U.S. patent application number 14/459877 was filed with the patent office on 2015-02-05 for crystalline solid rasagiline base.
This patent application is currently assigned to TEVA PHARMACEUTICAL INDUSTRIES, LTD.. The applicant listed for this patent is Anton Frenkel, Tamas Koltai. Invention is credited to Anton Frenkel, Tamas Koltai.
Application Number | 20150038744 14/459877 |
Document ID | / |
Family ID | 39536623 |
Filed Date | 2015-02-05 |
United States Patent
Application |
20150038744 |
Kind Code |
A1 |
Frenkel; Anton ; et
al. |
February 5, 2015 |
Crystalline Solid Rasagiline Base
Abstract
The subject invention provides crystalline
R(+)-N-propargyl-1-aminoindan, pharmaceutical compositions and
methods of manufacture thereof.
Inventors: |
Frenkel; Anton; (Netanya,
IL) ; Koltai; Tamas; (Netanya, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Frenkel; Anton
Koltai; Tamas |
Netanya
Netanya |
|
IL
IL |
|
|
Assignee: |
TEVA PHARMACEUTICAL INDUSTRIES,
LTD.
Petach-Tikva
IL
|
Family ID: |
39536623 |
Appl. No.: |
14/459877 |
Filed: |
August 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12655828 |
Jan 8, 2010 |
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14459877 |
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12002082 |
Dec 13, 2007 |
7750051 |
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12655828 |
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60875011 |
Dec 14, 2006 |
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Current U.S.
Class: |
564/428 |
Current CPC
Class: |
C07C 209/82 20130101;
C07C 211/42 20130101; A61P 25/16 20180101; C07C 2602/08 20170501;
C07B 2200/13 20130101 |
Class at
Publication: |
564/428 |
International
Class: |
C07C 209/82 20060101
C07C209/82 |
Claims
1-18. (canceled)
19. A process for manufacturing a rasagiline salt comprising
reacting crystalline R(+)-N-propargyl-1-aminoindan characterized by
an X-ray powder diffraction pattern having peaks at 8.5, 12.6, 16.1
and 16.9 in degrees two theta .+-.0.2, with an acid, so as to form
the rasagiline salt.
20. The process of claim 19, wherein the crystalline
R(+)-N-propargyl-1-aminoindan is further characterized by a melting
point of 38-39.degree. C. when determined in an open capillary or
41.degree. C. when determined by differential scanning
calorimetry.
21. The process of claim 19, wherein the crystalline
R(+)-N-propargyl-1-aminoindan is further characterized by an X-ray
powder diffraction pattern having peaks at 20.3, 20.9, 25.4, 26.4
and 28.3 in degrees two theta .+-.0.2.
22. A process for manufacturing a pharmaceutical composition
comprising a pharmaceutically acceptable excipient and a rasagiline
salt which process comprises contacting crystalline
R(+)-N-propargyl-1-aminoindan characterized by an X-ray powder
diffraction pattern having peaks at 8.5, 12.6, 16.1 and 16.9 in
degrees two theta .+-.0.2, with an acid, so as to form the
pharmaceutical composition.
23. The process of claim 22, wherein the crystalline
R(+)-N-propargyl-1-aminoindan is further characterized by a melting
point of 38-39.degree. C. when determined in an open capillary or
41.degree. C. when determined by differential scanning
calorimetry.
24. The process of claim 22, wherein the crystalline
R(+)-N-propargyl-1-aminoindan is further characterized by an X-ray
powder diffraction pattern having peaks at 20.3, 20.9, 25.4, 26.4
and 28.3 in degrees two theta .+-.0.2.
25. The process of claim 22, wherein the pharmaceutical composition
further comprises levodopa, L-carbidopa, beserazide, ladostigil,
pentahydric alcohol, hexahydric alcohol, or riluzole.
Description
[0001] This application claims benefit of U.S. Provisional
Application No. 60/875,011, filed Dec. 14, 2006, the contents of
which are hereby incorporated by reference.
