FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"PALONOSETRON FREE BASE AND PROCESS FOR THE PREPARATION OF THE
SAME "
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
[0001] The present invention generally relates to palonosetron free base, processes
for their preparation, a process for their conversion into palonosetron, its pharmaceutically acceptable salts thereof and method of use to prevent nausea and vomiting that may be caused by surgery or by medicine to treat cancer.
BACKGROUND OF THE INVENTION
[0002] Palonosetron, also known as (3aS)-2-[(S)-1-azabicyclo [2.2.2] oct-3-yl]-
2,3,3a,4,5,6-hexahydro-1-oxo-1H benz[de]isoquinoline, is represented by the structure of Formula I:
N.

(I)
[0003] Palonosetron is a selective receptor antagonist with a strong binding affinity for
this receptor and little or no affinity for other receptors. 5-HT3 receptors are located in high densities on neurons associated with the emetic reflex and drugs which block the interactions of serotonin at the 5-HT3 receptor level, i.e., 5-HT3 receptor antagonists, possess potent antiemetic properties. Such antagonists demonstrate utility for counteracting the emetic effects of cancer chemotherapy and radiotherapy (see Drugs Acting on 5-Hydroxytryptamine Receptors: The Lancet Sep. 23, 1989 and refs. cited therein).
[0004] Palonosetron hydrochloride (hydrochloride salt of (3aS)-2-[(S)-1-azabicyclo
[2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1/-y benz[de]isoquinoline) is sold under the brand name Aloxi®.
[0005] U.S. Patent No. 5,202,333 ("the '333 patent") discloses 5-HT3 receptor
antagonists such as palonosetron, its hydrochloride salt form. The '333 patent further discloses a process for the preparation of 5-HT3 receptor antagonists palonosetron hydrochloride by reduction of 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one using palladium catalyst in acetic acid and perchloric acid and the resultant palonosetron is converted to its hydrochloride salt. The palonosetron prepared was isolated as the hydrochloride. Furthermore, the palonosetron base was obtained as semi solid. A main drawback of this process is the need to involve repeated purifications to achieve


the required purity levels. This process is time consuming and results into relatively low yields of product.
[0006] Accordingly, the present inventors discovered a novel process to prepare pure
palonosetron hydrochloride through isolating the palonosetron free base to overcome the prior art difficulty.
SUMMARY OF THE INVENTION
[0007] In accordance with one embodiment of the present invention, isolated
palonosetron free base is provided.
[0008] In accordance with a second embodiment of the present invention,
palonosetron free base in an amorphous form is provided.
[0009] In accordance with a third embodiment of the present invention, palonosetron
free base in crystalline form-G is provided.
[0010] In accordance with a fourth embodiment of the present invention, palonosetron
free base in an amorphous form characterized by an X-ray powder diffraction pattern (XPRD)
substantially in accordance with Figure 1 is provided.
[0011] In accordance with a fifth embodiment of the present invention, palonosetron
free base in crystalline form-G characterized by an X-ray powder diffraction pattern (XPRD)
substantially in accordance with Figure 4 is provided.
[0012] In accordance with a sixth embodiment of the present invention, palonosetron
free base in crystalline form-G characterized by a differential scanning calorimetric (DSC)
thermogram substantially in accordance with Figure 5 is provided.
[0013] In accordance with a seventh embodiment of the present invention, a process
for the preparation of palonosetron, its pharmaceutically acceptable salts thereof are provided,
the process comprising
a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-
benz[de]isoquinolin-1-one of formula-ll with a hydrogenation catalyst, in water
solvent,
Formula-ll
b) isolating the palonosetron free base,
c) converting the palonosetron free base into its pharmaceutically acceptable salts thereof.


