure 3.
Crystallization of small scale normally takes about 2.5 hours, but the large scale was processed during 6.5 hours. The eff0ct of processing time on optical purification was studied in the following experiments.
Example 41. Rasagiline base preparation
lO0g of wet Rasagiline Tartrate was mixed with 160ml water at stirring. 63g of 25% NaOH solution and 2 00g toluene were added to the mixture, the batch was stirred for 1 hour at 40-50SC (pH=13) and then settled at this temperature for 0.5 hour. Lower aqueous phase was separated and discarded and 100ml of water was added to the batch. Then the mixture was stirred for 0.5 hour and settled for 0.5 hour at 40-502. Lower aqueous phase was separated and discarded. Upper organic phase was evaporated on rotary evaporator under v0cuum. Temperature profile of the evaporation was the same as in the pilot batch - total evaporation time was 3hrs 2 0 min, the residue was exposed to temperature 550c during lhr 20 min and to 600c during 2 hrs.
After evaporation of toluene 75 g of absolute ethanol was added to the residue and the evaporation was continued. Total evaporation time was 2 hrs 40 min, the residue was exposed during the evaporation to temperature 559C and then to 600c.
Residual product - oil of Rasagiline base (52g) was cooled and stored at 59C overnight. Then the base was dissolved in 52g of absolute ethanol at stirring and 24ml of water was added. Then the resulting clear solution was cooled to 12.50c and seeded with crystalline Rasagiline base. The crystallizing batch was stirred at 11 - 12BC for 2 hours. 103g of water was introduced dropwise during one hour at

cooling then the batch was cooled to 4QC during 1 hour 45 min and stirred at 1 - 4SC for 30 min.
One half of the batch was withdrawn out of crystallizer and filtered. The solid was washed with 50 ml of water and dried under v0cuum. Dry product (26.2g) and filtrate (mother liquor) were sampled - Samples 4 (solid) and 2 (M.L.)
The s0cond half of the batch was stirred at cooling (l0c)
overnight, total holding time at T<4SC was 14 hrs. Then
this half batch was filtered, the solid was washed with
50ml water and dried under v0cuum. Dry product (17.8g) and
filtrate (mother liquor) were sampled - Samples 7 (solid)
and 5 (M.L.)
Analysis:
Solids:
Sample 4:
S-isomer - N.D.
Assay by HPLC - 99.4%
Purity by HPLC (IDD) - N.D.
Melting range - 39.8 - 40.50c
Sample 7:
S-isomer - N.D.
Assay by HPLC - 99.5%
Purity by HPLC (IDD) - N.D.
Melting range - 39.5 - 40.70c
Mother Liquors:
Sample 2:
S-isomer - 31.3%
Rasagiline concentration by HPLC - 5.8 mg/ml
Purity by HPLC (IDD) - 1-Aminoindan - 1.37%; RRT=1.47 -
0.03%; RRT=1.60 - 0.05%; 1-Indanone - 0.15%, RRT=7.8 -
0.07%
Sample 5:
S-isomer - 26.9%
Rasagiline concentration by HPLC - 6.8 mg/ml
Purity by HPLC (IDD) - 1-Aminoindan - 1.17%; RRT=1.47 -
0.03%; RRT=1.60 - 0.04%; 1-Indanone - 0.13%

1.2.4.2. Results, discussion and conclusion
Level of S-isomer in Rasagiline base prepared using prolonged crystallization (14 hours, Sample 7) was undet0ctable. The same level of this impurity was found in the product crystallized during 1 hour (Sample 4).
In Table 3.1 composition of mother liquors of the small scale experiments is compared to the mother liquor of a large batch. Table 3.1 shows that purity profiles of the mother liquor in the simulation experiments are very similar to the large scale batch. At the same time concentration of S-isomer in large scale mother liquor is about 3 times lower than in the small scale experiments.

Table 3.1. Composition of laboratory and pilot mother liquors of Rasagiline base crystallization

Example No. 41 -Sample 5 Example No. 41 -Sample 2 Example No. 3 8
Holding at T<40c hrs 14 1 1
S - isomer % 26.9 31.3 9.7
Rasagiline base cone. mg/ml 6.8 5.8 7.9
IDD:
RRT=0.45 1-AI RRT=1.5 RRT=1.6 1-Indanone RRT=7.8 % area N.D. 1.17 0.03 0.04 0.13 N.D. 0.02 1.37 0.03 0.05 0.15 0.07 N.D. 0.93 N.D. 0.05 0.02 2.06
The data show that the r0cemization of R-isomer of Rasagiline base does not take pl0ce under the large scale process conditions. The results of simulation experiment show that processing time has no eff0ct on optical purification of Rasagiline base.
Two possible solutions for the S-isomer problem:
i) Re-crystallization of S-isomer contaminated Rasagiline
base; and
ii) Additional optical purification of starting material -
Rasagiline Tartrate.
These two appro0ches were studied on both small scale and large scale for the production of Rasagiline base Drug Substance. The study is described in the following s0ctions.
2. Optical purification of Rasagiline base
2.1. Re-crystallization of Rasagiline base - small scale
Rasagiline base with 0.35% of S-isomer from the rej0cted

