The present invention relates to novel polymorphic forms of Milnacipran hydrochloride. The novel polymorphic forms are designated as Forms I, II, III, IV and V of milnacipran hydrochloride. The present invention also relates to processes for the preparation of the novel polymorphic forms.
(1 R,2S)-rel-2-(Aminomethyl)-N, N-diethyl-1 -phenylcyclopropanecarboxamide hydrochloride is commonly known as milnacipran hydrochloride of Formula I:
(Figure Removed)
Milnacipran hydrochloride is a Norepinephrine Serotonin Reuptake Inhibitor (NSRI) and it is useful in the treatment of depression and chronic pain conditions like Fibromyalgia and Lupus.
US Patent No 4,478,836 provides a process for the preparation of milnacipran hydrochloride by salifying milnacipran base with hydrochloric acid. In this method, milnacipran hydrochloride is obtained as white crystals with a melting point of 180°C and a characteristic IR peak at 1620 cm"1. However, the solvents involved in the salification step are not disclosed in this patent.
EP Patent No 0,200,638 provides a process for the preparation of milnacipran hydrochloride by the addition of ethanolic hydrochloric acid to crude milnacipran base. In this method, milnacipran hydrochloride is obtained with a melting point of 180°C and a characteristic IR peak at 1610 cm"1.
JP Unexamined Publication No 2006-008569 A provides a process for the preparation of milnacipran hydrochloride. In this method, milnacipran base is treated with hydrogen chloride-ethylacetate followed by the addition of ethyl acetate and isopropyl alcohol, and concentration of the reaction mixture to obtain milnacipran hydrochloride as white powder.
The present inventors have now prepared milnacipran hydrochloride in novel polymorphic forms, designated as Forms I, II, III and IV. The present polymorphic forms have characteristic XRPD pattern, and are further characterized by IR and DSC patterns.
A first aspect of the present invention provides a novel polymorphic Form I of milnacipran hydrochloride having typical XRPD pattern as depicted in Figure 1 of the accompanied drawing. The XRPD of Form I shows characteristic 29 values at 5.97, 7.75, 11.46, 11.93, 12.48, 13.52, 14.32, 15.52, 16.56, 17.03, 17.63, 18.37, 18.67, 19.26, 19.63, 20.54, 21.11, 21.68, 22.15, 22.96, 24.24, 24.38, 24.58, 25.12, 25.91, 26.69, 26.93, 27.31, 27.98, 28.70, 29.51, 30.25, 30.70, 31.15, 31.84, 32.29, 32.87, 34.13, 34.83 and 35.64. The novel polymorphic Form I has characteristic FTIR pattern as depicted in Figure 2 of the accompanied drawing. The novel polymorphic Form I has characteristic DSC thermogram as depicted in Figure 3 of the accompanied drawing. The DSC thermogram shows one characteristic endothermic peak at 177°-179°C.
A second aspect of the present invention provides a process for the preparation of the novel polymorphic Form I of milnacipran hydrochloride, which comprises
a) dissolving milnacipran hydrochloride in a C-|.3 alkanol,
b) treating the solution obtained in step a) with an ether solvent, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is dissolved in a C-i-3 alkanol, preferably in methanol. The dissolution process may also be accompanied by stirring and/or heating to effect complete dissolution. The solution so obtained is treated with ether solvent. The ether solvent is employed in this step as an anti-solvent. The ether solvent is selected from a group consisting of diisopropyl ether, diethyl ether, methyl t-butyl ether and di-t-butyl ether. Diisopropyl ether is preferably used. The treatment with ether solvent is preferably carried out by adding the alcoholic solution of milnacipran hydrochloride to the ether solvent at about 0°C to about 30°C. The reaction mixture so obtained is stirred to effect complete precipitation of the solid. The solid so
obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form I of milnacipran hydrochloride.
A third aspect of the present invention provides a process for the preparation of the novel polymorphic Form I of milnacipran hydrochloride, which comprises
a) dissolving milnacipran hydrochloride in a d.3 alkanol,
b) partially or completely removing the solvent from the solution obtained in step a), and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is dissolved in a Ci.3 alkanol, preferably in methanol. The dissolution process may also be accompanied by stirring and/or heating to effect complete dissolution. The solvent is removed from the solution so obtained. The solvent is removed partially or completely by vacuum or by distillation. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form I of milnacipran hydrochloride.