wherein the hydrogenation catalyst is selected from the group consisting of palladium, platinum, nickel, and rhodium.
[0014] In accordance with an eighth embodiment of the present invention, a process
for the preparation of palonosetron free base is provided, the process comprising
a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-
benz[de]isoquinolin-1-one of formula-ll with a hydrogenation catalyst, in water solvent,
Formula-ll
b) isolating the palonosetron free base.
wherein the hydrogenation catalyst is selected from the group consisting of palladium,
platinum, nickel, and rhodium.
[0015] In accordance with a ninth embodiment of the present invention, a process for
the preparation of palonosetron free base in crystalline form-G is provided, the process
comprising providing a solution of palonosetron, its pharmaceutically acceptable salts thereof
in a water immiscible organic solvent and water; treating with a base; concentrating the water
immiscible organis solvent under vacuum; crystallizing the resultant residue in a suitable
organic solvent.
[0016] In accordance with a tenth embodiment of the present invention, a process for
converting a palonosetron free base in crystalline form-G into its its pharmaceutically
acceptable salts thereof is provided.
[0017] In accordance with an eleventh embodiment of the present invention, a
pharmaceutical composition is provided comprising a therapeutically effective amount of a
palonosetron free base and at least one pharmaceutically acceptable carrier.
[0018] In accordance with an eleventh embodiment of the present invention, a method
of use to prevent nausea and vomiting that may be caused by surgery or by medicine to treat
cancer (chemotherapy or radiation) by administration of a pharmaceutically acceptable carrier
comprising the effective amount of palonosetron free base .
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 is a characteristic XRPD of palonosetron free base in amorphous
form.


[0020] Figure 2 is a characteristic DSC thermogram of palonosetron free base in
amorphous form.
[0021] Figure 3 is a characteristic thermogravimetric analysis (TGA) of palonosetron
free base in amorphous form.
[0022] Figure 4 is a characteristic XRPD of palonosetron free base in crystalline form-
G.
[0023] Figure 5 is a characteristic DSC thermogram of palonosetron free base in
crystalline form-G.
[0024] Figure 6 is a characteristic thermo gravimetric analysis (TGA) of palonosetron
free base in crystalline form-G.
[0025] Figure 7 is a characteristic XRPD of palonosetron hydrochloride as obtained
from example-3
[0026] Figure 8 is a characteristic DSC thermogram of palonosetron hydrochloride as
obtained from example-3
[0027] Figure 9 is a characteristic thermo gravimetric analysis (TGA) of palonosetron
hydrochloride as obtained from example-3
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention provides palonosetron free base and process for the
prepration of palonosetron free base and its conversion to palonosetron and pharmaceutically acceptable salts thereof.
[0029] One embodiment of the present invention is directed to palonosetron free base
in an amorphous form and crystalline form-G. The palonosetron free base in an amorphous form and crystalline form-G may be characterized by, for example, X-ray powder diffraction pattern and/or melting point. The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer equipped with a Cu-anode (A=1.54 Angstrom), X-ray source operated at 45kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50" 26; step width=0.017°; and measuring time per step=5 sec.
[0030] Palonosetron free base in crystalline form-G exhibits a predominant endotherm
peak at about 95.71 °C as measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per minute with an Indium standard. In this regard, it should be understood that the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the


calibration standard utilized, instrument calibration, relative humidity, and upon the chemical
purity of the sample being tested. Thus, an endotherm as measured by DSC on the
instrument identified above may vary by as much as ±1°C or even ±2°C.
[0031] Thermogravimetric analysis of palonosetron free base in an amorphous form
and crystalline form-G recorded on TGA Q500 V 20.6 in platinum pan with temp rise 10°C/min
in the range 30°C to 350°C.
[0032] In one embodiment, a process for the preparation of palonosetron, its
pharmaceutically acceptable salts thereof such as hydrochloride salt, which process
comprises
a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-
benz[de]isoquinolin-1-one of formula-ll with hydrogenation catalyst, in water solvent,
formula-ll
b) isolating the palonosetron free base,
c) converting the palonosetron free base into its pharmaceutically acceptable salts thereof.
[0033] The compounds of formulae II is known in the art and can be prepared by any
known method, for example, a compound of formula II is disclosed in U.S. Patent No. 5,202,333, the conent of which is incorporated herein by reference.
[0034] Step a) of the foregoing process hydrogenation may be carried out in presence
of suitable hydrogenation catalyst; suitable hydrogenation catalysts selected from the group consisting of palladium salts such as palladium hydroxide, palladium hydroxide on carbon, Pearlman's catalyst, and the like and the palladium content in catalyst may be any ratio, preferably 5 to 20%; platinum, nickel, and rhodium on alumina. Depending upon the catalyst, pressure and temperature chosen, the reduction process may take from about 5 hours to about 30 hours to complete. As an example, a reaction carried out with 20% palladium carbon at 65 to 70°C.
[0035] After completion of the hydrogenation the catalyst may be separated from the
reaction mixture by any known method. The resultant water containing product may be extracted to an organic solvent under basic conditions by adjusting the pH of the reaction mixture, wherein the organic solvent can be selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrahydrochloride and the like, hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene and