[0002] Throughout this application various publications, published
patent applications 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.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133,
5,599,991, 5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061,
5,786,390, 6,316,504, 6,630,514 disclose
R(+)-N-propargyl-1-aminoindan ("R-PAI"), also known as rasagiline.
Rasagiline has been reported to be a selective inhibitor of the
B-form of the enzyme monoamine oxidase ("MAO-B") and is useful in
treating Parkinson's disease and various other conditions by
inhibition of MAO-B in the brain. U.S. Pat. No. 6,126,968 and PCT
publication WO 95/11016 disclose pharmaceutical compositions
comprising rasagiline salts.
[0004] Rasagiline mesylate is approved for treating Parkinson's
disease either as monotherapy or as an adjunct with other
treatments. See, e.g. AGILECT.RTM., Physician's Desk Reference
(2006), 60.sup.th Edition, Thomson Healthcare.
[0005] A synthesis of rasagiline is disclosed in U.S. Pat. No.
5,532,415 in which example 3 describes recovery of rasagiline base
as an oil after chromatographic separation. The other synthetic
examples in U.S. Pat. No. 5,532,415 show rasagiline salt
preparation from its crude form or its racemic form which is
further reacted with appropriate acids to form pharmaceutically
acceptable salts.
[0006] However, the existence or preparation of a crystalline form
of rasagiline free base is not disclosed in the art.
SUMMARY OF THE INVENTION
[0007] The subject invention provides crystalline
R(+)-N-propargyl-1-aminoindan.
[0008] The subject invention also provides a process for
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
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.degree. 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.
[0009] The subject invention also provides a process for
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
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 vacuum to form a
residue; c) dissolving the residue in a second organic solvent to
form a second organic solution; d) completely evaporating the
second organic solvent from the second organic solution under
vacuum to form a residue; and e) maintaining the second residue at
a temperature between 0 and 25.degree. C. to form crystalline
R(+)-N-propargyl-1-aminoindan.
[0010] The subject invention also provides a process for
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
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.degree. C. to form crystalline
R(+)-N-propargyl-1-aminoindan; and d) isolating the crystalline
R(+)-N-propargyl-1-aminoindan.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1: X-Ray Diffraction diffractogram of rasagiline base
prepared according to Example 4.
[0012] FIG. 2: Micrograph of rasagiline base prepared according to
Example 4.
[0013] FIG. 3: Micrograph of rasagiline base prepared according to
Example 5.
[0014] FIG. 4: Micrograph of rasagiline base prepared according to
Example 6.
[0015] FIG. 5: Micrograph of rasagiline base prepared according to
Example 7.
[0016] FIG. 6: Micrograph of rasagiline base prepared according to
Example 8a.
[0017] FIGS. 7-10: FTIR spectra of rasagiline base prepared
according to example 5.
[0018] FIG. 11: Micrograph of rasagiline base prepared according to
Example 9.
[0019] FIG. 12: Micrograph of rasagiline base prepared according to
Example 10.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The subject invention provides crystalline
R(+)-N-propargyl-1-aminoindan.
[0021] The subject invention also provides
R(+)-N-propargyl-1-aminoindan characterized by a powder X-ray
diffraction pattern having peaks at 8.5, 12.6, 16.1, and 16.9 in
degrees two theta .+-.0.2. It can be further characterized by an
X-ray powder diffraction 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.degree. C.
[0022] The subject invention also provides a the pharmaceutical
composition comprising crystalline R(+)-N-propargyl-1-aminoindan
and a pharmaceutically acceptable carrier.
[0023] The pharmaceutical composition may be formulated for
transdermal application. The pharmaceutical composition may be in
the form of a transdermal patch.
[0024] The subject invention also provides a process for the
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
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.degree. 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.
[0025] In an embodiment of the process, wherein the crystalline
R(+)-N-propargyl-1-aminoindan is of enhanced optical purity
reoative to the R(+)-N-propargyl-1-aminoindan prior to
crystallization.
[0026] The subject invention also provides a process for the
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
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 vacuum to form a
residue; c) dissolving the residue in a second organic solvent to
form a second organic solution; d) completely evaporating the
second organic solvent from the second organic solution under
vacuum to form a second residue; and e) maintaining the second
residue at a temperature between 0 and 25.degree. C. to form
crystalline R(+)-N-propargyl-1-aminoindan.