pilot batch 255500208 was re-crystallized in the laboratory using the same crystallization procedure as was used on pilot scale.
Example 42. Rasagiline base re-crystallization
49.5g of Rasagiline base introduced into 0.5 liter j0cketed glass re0ctor with 52g of absolute ethanol. The batch was stirred and heated (Tj=3 5sC) until complete dissolution of the solid.
The solution was cooled and 24g of water was added at stirring. The resulting clear solution was seeded at 120c with solid Rasagiline base and stirred at 11 - 120c for one hour. Crystallization was observed on this step.
103g of water was added at cooling and stirring during 2 0 minutes then the batch was cooled to 40c and stirred at 2-40c for 45 minutes.
The batch was cooled, the solid washed with 2x50ml water
and dried under v0cuum to constant weight.
The solid product (45.5g) was sampled (Sample 1)
Filtrate (combined Mother Liquor and washes) was evaporated
under v0cuum in rotary evaporator. The oily evaporation
residue (l.lg) was sampled (Sample 2) and subj0cted to
analysis with the solid product.
Analysis:
Solid:
Sample 1:
S-isomer - N.D.
Assay by HPLC - 98.8%
Purity by HPLC (IDD) - 3PAIO - L.T. 0.05% (QL); 1-
Aminoindan - L.T. 0.05% (QL); 1-Indanone - L.T. 0.05% (QL)
Melting range - 39.1 - 39.80c
Mother Liquor:
Sample 2 (residue after evaporation):
Assay by HPLC - 91.3%
S-isomer - 7.8%
Purity by HPLC (IDD) - 3PAIO - L.T. 0.05% (QL);1-Aminoindan

- 0.2%; RRT=0.92 - 0.08%; RRT=1.62 - 0.13%; RRT=2.27 -0.05%; 1-Indanone - L.T. 0.05% (QL); RRT=6.6 - 0.1%; Total IDD - 0.5%
2.2. Discussion and conclusions
The experiment detailed above demonstrates the possibility of complete separation of S-isomer from Rasagiline base having 0.35% of this impurity. This result is in 0ccordance with our previous findings of optical purification on laboratory scale.
3. Purification of Rasagiline Tartrate
3.1. General considerations
Crystallization of Rasagiline salts as Rasagiline Tartrate could result in complete separation of S-isomer from the Tartrate. Purified Rasagiline Tartrate with very low level of S-isomer could be converted into Rasagiline base with almost zero content of this impurity with eff0ct on the optical purity in a large scale batch.
Study of Rasagiline Tartrate re-crystallization was performed in order to evaluate the possibility of additional optical purification of this intermediate.
3.2. Re-crystallization of Rasagiline Tartrate
3.2.1. Procedure evaluation
Rasagiline Tartrate crystallization experiments were performed in 0.5 liter j0cketed glass re0ctors equipped with stirrer, circulating oil bath for heating and cooling, condenser and thermometer. V0cuum oven was used for solid drying.
Starting material with 0.7% of S-isomer was used in all experiments. Solid and liquid products were analyzed for IDD and S-isomer by HPLC.
Example 43. Crystallization from 8 volumes of water
50. 0g of Rasagiline Tartrate was introduced into re0ctor, 300 ml of water was added, the mixture was stirred and

heated (Tj=85sC), at 720c complete dissolution of solids was observed.
The re0ctor was cooled slowly and seeded with Rasagiline
Tartrate at 630c. Then crystallization was observed and the
re0ctor was cooled to 209C during 2 hrs. After stirring for
30 min at 2 00c the batch was filtered, the solid washed
with 30 ml water and dried under v0cuum at 500c to constant
mass.
Wet solid - 36.9g
Dry solid - 26.6g
Yield - 70.9%
Analysis;
Solid:
Appearance - White solid
S-isomer - 0.01% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Mother Liquor:
S-isomer - 2.48% area
1-Aminoindan - 0.26% area, IDD - RRT=1.96 - 0.01% area;
RRT=2.29 - 0.02% area against the main peak of Rasagiline
Example 44. Slurry-to-slurry re-crystallization from 4 volumes of water
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water, the mixture was stirred and heated (Tj=85sC), to 750c , no dissolution of solids was observed.
The resulting slurry was stirred at 750c for 90 minutes and
cooled to 120c during 40min. After stirring for 40 min at
10-120c the batch was filtered, the solid washed with 40 ml
water and dried under v0cuum at 500c to constant mass.
Wet solid - 38.4g
Dry solid - 26.7g
Yield - 71.1%
Analysis:
Solid:
Appearance - White solid