the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate
and the like; and mixtures thereof. The adjustement of pH may be carried out with bases,
wherein the bases are used for adjusting the pH known in the art, for example sodium
hydroxide, potassium hydroxide and the like. The resultant organic solvent containing
palonosetron free base may be concentrated under vacuum to get the residue by the method
known in the art, for example distillation, evaporation, rotational drying (such as with the Buchi
Rotavapor), freeze-drying, fluidized bed drying, flash drying, spin flash drying, and the like.
[0036] The resultant residue may be dissolved in a suitable organic solvent at ambient
temperatutre to reflux temperature of the solvent chosen, suitable organic solvent includes,
but are not limited to alcohols such as C1-4 alcohols suae as methanol, ethanol, propanol,
butanol, and the like, esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary
butyl acetate and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene,
toluene and the like, and halogenated solvents such as dichloromethane, ethylene dichloride,
chloroform, carbon tetrahydrochloride and the like; water and their mixtures.
[0037] The palonosetron free base recovered using the process of the present
invention is substantially in solid form, preferably it is an amorphous form.
[0038] In one embodiment of the present invention, palonosetron free base can be
isolated by crystallization, solvent precipitation, concentration by subjecting to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like. The palonosetron free base can be recovered by any conventional technique for example filtration. The isolated solids can then be further dried. The temperature during stirring can range from about -10 to about +10°C. The resulting solid can then be filtered and washed with crystallization solvent, to provide palonosetron free base. Palonosetron free base obtained by the present process can be dried using conventional drying process, as appropriate.
[0039] The palonosetron free base may be dissolved in one or more organic solvents
such as water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like, ethers selected from tetrahydrofuran (THF), dimethylether, diethyl ether, methylethylether, diisopropylether, methyltertiarybutyl ether and the like and mixtures thereof at a temperature of from about ambient temperature to about reflux temperature and treating with hydrochloric acid in the form of an aqueous, anhydrous or gas form at a temperature of from about ambient temperature to about reflux temperature, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas can be used; to obtain palonosetron hydrochloride.
[0040] In another embodiment of the present invention, palonosetron hydrochloride
thus obtained may be further purified by dissolving the palonosetron hydrochloride in an organic solvent, organic solvent includes, but are not limited to C1-4 alcohol such as methanol,


ethanol, propanol, butanol and the like and mixture thereof, esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like and mixtures thereof; hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene and the like and mixtures thereof. The solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature. The reaction solution may be cooled at a temperature from about 10°C or less such that the palonosetron hydrochloride can be isolated by conventional techniques.
[0041] The resultant product may optionally be further dried. Drying can be suitably
carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash
dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to
about 90°C. The drying can be carried out for any desired time until the required product
purity is achieved, e.g., a time period ranging from about 1 to about 20 hours.
[0042] In prefered embodiment, palonosetron hydrochloride of the present invention
having a chemical purity of at least about 97% by HPLC preferably at least about 99% by HPLC and more preferably at least about 99.8% by HPLC; a daistereomeric purity of at least about 99.5% by HPLC preferably at least about 99.8% by HPLC and substantially free of 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-benz[de]isoquinolin-1-one of formula-ll, wherein the word "substantially free" means palonosetron hydrochloride having less than about 0.1% by HPLC of formula-ll, more preferably less than about 0.05% by HPLC of formula-ll.
[0043] In a further embodiment, a process for the preparation of palonosetron free
base can be prepared by
a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-
benz[de]isoquinolin-1-one of formula-ll with hydrogenation catalyst, in water solvent,
formula-ll
b) isolating the palonosetron free base.
[0044] Step a) of the foregoing process hydrogenation may be carried out in presence
of hydrogenation catalyst; suitable catalysts selected from the group consisting of palladium salts such as palladium hydroxide, palladium hydroxide on carbon, Pearlman's catalyst, and the like and the palladium content in catalyst may be any ratio, preferably 5 to 20%; platinum, nickel, and rhodium on alumina. Depending upon the catalyst, pressure and temperature