[0027] In an embodiment of the process, the organic solvent and the
second organic solvent are the same.
[0028] In another embodiment, the organic solvent and the second
organic solvent are alcohols.
[0029] In yet another embodiment, the organic solvent and the
second organic solvent are isopropanol.
[0030] In yet another embodiment of the process, wherein the
crystalline R(+)-N-propargyl-1-aminoindan is of enhanced optical
purity reoative to the R(+)-N-propargyl-1-aminoindan prior to
crystallization.
[0031] The subject invention also provides a process for
manufacture of crystalline R(+)-N-propargyl-1-aminoindan which
comprises: 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.degree. C. to
form crystalline R(+)-N-propargyl-1-aminoindan; and d) isolating
the crystalline R(+)-N-propargyl-1-aminoindan.
[0032] In an embodiment of the process, the water-soluble organic
solvent is an alcohol.
[0033] In another embodiment, the alcohol is either ethanol or
isopropanol or a mixture of ethanol and isopropanol.
[0034] In yet another embodiment of the process, wherein the
crystalline R(+)-N-propargyl-1-aminoindan is of enhanced optical
purity reoative to the R(+)-N-propargyl-1-aminoindan prior to
crystallization.
[0035] In development of pharmaceutical compositions, crystallinity
is a desirable property in an active pharmaceutical ingredient.
Crystal substances allow for ease in processing and formulating
into most types of pharmaceutical dosage forms.
[0036] Previously, rasagiline base has been isolated as an oil and
not as a crystalline solid. Without being bound by theory, it is
possible that rasagiline has been previously isolated as an oil due
to presence of residual solvents, such as toluene or isopropanol.
The inventors have surprisingly found that rasagiline base may be
isolated in a non-hygroscopic form that remains crystalline at room
temperature.
[0037] Crystalline rasagiline base has lower water solubility than
many rasagiline salts, especially 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 570 mg/ml at a pH of 3.3, both measured at
25.degree. C. At the same temperature, the solubility of rasagiline
base in water is 5.5 mg/ml at a pH of 11.
[0038] 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 reacted with an
acid to form a pharmaceutically acceptable acid addition salt. The
crystallization of rasagiline base could provide additional
purification of the acid addition salt.
[0039] Water solubility is often an important characteristic of an
active pharmaceutical ingredient, especially when formulating oral
compositions. Sometimes, lipophilicity of an active pharmaceutical
ingredient is desired when formulating other pharmaceutical
compositions. Crystalline rasagiline base may be useful for
formulating pharmaceutical 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.
Transdermal Formulations and Transdermal Patches
[0040] Transdermal patches are medicated adhesive patches placed on
the skin to deliver a time-released dose of medication through the
skin and into the bloodstream. A wide variety of pharmaceuticals
can be delivered through transdermal patches, such as nicotine for
smoking cessation, scopolamine for motion sickness, estrogen for
menopause and prevention of osteoporosis, nitroglycerin for angina,
lidocaine for pain relief from shingles. Some pharmaceuticals must
be combined with other substances, such as alcohol, to increase
their ability to penetrate the skin. Molecules of insulin, and many
other pharmaceuticals; however, are too large to pass through the
skin. Transdermal patches have several important components,
including a liner to protect the patch during storage, the drug,
adhesive, a membrane (to control release of the drug from the
reservoir), and a backing to protect the patch from the outer
environment. The two most common types of transdermal patches are
matrix and reservoir types. ("Transdermal Patches", Wikipedia, Nov.
15, 2007, Wikipedia Foundation, Inc., Dec. 13, 2007
<http://en.wikipedia.org/wiki/Transdermal_patch>; and
Remington, The Science and Practice of Pharmacy, 20.sup.th Edition,
2000)
[0041] In reservoir type patches, a drug is combined with a
non-volatile, inert liquid, such as mineral oil, whereas drug in
matrix type patches a drug is dispersed in a lipophilic or
hydrophilic polymer matrix such as acrylic or vinylic polymers.