S-isomer - 0.11% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Mother Liquor:
S-isomer - 2.62% area
1-Aminoindan - 0.35% area, IDD - RRT=1.96 - 0.02% area -
against the main peak of Rasagiline
Example 45. Slurry-to-slurry re-crystallization from 4 volumes of water, crop B pr0cipitation with anti-solvent Crop A:
50.0g of Rasagiline Tartrate was introduced into re0ctor
with 150 ml of pre-heated water (Tj=850c) , the mixture was
stirred and heated, to 750c , no dissolution of solids was
observed. The resulting slurry was stirred at 75-770c for
90 minutes and cooled to 70c during one hour. After
stirring for 40 min at 5-70c the batch was filtered, the
solid washed with 75 ml water and dried under v0cuum at
500c to constant mass.
Wet solid - 40.5g
Dry solid - 30.7g
Yield - 81.9%
Analysis;
Solid:
Appearance - White solid
S-isomer - 0.11% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Mother Liquor:
S-isomer - 4.47%
1-Aminoindan - 0.62% area; IDD - RRT=1.96 - 0.06% area -
against the main peak of Rasagiline
Crop B:
Mother Liquor from Crop A filtration divided on two equal
portions (70ml e0ch)
1st portion, pr0cipitation with Isopropanol
Mother Liquor cooled to 70c at stirring, 20ml IPA was added, solid pr0cipitation observed. The suspension was

stirred at 5-79C for 30 min and filtered. The solid washed
with IPA and dried under v0cuum at 509C to constant mass.
Wet solid - 0.9g
Dry solid - 0.7g
Yield - 1.9%
Analysis:
Solid:
Appearance - White solid
S-isomer - 0.15% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Mother Liquor:
S-isomer - 8.3 6% area
1-Aminoindan - 1.14% area; IDD - RRT=0.37 - 0.02% area;
RRT=0.79 - 0.01% area; RRT=1.32 - 0.01% area; RRT=1.40 -
0.02% area; RRT=1.88 - 0.03% area; RRT=1.96 - 0.11% area -
against the main peak of Rasagiline
2nd portion, pr0cipitation with Ethanol
Mother Liquor cooled to 79C at stirring, 20ml Ethanol was
added, solid pr0cipitation observed. The suspension was
stirred at 5-70c for 30 min and filtered. The solid washed
with Ethanol and dried under v0cuum at 509C to constant
mass.
Wet solid - 0.9g
Dry solid - 0.6g
Yield - 1.6%
Analysis:
Solid:
Appearance - White solid
S-isomer - 0.07% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Mother Liquor:
S-isomer - 6.76% area
1-Aminoindan - 0.93% area; IDD - RRT=0.37 - 0.01% area;
RRT=0.79 - 0.02% area; RRT=1.32 - 0.01% area; RRT=1.96 -
0.08% area - against the main peak of Rasagiline

Example 46. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=850c), to 75SC, no dissolution of solids was observed. The resulting slurry was stirred at 77-790c for 90 minutes and then cooled to 250c. 40 ml of IPA was added and the batch was cooled to 50c. After stirring for 30 min at 59C the batch was filtered, the solid washed with 3 0 ml IPA and dried under v0cuum at 500c to constant mass. Wet solid - 47.9g Dry solid - 35.9g Yield - 95.7% Analysis; Solid:
Appearance - White solid S-isomer - 0.07% area
1-Aminoindan < 0.08% by HPLC against analytical standard IDD - no additional peaks det0cted

Table 4.1. Rasagiline Tartrate re-crystallization

Example No.: 43 44 45 (crop A) 46
Purification procedure Crystallization from solution Slurry
to
slurry Slurry
to
slurry Slurry
to
slurry
Water to Tartrate ratio (on dry basis) g/g 8 4 4 4
Anti-solvent (ratio to water) ml/ml - - - I PA (0.27)
Cooling temperature 0c 20 12 7 5
Washing ml/g
dry
solid Water 1.1 Water 1.5 Water 2.4 I PA 0.8
Pure Tartrate yield (on dry basis) % 70.9 71.1 81.9 95.7
S-isomer content: In Tartrate In Mother Liquor % area 0.01 2.48 0.11 2.62 0.11 4.47 0.07 N.A.
1-Aminoindan content: In Tartrate In mother liquor % wt.
%
area L.T. 0.08 0.26 L.T. 0.08 0.35 L.T. 0.08 0.62 N.A. N.A.
The results in the above Table 4.1 show that re-crystallization of Rasagiline Tartrate from 4 volumes of water in slurry-to-slurry regime is very eff0ctive providing good yield and high optical purity. Additional work was performed in order to optimize the method and to evaluate the eff0ct of process parameters on Rasagiline Tartrate purification.