chosen, the reduction process may take from about 5 hours to about 30 hours to complete. As
an example, a reaction carried out with 20% palladium carbon at 65 to 70°C.
[0045] After completion of the hydrogenation the catalyst may be separated from the
reaction mixture by any known method. The resultant water containing product may be
extracted to an organic solvent under basic conditions by adjusting the pH of the reaction
mixture, wherein the organic solvent can be selected from the group consisting of halogenated
solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrahydrochloride
and the like, hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene and
the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate
and the like; and mixtures thereof. The adjustement of pH may be carried out with bases,
wherein the bases are used for adjusting the pH known in the art, for example sodium
hydroxide, potassium hydroxide and the like. The resultant organic solvent containing
palonosetron free base may be concentrated under vacuum to get the residue by the method
known in the art, for example distillation, evaporation, rotational drying (such as with the Buchi
Rotavapor), freeze-drying, fluidized bed drying, flash drying, spin flash drying, and the like.
[0046] The resultant residue may be dissolved in a suitable organic solvent at ambient
temperatutre to reflux temperature of the solvent chosen, suitable organic solvent includes,
but are not limited to alcohols such as C1-4 alcohols such as methanol, ethanol, propanol,
butanol and the like, esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary
butyl acetate and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene,
toluene and the like, and halogenated solvents such as dichloromethane, ethylene dichloride,
chloroform, carbon tetrahydrochloride and the like; water and their mixtures.
[0047] The palonosetron free base recovered using the process of the present
invention is substantially in solid form, preferably it is an amorphous form.
[0048] In one embodiment of the present invention, palonosetron free base can be
isolated by crystallization, solvent precipitation, concentration by subjecting to heating, spray
drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film
evaporator (ATFE) and the like. The palonosetron free base can be recovered by any
conventional technique for example filtration. The isolated solids can then be further dried.
The temperature during stirring can range from about -10 to about +10°C. The resulting solid
can then be filtered and washed with crystallization solvent, to provide palonosetron free base.
Palonosetron free base obtained by the present process can be dried using conventional
drying process, as appropriate. This may allow for a high purity level of the resulting
palonosetron free base, e.g., a chemical purity of at least about 97% by HPLC preferably at
least about 99% by HPLC and more preferably at least about 99.5% by HPLC.
[0049] When using the free base of palonosetron according to the present invention
as a starting material or as an intermediate, the yield and the purity of the resulting