Adhesive polymers, such as polyisobutylene, are used to hold the
patch in place on the skin. (Stanley S Scheindlin, (2004)
"Transdermal Drug Delivery: PAST, PRESENT, FUTURE," Molecular
Interventions, 4:308-312)
[0042] 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 surface and cause faster drug delivery. Typical
penetration enhancers include high-boiling alcohols, diols, fatty
acid esters, oleic acid 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 Delivery)
[0043] Rasagiline may also be used in combination with other drugs
in a transdermal patch, such as levodopa, L-carbidopa, beserazide,
ladostigil, pentahydric alcohol, hexahydric alcohol, or
riluzole.
EXPERIMENTAL DETAILS
Example 1
Isolation of Rasagiline Base by Splitting and Extraction
[0044] Rasagiline mesylate was prepared essentially as described in
U.S. Pat. No. 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 acid.
[0045] 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 extracted
with 200 ml of toluene. The phases were allowed to separate and the
aqueous phase was discarded.
[0046] The two toluenic extractions were combined and the solvent
was distilled under vacuum. The yield of rasagiline base was 88.5 g
of a yellowish oil with a melting point of below 20.degree. C.
[0047] 25.1 g of the liquid rasagiline base was sampled. The sample
was mixed with ethanol and the solvent was distilled under vacuum.
22.6 g 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 Extraction
[0048] 155 g of rasagiline tartrate, prepared essentially as
described in U.S. Pat. No. 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.+-.5.degree. C.
[0049] After stirring, two phases were separated. The lower water
phase was extracted twice with 300 ml of toluene at 45.+-.5.degree.
C. The organic phases were combined and the aqueous phase was
discarded.
[0050] The combined organic phase was washed with 200 ml of
deionized water. Then the solvent was distilled under vacuum and 50
ml isopropanol were added to the resulting residue. The solvent was
removed by vacuum and additional 50 ml isopropanol were added and
then removed by vacuum. 100 g of syrup-like liquid rasagiline base
were formed.
Example 3
Splitting and Spontaneous Crystallization from Water
[0051] 15 g of rasagiline mesylate were dissolved in 150 ml water
while stirring. The solution was cooled to 5.degree. C. and 25%
NaOH solution was added slowly. During the addition, batch
temperature was maintained between 3 and 5.degree. C. Solid
precipitation was observed after reaching a pH of 7.5. After
reaching 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 vacuum.
[0052] 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 38.2-38.4.degree. C.
Example 4
Melt Crystallization
[0053] 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 vacuum until complete solvent
removal. The residue was then dissolved in an additional 20 ml 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
[0054] 2.4 g of rasagiline base from example 1 were dissolved in
2.4 g of ethanol. The solution was added dropwise to 5 ml of cold
(0-5.degree. C.) water while stirring, and a white precipitate 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 vacuum.
[0055] 2.15 g of solid crystalline rasagiline were attained, with a
yield of 89.6%.
[0056] Analysis: Chromatographic purity by HPLC .about.100%, Assay
by HPLC--99.0%.
Example 6
Addition of Water to Rasagiline Ethanolic Solution
[0057] 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 precipitation occurred. The resulting
solution was cooled, and at 12.degree. C. precipitation of a white
material was observed. The mixture was cooled to .about.0.degree.
C., 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 vacuum.
[0058] 2.72 g of solid crystalline rasagiline were attained, with a
yield of 90.0%.
[0059] Analysis: Chromatographic purity by HPLC--100%, Assay by
HPLC--100.0%.
Example 7
Addition of Rasagiline Isopropanolic Solution to Water
[0060] 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 precipitation occurred. The resulting
solution was cooled, and at 17.degree. C. precipitation of white
material was observed. 20 ml of deionized water were added to the
mixture and the mixture was further cooled to .about.0.degree. C.,
stirred at this temperature for 30 min, and filtered.
[0061] The filtration proceeded quickly. The solid product was
washed with water on the filter and dried under vacuum. 5.96 g of
solid crystalline rasagiline were attained, with a yield of
72.7%.