3.2.2. Process parameterization
The following examples were performed to study the eff0ct of most important process parameters on yield and purity of re-crystallized Rasagiline Tartrate.
Example 47. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 1000c
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=1000c), to 900c, dissolution of most of the solid was observed. The resulting slurry was stirred at 900c for 90 minutes and then cooled to 250c. 40 ml of IPA was added and the batch was cooled to 50c. After stirring for 30 min at 59C the batch was filtered, the solid washed with 3 0 ml IPA and dried under v0cuum at 500c to constant mass. Wet solid - 57.7g Dry solid - 37.9g
Yield - 93.7% (calculated 0ccording to starting material L.O.D. = 20%) Analysis; Solid:
Appearance - White solid S-isomer - 0.01% area IDD - no additional peaks det0cted 1-Aminoindan - N.D.
Example 48. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 650c
50. 0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=650c), to 63SC, no dissolution of solids was observed. The resulting slurry was stirred at 63-64sC for 90 minutes and then cooled to 250c. 40 ml of IPA was added and the batch was cooled to 50c. After stirring for 30 min at 50c the batch was filtered, the solid washed with 30 ml IPA and dried under v0cuum at 509C to constant mass. Wet solid - 55.0g Dry solid - 37.7g Yield - 94.5%

Analysis: Solid:
Appearance - White solid
S-isomer - 0.32% area
1-Aminoindan < 0.08% by HPLC against analytical standard
IDD - no additional peaks det0cted
Example 49. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 850c, stirring time -15 min
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=85sC) , to 750c, dissolution of most of the solid was observed. The resulting slurry was stirred at 759C for 15 minutes and then cooled to 259C. 40 ml of IPA was added and the batch was cooled to 59C. After stirring for 30 min at 50c the batch was filtered, the solid washed with 3 0 ml IPA and dried under v0cuum at 500c to constant mass. Wet solid - 55.0g Dry solid - 37.5g
Yield - 93.7% (calculated 0ccording to starting material L.O.D. = 20%) Analysis: Solid:
Appearance - White solid S-isomer - 0.19% area IDD - no additional peaks det0cted 1-Aminoindan - N.D.
Example 50. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 85-C, stirring time -150 min
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=850c) , to 750c, dissolution of most of the solid was observed. The resulting slurry was stirred at 750c for 150 minutes and then cooled to 250c. 40 ml of IPA was added and the batch was cooled to 50c. After stirring for 30 min at 50c the batch was filtered, the solid washed with 3 0 ml IPA

and dried under v0cuum at 50SC to constant mass.
Wet solid - 51.9g
Dry solid - 38.4g
Yield - 96.0% (calculated 0ccording to starting material
L.O.D. = 20%)
Analysis;
Solid:
Appearance - White solid
S-isomer - 0.10% area
IDD - no additional peaks det0cted
1-Aminoindan - N.D.
Example 51. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 85SC, 100ml of IPA
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=850c) , to 75SC, dissolution of most of the solid was observed. The resulting slurry was stirred at 75SC for 90 minutes and then cooled to 250c. 100 ml of IPA was added and the batch was cooled to 50c. After stirring for 30 min at 5SC the batch was filtered, the solid washed with 3 0 ml IPA and dried under v0cuum at 500c to constant mass. Wet solid - 50.2g Dry solid - 37.7g
Yield - 93.2% (calculated 0ccording to starting material L.O.D. = 20%) Analysis: Solid:
Appearance - White solid S-isomer - 0.10% area IDD - no additional peaks det0cted 1-Aminoindan - N.D.
Example 52. Slurry-to-slurry re-crystallization from 4 volumes of water and Isopropanol, Tj = 85-C, prolonged cooling time
50.0g of Rasagiline Tartrate was introduced into re0ctor with 150 ml of water. The mixture was stirred and heated (Tj=850c) , to 750c, dissolution of most of the solid was

observed. The resulting slurry was stirred at 75BC for 90
minutes and then cooled to 259C. 40 ml of IPA was added and
the batch was cooled to 20c. After stirring for 12 hours at
1-20c the batch was filtered, the solid washed with 30 ml
IPA and dried under v0cuum at 50SC to constant mass.
Wet solid - 52.5g
Dry solid - 38.lg
Yield - 95.2% (calculated 0ccording to starting material
L.O.D. = 20%)
Analysis:
Solid:
Appearance - White solid
S-isomer - 0.05% area
IDD - no additional peaks det0cted
1-Aminoindan - N.D.
The results of parameterization experiments are summarized
below in Table 5. The data show that re-crystallization
process parameter as processing time and temperature have
strong eff0ct on Tartrate optical purification.
Table 5.1. Eff0ct of process parameters on Rasagiline Tartrate purification