palonosetron hydrochloride salt can be equal to or greater than about 99.8% as determined by HPLC when using the palonosetron from methods known in the art.
[0050] In another embodiment, a process for the preparation of palonosetron free
base in crystalline form-G can be prepared by
a) providing a solution of palonosetron hydrochloride in a water immiscible organic solvent and water,
b) treating with a base,
c) concentrating the water immiscible organic solvent under vacuum,
d) crystallizing the resultant residue in a suitable organic solvent.
[0051] Useful water immiscible organic solvent for carrying out the process of the
present invention include, but are not limited to C4 to C7 ketones such as methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrahydrochloride and the like; ethers such as dimethylether, diethyl ether, methylethylether, diisopropylether, methyltertiarybutyl ether and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, benzene, toluene and the like; and mixtures thereof.
[0052] Suitable bases includes alkali or alkaline earth metals such as sodium
hydroxide, potassium hydroxide, barium hydroxide, potassium t-butoxide, and the like and mixtures thereof. The source of base can be added either as solution in water or it may be added as solid to the solution of palonosetron hydrochloride in organic solvent. The sequence of addition of water and/or base is not a criteria which needs monitoring, either can be added first.
[0053] Separating the layers can be carried out by employing any conventional
technique and the solvent can also be removed from the solution using techniques known in the art including, for example, distillation, evaporation, rotational drying (such as with the Buchi Rotavapor), freeze-drying, fluidized bed drying, flash drying, spin flash drying, and the like.
[0054] Suitable organic solvent is added to the residue obtained from step-c. Suitable
organic solvent includes, but are not limited to alcohols such as C1-4 alcohols such as methanol, ethanol, propanol, butanol and the like, esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene and the like, and halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrahydrochloride and the like; water and their mixtures.
[0055] The product may optionally be further dried. Drying can be suitably carried out
in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the


like. The drying can be carried out at a temperature ranging from about 30°C to about 60°C. The drying can be carried out for any desired time until the required product purity is achieved, for example, a time period ranging from about 1 to about 20 hours.
[0056] Any form of a palonosetron hydrochloride, can be used as a starting material in
the process of making the palonosetron free base in crystalline form-G of the present invention.
[0057] In yet another embodiment of the present invention, a process for the
conversion of a palonosetron free base in crystalline form-G into its hydrochloride salt is provided. The crystalline free base may be dissolved in one or more organic solvents such as water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like, ethers selected from tetrahydrofuran (THF), dimethylether, diethyl ether, methylethylether, diisopropylether, methyltertiarybutyl ether and the like and mixtures thereof at a temperature of from about ambient temperature to about reflux temperature and treating with hydrochloric acid in the form of an aqueous, anhydrous or gas form at a temperature of from about ambient temperature to about reflux temperature, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas can be used; to obtain palonosetron hydrochloride.
[0058] In another embodiment of the present invention, palonosetron free base in an
amorphous form and in crystalline form-G can be used as starting material or as an
intermediate for the preparation of pharmaceutically acceptable salts of palonosetron. Such
pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like;
or acid addition salts formed with organic acids such as acetic acid, propionic acid, succinic
acid, oxalic acid, malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, and the like.
[0059] In one embodiment, free base of palonosetron disclosed herein for use in the
pharmaceutical compositions of the present invention can independently have a D50 and D90 particle size less than about 300 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 10 microns. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus, a D50 of about 300 microns means that 50% of the micronized particles in a composition have a diameter less than about 300 microns. Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state free base of palonosetron into any desired particle size range set forth above.
[0060] The novel amorphous and crystalline form-G of palonosetron free base of the
present invention are believed to be useful for pharmaceutical composition for use an


antiemetic and antinauseant agents, because they may be stable under conditions of high relative humidity and elevated temperatures.
[0061] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLE 1
Process for the preparation of palonosetron free base from 2-(1-azabicyclo [2.2.2]oct-3-yl) -2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one of formula-ll. This reaction is generally shown below in Scheme 1.
SCHEME 1



Pd/C

[0062] Charged water (400 ml) and 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-
1H-benz[de]isoquinolin-1-one (50 gm) in autoclave. Charged 20% palladium carbon (5 gm) at 25 - 30°C and heated the reaction mass at 65 - 70°C. Passed hydrogen gas upto 8 kg at 65 -70°C and maintained for 25 hours. Filtered the reaction mass through hyflo bed at 25-30°C and adjusted the pH to 12 with aqueous sodium hydroxide (20 gm) dissolved in water (40 ml). Extracted the reaction product with methylene chloride (1x250 ml and 2x125 ml) and washed with water (2x125 ml) and methylene chloride was removed by distillation from the reaction mass under vacuum at 30 - 35°C. The resulting residue was dissolved in ethyl acetate (35 ml) and methanol (70 ml) at 25 - 30°C and added water (525 ml) at 25 to 30°C. Cooled the solution to 0 - 5°C and stirred for 2 hours. The resulting solid was filtered and washed with purified water (50 ml). The wet product was dried at 40 - 45°C under reduced pressure to provide the crude palonosetron free base (21.0 g).
[0063] Mass m/z 297.40
[0064] HPLC: daistereomeric purity
S-isomer: 55.10%, R-isomer: 44.89%,
[0065] HPLC chemical purity: 99.49%.
[0066] Unreacted impurity: 0.276%
[0067] The XRD is set forth in Figure 1.
[0068] The DSC is set forth in Figure 2.
[0069] The TGA is set forth in figure 3.