[0062] Analysis: Chromatographic purity by HPLC .about.100%, Assay
by HPLC--99.7%
Example 8
Addition of Water to Rasagiline Isopropanolic Solution
[0063] Crop A
[0064] 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 17.degree. C. and 252 ml of deionized water
were added at this temperature. The solution was cooled to
10.degree. C. 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 1.degree. C., stirred at
this temperature for 30 min and filtered. The solid was washed on
the filter with 200 ml of water and dried under vacuum.
[0065] 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 39.0-39.2.degree. C.
[0066] Analysis: Chromatographic purity by HPLC .about.100%, Assay
by HPLC--98.5%.
[0067] Crop B
[0068] The mother liquor and washing liquor from crop A were
combined, and solid product precipitated from the mixture.
Yellowish material was separated by filtration and dried under
vacuum.
[0069] 1.5 g of solid, crystalline rasagiline base were attained,
with a yield of 1.0%.
[0070] Discussion
[0071] The solid crystalline rasagiline base which was synthesized
in examples 3-8 was found to be of high purity.
[0072] The same melting point value (41.degree. C. by differential
scanning calorimetry (DSC) or 38-39.degree. 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 thermogravimetric
analysis (TGA) methods. This indicated that crystalline rasagiline
base is not hygroscopic.
[0073] Crystalline rasagiline base was found freely soluble in
polar and non-polar organic solvents--alcohols, acetone, ethyl
acetate, toluene, diethyl ether, dioxane, hexane and n-heptane.
[0074] All batches of solid rasagiline base were found highly
crystalline by powder X-ray diffraction (XRD) and DSC method.
Characteristic 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.
[0075] The X-Ray Diffraction equipment used was a Scintag X-Ray
powder diffractometer model X'TRA, Cu-tube, solid state
detector.
[0076] Sample holder: a round standard aluminum sample holder with
round zero background quartz plate with cavity of 25 (diameter)*0.5
(dept.) mm.
[0077] Scanning parameters: Range: 2-40 degrees two-theta.
[0078] Scan mode: Continuous scan
[0079] Step size: 0.05 deg.
[0080] Rate: 5 deg./min.
[0081] The peaks of a sample prepared according to Example 4 are
listed below. The most characteristic peaks are listed in bold.
TABLE-US-00001 Form I 8.5 12.6 16.1 16.9 20.3 20.9 25.4 26.4
26.3
[0082] FTIR analysis of the samples was performed as follows:
[0083] Equipment: Perkin Elmer Spectrum One FT-IR Spectrometer S/N
58001.
[0084] Parameters: The samples were studied in DRIFT mode. All the
spectra were measured in 16 scans. Resolution: 4.0 cm.sup.-1.
[0085] All samples of solid rasagiline base prepared in this study
appear as white crystalline powder (with the exception of Crop 8
from example which was isolated as a yellowish powder.) Microscopic
observation shows that the crystallization conditions strongly
affect the particle size and morphology. Seeded crystallization
provides large regular non-aggregated crystals while spontaneous
precipitation resulted in formation of small aggregated particles.
The difference in the particle morphology is not related to
polymorphism.
[0086] The morphology and particle size of the crystalline
rasagiline base from the examples above is shown in the table
below. The morphology and particle size was determined by
microscopic observation.
TABLE-US-00002 Particle Size Range Example Morphology (.mu.m) 4
Irregular particles 250-1000 5 Small rods 5-50 6 Rods 30-150 7
Small aggregated rods 5-50 8 Rods 250-2000
[0087] Starting Materials for Examples 9, 10 and 11:
[0088] (1) Wet Rasagiline Hemi Tartrate containing .about.10-15%
residual solvent and 0.7% S-isomer.
[0089] (2) Racemic RAI base, oil, PAI content--94% by HPLC.
Example 9
Splitting and Precipitation from Isopropanol-Water, Seeded Emulsion
Crystallization
[0090] 70.0 g of Rasagiline Tartrate salt (1) suspended in 320 ml
deionized water at stirring. The suspension heated to 45.degree. C.
and 31 ml 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 45.degree. C. and settled. Lower aqueous phase
(pH=9-10) was discarded.