Re-
crystallization temperature, 0c Time Cooling Time, Yield S-isomer IDD, (AI)
Example No. Tj Tr min hrs % % (%)
47 100 90 90 0.5 93.7 0.01 N.D.
48 65 63 90 0.5 94.5 0.32 L.T. 0.08
49 85 75 15 0.5 93.7 0.19 N.D.
50 85 75 150 0.5 96.0 0.10 N.D.
51 85 75 90 0.5 93.2 0.10 N.D.
52 85 75 90 12 95.2 0.05 N.D.
D0crease of re-crystallization temperature from 75 0c to 63 0c and re-crystallization time from 90 to 15 minutes causes significant increase of S-isomer level in the solid product. At the same time no significant eff0ct of the

process parameters on the Yield was observed.
Figure 4 shows that during the re-crystallization of the Tartrate salt significant change in the solid morphol0gy take pl0ce. Rasagiline Tartrate crystallized from isopropanol or any other organic solvent has needle-like crystal habit.
As shown in Figures 4 and 5, the needle-like crystals of starting Rasagiline Tartrate are transformed to rod-shaped crystals of re-crystallized product.
3.3. Purification of Rasagiline Tartrate on large scale
Two batches of purified Rasagiline Tartrate were produced on large scale 0ccording to the procedures described in S0ction 3.2. The process was based on the Example 46.
The results of the production are summarized in Tables 6.1 and 7.1 below.

Table 6.1. Large Scale production of Rasagiline Tartrate Pure, Process parameters

Process parameters: Batch 1 Batch 2
Starting Rasagiline
Tartrate Wet
Dry Kg kg 10.0 6.97 10.0 6.97
Stirrer speed rpm 240 240
Re-crystallization temperature: Start End 0c 0c 75 80 75 80
Re-crystallization time mm 93 90
Cooling to 300c time mm 116 121
Cooling to 100c time mm 137 141
Drying temperature (Bath) 0c 55 55
Drying pressure:
Start
End mm Hg 49 23 49 22
Drying duration hrs 15.3 15
Dry product yield Kg
% 6.1 87.5 6.0 86.0
Table 7.1. Quality of large batches of Rasagiline Tartrate Pure

Test Sp0cification Batch 1 Batch 2
Description (SI-2000) White solid White solid White solid
Enantiomeric purity (limit test by HPLC) S-isomer; NMT 0.3% LT 0.3% LT 0.3%
Identification (by HPLC) RT of the main peak Conforms Conforms
Chromat0graphic purity (by HPLC) AI - NMT 1.5%; Any other - NMT 0.1% LT 0.08% (QL) L.T. 0.02 LT 0.08% (QL) L.T. 0.02
L.O.D. NMT 0.5% 0.04% 0.04%

4. Reprocessing of Rasagiline base in Large Scale
The batch of Rasagiline base produced in Example 3 8 was reprocessed in order to reduce the level of S-isomer from 0.35% and to fit the sp0cifications.
The reprocessing procedure was based on re-crystallization Example 42. High yield and good product quality were 0chieved. Process parameters of the laboratory scale and pilot reprocessing batches are compared in Table 8.1. Product quality of the laboratory and pilot batches is presented in Table 9.1.
The data show that there is no significant eff0ct of the
process scale on the reprocessing results. The batch was
released by QC/QA and used for stability tests and
formulation development.
Table 8.1. Rasagiline base re-crystallization parameters on small scale and large scale batches

Small scale Large scale
Scale,
Batch size, starting
material kg 0.0495 3.43
Solvent ratio Ethanolrbase ml/g 1.33 1.35

Water:base ml/g 2.57 2.60
Percent of water introduced prior to seeding % 18.9 19.0
Seeding temperature 0c 12 12
Cooling temperature 0c 2-4 3-4
Cooling time min 45 30
Drying conditions Dryer Glass tray in v0cuum oven Hastelloy
agitated
filter-dryer

Temperature 0c Ambient 35

Pressure mbar 20 20 - 33

Duration hrs 16 14.6
Yield of dry Kg 0.0455 3.05
product % 91.9 89.0

Table 9.1. Major quality parameters of small scale and large scale batches of re-crystallized Rasagiline base