EXAMPLE 2
Process for the preparation of palonosetron hydrochloride from palonosetron free base.
[0070] Charged ethanol (100 ml) and palonosetron free base (20 g, obtained from ex-
1) in a round bottom flask. Heated the reaction mass at temperature 60-65°C and charged 20
% Isopropanolic hydrochloride (40ml). Stirred the reaction mass at temperature 60-65°C for
30 minutes. Cooled to 25-30°C and stirred for 2 hours. The resulting solid was filtered and
washed with ethanol (10 ml). The wet product was dried at 60 - 65°C under reduced pressure
to provide the palonosetron hydrochloride (21 g).
[0071] HPLC: daistereomeric purity
S-isomer: 95.19%, R-isomer: 4.80%,
[0072] HPLC chemical purity: 99.85%
[0073] Unreacted impurity: 0.11 %
EXAMPLE 3 Purification of palonosetron hydrochloride.
[0074] Palonosetron hydrochloride (20 g, obtained from ex-2) was dissolved in
methanol (30 ml) at temperature 60-65°C. Stirred the reaction mass at temperature 60-65°C
for 30 minutes. Cooled to 10-15°C and stirred for 60 minutes. The resulting solid was filtered
and washed with methanol (10 ml). The wet product was dried at 55 - 60°C under reduced
pressure to provide the palonosetron hydrochloride (17 g).
[0075] HPLC: daistereomeric purity
S-isomer: 99.88%, R-isomer: 0.11%,
[0076] HPLC chemical purity: 99.97%.
[0077] Unreacted impurity:0.02%
[0078] The XRD is set forth in Figure 7.
[0079] The DSC is set forth in Figure 8.
[0080] The TGA is set forth in figure 9.
EXAMPLE 4
Process for the preparation of palonosetron free base in crystalline form-G.
[0081] Palonosetron hydrochloride (50 g) was dissolved in methylene chloride (250
ml) and water (250 ml) followed by addition of aqueous sodium hydroxide (2 g) dissolved in


water (20 ml) to adjusted the pH to 10. The reaction mass was stirred for 15 minutes at 25 -
30°C. Separated the methylene choloride layer and washed with water (2x125 ml) and
methylene chloride was removed by distillation from the reaction mass under vacuum at 30 -
35°C. The resulting residue was dissolved in ethyl acetate (20 ml) and methanol (40 ml) at 25
- 30°C and added water (300 ml) at 25 - 30°C. Cooled the solution to 0 - 5°C and stirred for 2
hours. The resulting solid was filtered and washed with purified water (20 ml). The wet
product was dried at 40 - 45°C under reduced pressure to provide the palonosetron free base
(13.0 g).
[0082] HPLC: daistereomeric purity
S-isomer: 99.94%, R-isomer: 0.05%
HPLC chemical purity: 99.89%
[0083] The XRD is set forth in Figure 4.
[0084] The DSC is set forth in figure 5.
[0085] The TGA is set forth in figure 6.
COMPARITIVE EXAMPLE-1
Process for the preparation of palonosetron hydrochloride from 2-(1-azabicyclo [2.2.2]oct-3-yl) -2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one of formula-ll using acetic acid and perchloric acid as reaction solvent.
[0086] Charged acetic acid (1562.5 ml), 70 % perchloric acid solution (50 ml) and 2-
(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one (100 gm) in an autoclave. Charged 20% palladium hydroxide (31.25 gm) at 25 - 30°C and heated the reaction mass at 85°C. Passed hydrogen gas upto 50 psi at 85°C and maintained for 28 hours. Filtered the reaction mass through hyflo bed at 25-30°C and washed the hyflo bed with water (100 ml). The filtrate was concentrated under vacuum by distillation of water and the resulting residue was dissolved in water and basified to pH 10 with ammonium hydroxide solution (200 ml). Extracted with ethyl acetate and the ethyl acetate layer was dried over anhydrous potassium carbonate, filtered, and evaporated to give a semi solid mass. The resulting semisolid was dissolved in ethanol and added ethanolic hydrochloric acid at 25-30°C. filtered and washed with ethanol (50 ml). The wet product was dried at 60 - 65°C under reduced pressure to provide the crude palonosetron hydrochloride (56.25 g). The crude palonosetron hydrochloride was further purified in ethanol for four times to gave the pure palonosetron hydrochloride.
[0087] The HPLC analysis of three batches of palonosetron hydrochloride being
prepared as in comparitive example-1 is set forth below in Table I.