[0091] Toluenic solution was evaporated under vacuum in evaporator,
after the solvent evaporation completion 50 ml isopropanol was
added to the residue and evaporation was continued.
[0092] After completion of the evaporation 25 ml of isopropanol was
added and distilled out under the same conditions.
[0093] The residue, oil of R-PAI base (33.9 g), was dissolved in 41
ml isopropanol.
[0094] The solution was cooled to 15.degree. C. and 58 ml of
deionized water was added by portions in 2 hr at cooling and
stirring. During the addition of water oily precipitate was formed.
The resulting emulsion of oil in water was stirred at 1-3.degree.
C. for one hour, no crystallization was observed.
[0095] The batch was seeded with crystalline Rasagiline base at
1-3.degree. C. and immediate exothermic crystallization took place.
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 vacuum.
[0096] 31.5 g of solid dry R-PAI base were attained, with a yield
of 92% on oil base. FIG. 11 is a micrograph of this rasagiline
base.
[0097] Analysis: Melting point (by DSC)--40.8.degree. C., S-isomer
by HPLC 0.02%, Purity by HPLC--100%, Assay by HPLC--98%.
Example 10
Splitting and Precipitation from Isopropanol-Water, Seeded
Crystallization from Solution Isopropanol-Water
[0098] 100.0 g of Rasagiline Tartrate (1) was suspended in 458 ml
deionized water, 229 ml Toluene was added and 46 ml of 25% NaOH
solution was introduced at stirring. The mixture was heated to
45.degree. C., stirred at 45 C for 15 minutes and settled at this
temperature.
[0099] 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 vacuum in
evaporator.
[0100] After the solvent evaporation completion 60 ml isopropanol
was added to the residue and evaporation was continued.
[0101] After completion of the evaporation 50 ml of isopropanol was
added and distilled out under the same conditions.
[0102] The residue, oil of R-PAI base (46.4 g), was dissolved in 56
ml isopropanol.
[0103] The solution was cooled to 16.degree. C. and 147.5 ml of
deionized water was added by portions in 3 hr at cooling and
stirring. During the addition of water precipitation development
was observed and the batch was immediately seeded with crystalline
R-PAI base.
[0104] The resulting suspension was cooled to 2.degree. C., stirred
at this temperature overnight and filtered. The solid was washed
with water and dried at room temperature under vacuum.
[0105] 48.1 g of Solid dry R-PAI base were attained, with a yield
of 96% on oil base. FIG. 12 is a micrograph of this rasagiline
base.
[0106] Analysis: Melting point (by DSC)--41.3.degree. C., S-isomer
by HPLC 0.01%, Purity by HPLC--100%, Assay by HPLC--96%
Example 11
Racemic PAI Base Crystallization (AF-8026) Precipitation from
Isopropanol-Water
[0107] 51.0 g of racemic PAI base oil (2) dissolved in 50 ml
isopropanol. The solvent was distilled out of the solution under
vacuum at evaporator.
[0108] The residue (49.4 g) was dissolved in 60 ml isopropanol,
stirred and cooled. 156 ml of deionized water was added by portions
in 3 hr at cooling and stirring. During the addition of water oily
precipitate was formed. The batch was seeded with crystalline
Rasagiline base, no crystallization was observed.
[0109] The resulting emulsion of oil in water was stirred at
3.degree. C. for 1 hour, no crystallization was observed.
[0110] The batch was crystallized spontaneously during stirring
overnight at 1.degree. C. 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.
[0111] The material was sampled before the melting completion.
[0112] Analysis: S-isomer by HPLC 49.4%, Assay by HPLC
.about.87%.
[0113] Discussion
[0114] 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). Racemic PAI base exists at room
temperature only in liquid form, its melting point being between 1
and 18.degree. C. (Example 11).
[0115] 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.
[0116] 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.degree. C.
(Example 9) provides higher particle size of Rasagiline base than
emulsion crystallization at 1-3.degree. C. (Example 10).
* * * * *
References