Small scale Large scale
Color Off-white Off-white
Enantiomeric purity (S-isomer) % N.D. Passes (N.D.)
Assay by HPLC % 99.8 99.7
IDD by HPLC:
1- Aminoindan
1- Indanone
3-PAIO
Any other impurity % L.T. 0.05
(Q.L.)
L.T. 0.05
(Q.L.)
L.T. 0.05
(Q.L.) N.D. L.T. 0.02
(D.L.)
L.T. 0.02
(D.L.)
L.T. 0.02
(D.L.)
L.T. 0.02
(D.L.)
Melting range 0c 39.1 - 39.8 39.2 - 40.6
5. Production of Rasagiline base from purified Rasagiline Tartrate
Two large scale batches of Rasagiline base were produced with purified Rasagiline Tartrate. In addition, Rasagiline base was held in ethanol solution prior to crystallization during the process.
Process parameters and conditions are summarized below in Tables 10.1, 10.2, and 10.3 in step-by-step order. The data presented in Tables 10.1-10.3 demonstrate good process reproducibility in large scale and scalabilty of the production procedure.

Table 10.1. Process parameters or Rasagiline base production. Large scale
Tartrate splitting and Rasagiline base isolation Steps

Process parameters: Batch 1 Batch 2
Amount of Rasagiline Tartrate Pure (starting material) kg 6.1 6.0
Total amount of 25% NaOH solution kg 5.8 5.8
pH after basification 13 13
Re0ctor temperature during the basification and splitting 0c 43 - 49 40 - 50
Duration of the basification and splitting hrs 4 4
Toluene evaporation Duration hrs 2.3 2.1

Temperature 0c 22 - 60 22 - 60

Pressure mmH
g 67 - 43 70 - 43
Ethanol evaporation Duration hrs 1.5 1.3

Temperature 0c 21 - 60 19 - 60

Pressure mmH
g 49 45-46
Rasagiline base oil dissolution Duration min 32 30

Temperature 0c 38 39
Filtration (0.2u) and wash Duration mm 7 5

Temperature 0c 38 39

Table 10.2. Process parameters or Rasagiline base production, Large scale
Rasagiline base crystallization Steps

Process parameters: Batch 1 Batch 2
Ethanolic
solution
holding Duration hrs 11.6 12.8

Temperature 9C 10-2 10 - 17*
Amount of water introduced prior to seeding kg 2.0 2.0

% 19 19
Seeding and breeding Temperature 0c 11 - 12 11 - 12

Stirrer speed rpm 153 180

Duration mm 116 67
Water addition Temperature 0c 11 - 14 12

Duration mm 77 60
Cooling End temperature 0c 6 6

Stirrer speed rpm 185 178

Duration mm 120 78
Batch stirring prior to filtration Duration mm 98 60

Temperature 0c 6 5
* - Cooling system failure during the overnight holding of
the batch

Table 10.3. Process parameters or Rasagiline base production. Large scale
Solid Rasagiline base isolation - filtration, washing, drying Steps

Process parameters: Batch 1 Batch 2
Filtration and cake purging time mm 6 15
Washing time (two washes) mm 15 17
Drying Pressure mmHg 37 - 22 41 - 22

Temperature (Tj) 0c 35 35

Agitator speed rpm 7 15

Duration hrs 20.2 22
Water in dry product by
K.F. % 0.07 0.06
Dry product yield kg 3.6 3.7
% 85.0 88.7

Quality data for batches of Rasagiline base produced are summarized in Tables 11.1 and 11.2 below.
The data show high purity of the Rasagiline base and reproducibility of its physical properties on pilot scale.
Table 11.1. Rasagiline base DS quality

Test Batch No.

1 2 3
Description Off-white powder Yellowish solid Off-white solid
Melting range by USP 0c 39.2 -40.6 39.4 -40.5 39.7 -40.6
Water content by coulometric K.F. % 0.08 0.07 0.03
Residue on ignition by USP % 0.03 0.00 0.01
Heavy metals by USP % L.T. 0.002 L.T. 0.002 L.T. 0.002
Impurities and
degradation products by
HPLC:
1-Aminoindan
1-Indanone
3-PAIO
Any other impurity
Total impurities % L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02 L.T. 0.02
N -(2-Chloroallyl)-l-aminoindan by LC-MS Ppm L.T. 1 (passes) L.T. 1 (passes) L.T. 1 (passes)
Enantiomeric purity (S-isomer by HPLC) % L.T. 0.1 L.T. 0.1 L.T. 0.1
OVI/Residual Solvents:
Ethanol
Toluene
Isopropanol ppm 295
L.T. 200
L.T. 200 205 250 L.T. 200 L.T. 200
42
L.T. 200
Assay on dry basis by HPLC % 99.7 99.9 100.2

Table 11.2. Physical properties of Rasagiline base DS

Test Batch No.