Table-I

Batch Palonosetron hydrochloride (crude) Pure Palonosetron hydrochloride (after four purifications)
1 S-isomer: 78.27% R-isomer: 16.41% Unreacted impurity: 0.33% S-isomer: 97.63% R-isomer: 1.59% Unreacted impurity: 0.28%
2 S-isomer: 87.96% R-isomer: 8.17% Unreacted impurity: 0.47% S-isomer: 98.19% R-isomer: 1.13% Unreacted impurity: 0.34%
3 S-isomer: 84.80% R-isomer: 12.43% Unreacted impurity: 1.34% S-isomer: 96.53% R-isomer: 2.10% Unreacted impurity: 0.89%
COMPARITIVE EXAMPLE-2
Process for the preparation of palonosetron hydrochloride from 2-(1-azabicyclo [2.2.2]oct-3-yl) -2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one of formula-ll using ethanol and water as reaction solvent.
[0088] Charged ethanol (160 ml), water (640 ml) and 2-(1-azabicyclo[2.2.2]oct-3-yl)-
2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one (100 gm) in an autoclave. Charged 20% palladium carbon (10 gm) at 25 - 30°C and heated the reaction mass at 70°C. Passed hydrogen gas upto 8 kg at 70°C and maintained for 48 hours. Filtered the reaction mass through hyflo bed at 25-30°C and washed the hyflo bed with water (100 ml). Adjusted the pH to 12 with aqueous sodium hydroxide (40 gm of sodium hydroxide dissolved in 80 ml of water). Extracted the reaction product with methylene chloride (1x500 ml and 2x250 ml) and washed with water (2x500 ml), dried the methylene chloride layer with sodium sulphate (50 gm) and methylene chloride was removed by distillation from the reaction mass under vacuum at 30 - 35°C. The resulting residue was dissolved in ethanol (250 ml) and heated to 65°C. Charged 20% Isopropanolic hydrochloric acid (160 ml) at temperature 65°C, cooled the solution to 25-30°C and stirred the reaction for 2 hours. The resulting solid was filtered and washed with ethanol (2x50 ml). The wet product was dried at 60 to 65°C under reduced pressure to provide the crude palonosetron hydrochloride (42.0 g). The crude palonosetron hydrochloride was further purified in ethanol for three times to gave the pure palonosetron hydrochloride.


[0089] The HPLC analysis of three batches of palonosetron hydrochloride being
prepared as in comparitive example-2 is set forth below in Table II.
Table-ll

Batch Palonosetron hydrochloride (crude) Pure Palonosetron hydrochloride (after Three purifications)
1 S-isomer: 88.42% R-isomer: 10.47% Unreacted impurity: 0.38% S-isomer: 97.29% R-isomer: 1.80% Unreacted impurity: 0.44%
2 S-isomer: 74.47% R-isomer: 22.55% Unreacted impurity: 1.18% S-isomer: 96.78% R-isomer: 2.04% Unreacted impurity: 0.96%
3 S-isomer: 89.17% R-isomer: 9.58% Unreacted impurity: 0.40% S-isomer: 97.75% R-isomer: 1.73% Unreacted impurity: 0.33%
[0090] It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.