1 2 3
Powder density by USP: Bulk (BD) Tapped (TD) g/ml 0.497 0.727 0.426 0.579 0.443 0.624
Particle Size
Distribution by
Malvern:
D(0.1)
D(0.5)
D(0.9) um 112.5 404.1 1099.4 146.3 386.9 968.6 144.7 388.1 988.6
Morphol0gy by light microscope observation Rod shape prime particles Group I Rod shape prime particles Group I Rod shape prime particles Group I
6. Intermediate products - time limitations
5 There are three new intermediate solid products in the production procedure of Rasagiline base DS:
Wet Rasagiline Tartrate pure
Dry Rasagiline Tartrate pure
Wet Rasagiline base The intermediates should be held for a long period of time between the process operations. A sp0cial study was performed in order to prove the stability of the materials under the storage conditions.
6.1. Small scale experiments
Example 53. Stability test for wet Rasagiline Tartrate Pure
Rasagiline Tartrate Pure wet with isopropanol and water was stored at ambient temperature (RT) in polyethylene bag. The solid was sampled, dried to constant weight and analyzed. The sampling and analysis were performed at time zero, than after 2 weeks and 4 weeks from time zero. The results are presented in Table 12 below.

Example 54. Stability test for dried Rasagiline Tartrate Pure
A batch of dry Rasagiline Tartrate Pure produced in Example ?? was stored at ambient temperature (RT) in polyethylene bag. The solid was sampled and analyzed at time zero, than after 2 weeks and 4 weeks from time zero. The results are presented in Table 12.1 below.
Example 55. Stability test for wet Rasagiline Base
Rasagiline Base wet with water produced in Example ?? was stored at ambient temperature (RT) in polyethylene bag inside aluminium laminate bag prot0cted from light. The solid was sampled, dried to constant weight under v0cuum and analyzed. The sampling and analysis were performed at time zero, than after 2 weeks and 4 weeks from zero time. The results are presented in Table 13.1 below.

% L.T. L.T. L.T.
% 0.03 0.03 0.03
L.T. L.T. L.T.
0.03 0.03 0.03
% 0.01 0.05 0.04
Table 12.1. Stability tests Tartrate Pure
Material Test
Description
S-isomer by HPLC '
Dry ID by HPLC
GA-18062 Chromat0graphic
purity by HPLC:
1-Aminoindan i
Any other 5
L.O.D. Description
S-isomer by HPLC Wet ID by HPLC RB-2087 Chromat0graphic
purity by HPLC:
1-Aminoindan
Any other
L.O.D. *
* - Samples of wet Rasagiline analysis

for wet and dry Rasagiline

Start (t=0) 2 weeks 4 weeks
White White White
solid solid solid
L.T. 0. .3 L.T. 0.3 L.T. 0.3
Conforms Conforms Conforms

L.T. L.T. L.T.
0.03 0.03 0.03
L.T. L.T. L.T.
0.03 0.03 0.03
0.03 0.16 0.03
White White White
solid solid solid
L.T. 0.3 L.T. 0.3 L.T. 0
Tartrate were dried prior to
Conforms Conforms Conforms

Tablel3. Stability test
Test Description

for wet Rasagiline base
Start (t=0) 2 weeks 4 weeks White solid White solid White solid

% on
Assay by HPLC dry basis 100.1 100.5 100.7
IDD by HPLC:
1-Aminoindan % L.T. 0.02 L.T. 0.02 L.T. 0.02
1-Indanone % L.T. 0.02 L.T. 0.02 L.T. 0.02
3-PAIO % L.T. 0.02 L.T. 0.02 L.T. 0.02
Any other % L.T. 0.02 L.T. 0.02 L.T. 0.02
Total % L.T. 0.02 L.T. 0.02 L.T. 0.02
ID by HPLC Conforms Conforms Conforms
Water content by % 0.04 0.04 0.03
CKF
Enantiomeric % L.T. 0.1% L.T. 0.1% L.T. 0.1%
purity by HPLC (S- (Passes)
isomer) (Passes) (Passes)
6.2. Results and discussion
The data presented in the Tables 12.1 and 13.1 shows that no changes in purity of all solid intermediates occur during 4 weeks of storage. All products conformed to the sp0cifications after completion of 4-weeks stability test. Time limitations for the production intermediates are presented in Table 14.1.

Table 14.1. Rasagiline base intermediate product - time limitations
Time limitation
One month One month One month
Storage
temperature,
No. Product
1 Wet Rasagiline Tartrate R.T. Pure
2 Dry Rasagiline Tartrate R.T. Pure
3 Wet Rasagiline base +2 - +8UC

What is claimed is;
1. Crystalline R( + )-N-propargyl-1-aminoindan containing water at an amount of less than 0.5% by weight.
2. The crystalline R(+)-N-propargyl-1-aminoindan of claim 1 containing water at an amount of no more than 0.06% by weight.
3. A pharm0ceutical composition comprising R(+)-N-propargyl-1-aminoindan containing water at an amount of less than 0.5% by weight and a pharm0ceutically 0cceptable carrier.
4. The pharm0ceutical composition of claim 3, formulated for oral administration.
5. The pharm0ceutical composition of claim 3, formulated for transdermal application.
6. The pharm0ceutical composition of claim 5 in the form of a transdermal patch.
7. A process for drying solid R(+)-N-propargyl-1-aminoindan comprising exposing the solid R(+)-N-propargyl-1-aminoindan to a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R( + )-N-propargyl-1-aminoindan.
8. A process for preparing a pharm0ceutical composition comprising crystalline R(+)-N-propargyl-1-aminoindan containing water at an amount of 0.5% by weight and a pharm0ceutically 0cceptable carrier, comprising:

a) drying solid R(+)-N-propargyl-1-aminoindan at a temperature of less than 40°C and a pressure of between 2-1013.3 mbar for an amount of time suitable to dry the solid R(+)-N-propargyl-1-aminoindan; and
b) combining the dried R(+)-N-propargyl-1-

aminoindan r0covered in step a) with the pharm0ceutically 0cceptable carrier, thereby-preparing the pharm0ceutical composition.
9. The process of claim 7 or 8, wherein the temperature for drying is less than 35°C.
10. The process of any one of claims 7-9, wherein the temperature for drying is less than 25°C.
11. The process of any one of claims 7-10, wherein the pressure for drying is higher than 20 mbar.
12. The process of any one of claims 7-11, wherein the amount of time for drying is at least 45 hours.
13. A process for producing a validated batch of a drug product containing crystalline R(+)-N-propargyl-1-aminoindan and at least one pharm0ceutically 0cceptable carrier for distribution comprising:

a) producing a batch of the drug product;
b) determining the water content by weight with a sample of the batch; and
c) validating the batch for distribution only if the crystalline R(+)-N-propargyl-1-aminoindan in the batch contains less than 0.5% water by weight.

14. The process of claim 13, wherein the batch is validated only if the crystalline R( + )-N-propargyl-1-aminoindan in the batch contains less than 0.06% water by weight.
15. A process for producing crystalline R(+)-N-propargyl-1-aminoindan comprising:

a) purifying a salt of R(+)-N-propargyl-1-aminoindan;
b) dissolving the purified salt of R(+)-N-propargyl-1-aminoindan in water to form a solution;
c) cooling said solution to a temperature of 0-15°C;
d) basifying said solution to a pH of 9.5 - 12.5 to

form a suspension; and e) separating said crystalline rasagiline R(+)-N-propargyl-1-aminoindan from the suspension.
16. The process of claim 15, wherein step a) comprises:
i) dissolving the salt of R(+)-N-propargyl-l-aminoindan in water to form a solution;
ii) adding a water-soluble organic solvent to the solution;
iii) cooling the solution to a temperature of about 0-10°C; and
iv) obtaining the purified salt of R(+)-N-propargyl-l-aminoindan from the suspension.
17. The process of claim 16, wherein the purified salt of R(+)-N-propargyl-l-aminoindan obtained in step iv) is of enhanced optical purity relative to the R(+)-N-propargyl-1-aminoindan prior to crystallization.
18. The process of any one of claims 15-17, wherein the salt of R(+)-N-propargyl-l-aminoindan is a tartrate salt.
19. A process for producing crystalline R(+)-N-propargyl-l-aminoindan comprising:

a) obtaining a solution of R(+)-N-propargyl-l-aminoindan in a water-soluble organic solvent;
b) combining the solution with water;
c) cooling said solution to between 0 and 2 0°C to form crystalline R(+)-N-propargyl-l-aminoindan;
d) isolating the crystalline R(+)-N-propargyl-1-aminoindan; and
e) repeating steps a)-d) if the amount of S(+)-N-propargyl-1-aminoindan is more than 0.1 wt% relative to the total amount of R(+)-N-propargyl-l-aminoindan obtained in step d).
20. The process of claim 19, wherein the water-soluble
organic solvent is an alcohol.

The process of claim 20, wherein said alcohol is either ethanol or isopropanol or a mixture of ethanol and isopropanol.
The process of any one of claims 19-21, wherein the crystalline R(+)-N-propargyl-1-aminoindan is of enhanced optical purity relative to the R(+)-N-propargyl-1-aminoindan prior to crystallization.