FEATURES AND ADVANTAGES:
A) A process for the preparation of palonosetron, its pharmaceutical^ acceptable salts thereof, which process comprises
a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-benz[de]isoquinolin-1-one of formula-ll with hydrogenation catalyst, in water solvent,

b) isolating the palonosetron free base,
c) converting the palonosetron free base into its pharmaceutically acceptable salts thereof.

B) The process as defined in 'A' above, wherein the hydrogenation catalyst is selected from the group consisting of palladium, platinum, nickel, and rhodium
C) The process as defined in 'A(b)' above, wherein the isolation is carried out by crystallization from a suitable organic solvent.
D) The process as defined in 'C above, wherein the suitable organic solvent is selected from the group consisting of alcohols, esters, hydrocarbons, and chlorinated solvents, water and their mixtures.
E) The process as defined in 'A' above, further comprising the steps of
a) dissolving palonosetron, its pharmaceutically acceptable salts thereof in an organic solvent or mixture with water, wherein the organic solvent is selected from the group consisting of alcohols selected from methanol, ethanol, propanol, and butanol; esters selected from ethyl acetate, and isopropyl acetate; and hydrocarbons selected from n-hexane, n-heptane, cyclohexane, and toluene,
b) isolating the palonosetron, its pharmaceutically acceptable salts thereof.


F) A process for the preparation of palonosetron free base, which process comprises a) hydrogenating the 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1 H-benz[de]isoquinolin-1-one of formula-ll with hydrogenation catalyst, in water solvent,

Formula-ll b) isolating the palonosetron free base.
G) The process as defined in 'F(b)' above, wherein the isolation is carried out by crystallization from a suitable organic solvent.
H) The process as defined in 'G' above, wherein the suitable organic solvent is selected from the group consisting of alcohols, esters, hydrocarbons, and chlorinated solvents, water and their mixtures.
I) A process for the preparation of palonosetron free base, which process comprises
a) providing a solution of palonosetron hydrochloride in a water immiscible organic solvent and water,
b) treating with a base,
c) concentrating the water immiscible organic solvent under vacuum,
d) crystallizing the resultant residue in a suitable organic solvent.
J) The process as defined in '1(a)' above, wherein the water immiscible organic solvent is selected from the group consisting of esters, ethers, hydrocarbons, and chlorinated solvents.
K) The process as defined in '1(d)' above, wherein the suitable organic solvent is selected from the group consisting of alcohols, esters, hydrocarbons, and haloginated solvents, water and their mixtures.
L) A process for the preparation of Palonosetron hydrochloride, which process comprises a) providing a solution of palonosetron free base obtained from process defined in I, above,


b) treating with aqueous or anhydrous hydrochloric acid,
c) isolating the palonosetron hydrochloride.
M) Isolated palonosetron free base.
N) Palonosetron free base in an amorphous form.
0) Palonosetron free base in an amorphous form characterized by an XPRD pattern substantially in accordance with Figure 1.
P) Palonosetron free base in crystalline form -G.
Q) Palonosetron free base in crystalline form-G characterized by an XPRD pattern substantially in accordance with Figure 4.
R) Palonosetron free base in crystalline form-G characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5.
S) Palonosetron free base as defined in 'M' above, has a chemical purity greater than or equal to about 99.8% as determined by HPLC.
T) Palonosetron hydrochloride has a chemical purity greater than or equal to about 99.8% as determined by HPLC.
U) Palonosetron hydrochloride having less than about 0.2% by HPLC of R-isomer.
V) The use of palonosetron free base as defined in M - R above in a pharmaceutical composition for prevent nausea and vomiting that may be caused by surgery or by medicine.




ABSTRACT
Novel palonosetron free base in an amorphous form and crystalline form-G and processes for their preparation are disclosed. Process for the preparation of palonosetron hydrochloride from the novel free base of palonosetron are also disclosed.