A fourth aspect of the present invention provides a process for the preparation of the novel polymorphic Form I of milnacipran hydrochloride, which comprises
a) dissolving milnacipran hydrochloride in a water miscible aliphatic ether at a
temperature of about 50°C or above,
b) cooling the solution obtained in step a) to a temperature of about 35°C or less, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is treated with a water miscible aliphatic ether and further dissolved by heating the reaction mixture to a temperature of about 50°C or above. The water miscible aliphatic ether is preferably 1,4-dioxane. The solution so obtained is subsequently cooled to a temperature of about 35°C or less. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form I of milnacipran hydrochloride.
A fifth aspect of the present invention provides a process for the preparation of the novel polymorphic Form I of milnacipran hydrochloride, which comprises
a) treating milnacipran hydrochloride with an aromatic hydrocarbon solvent,
b) heating the reaction mixture obtained in step a) to a temperature of about 60°C or
more,
c) cooling the reaction mixture obtained in step b) to a temperature of about 35°C or
less, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is treated with an aromatic hydrocarbon solvent and heated to a temperature of about 60°C or above. The aromatic hydrocarbon solvent is preferably benzene substituted with one or more alkyl groups, more preferably toluene. The reaction mixture so obtained is subsequently cooled to a temperature of about 35°C or less. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form I of milnacipran hydrochloride.
A sixth aspect of the present invention provides a process for the preparation of the novel polymorphic Form I of milnacipran hydrochloride, which comprises
a) treating milnacipran hydrochloride with an aliphatic ester solvent and optionally a C-i-3
alkanol,
b) treating the reaction mixture obtained in step a) with an acid, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is treated with an aliphatic ester solvent. The aliphatic ester solvent is preferably ethyl acetate. The reaction mixture is optionally further treated with a Ci_3 alkanol. The Ci.3 alkanol is preferably isopropyl alcohol. The reaction mixture is subsequently treated with an acid.
The acid is preferably an alcoholic solution of hydrochloric acid. The mixture so obtained is heated to a temperature of about 60°C or above and cooled to a temperature of about 20°C or less. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form I of milnacipran hydrochloride.
A seventh aspect of the present invention provides a novel polymorphic Form II of milnacipran hydrochloride having typical XRPD pattern as depicted in Figure 4 of the accompanied drawing. The XRPD of Form II shows characteristic 20 values at 5.95, 11.45, 11.91, 14.32, 18.37, 18.66, 21.11, 21.67, 22.96, 24.23, 24.38, 24.57, 25.39 and 27.67. Form II is further characterized by 26 values at 5.95, 7.74, 11.45, 11.91, 12.48, 13.51, 14.32, 15.51, 16.53, 17.02, 17.62, 18.37, 18.66, 19.23, 19.63, 20.53, 21.11, 21.67, 22.13, 22.96, 24.23, 24.38, 24.57, 25.12, 25.39, 25.92, 26.68, 26.91, 27.31, 27.67, 27.95, 28.69, 29.50, 30.23, 30.69, 31.14, 31.85, 32.26, 32.88, 34.13, 34.80 and 35.63. The novel polymorphic Form II has characteristic FTIR pattern as depicted in Figure 5 of the accompanied drawing. The novel polymorphic Form II has characteristic DSC thermogram as depicted in Figure 6 of the accompanied drawing. The DSC thermogram shows one characteristic endothermic peak at 175°-177°C.
An eighth aspect of the present invention provides a process for the preparation of the novel polymorphic Form II of milnacipran hydrochloride, which comprises
a) dissolving milnacipran hydrochloride in an aqueous solvent,
b) spray drying the solution obtained in step a) in a spray dryer, and
c) collecting Form II of milnacipran hydrochloride from said spray dryer.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined Publication No 2006-008569 A. The milnacipran hydrochloride is dissolved in an aqueous solvent. The aqueous solvent can be water or a mixture of water with one or more water miscible organic solvents. Preferably water is used as the aqueous solvent. The dissolution process may also be accompanied by stirring and/or heating to effect complete dissolution. The resultant solution is fed to a spray dryer. The inlet and outlet temperatures, feed rate, and atomizer type are adjusted to optimize output and particle size. The air inlet temperature is preferably controlled from about 60°C to about 100°C. Compressed air or an inert gas such as nitrogen can be used as a carrier gas for drying
process. After the drying process, milnacipran hydrochloride is collected from the spray dryer and optionally further dried under vacuum to obtain Form II of milnacipran hydrochloride.
A ninth aspect of the present invention provides a novel polymorphic Form III of milnacipran hydrochloride having typical XRPD pattern as depicted in Figure 7 of the accompanied drawing. The XRPD of Form III shows characteristic 20 values at 5.94, 11.44, 11.90, 14.31, 18.36, 18.65, 21.10, 21.66, 22.95, 24.22, 24.57, 29.70, 31.68, 33.42, 33.93, and 35.39. Form III is further characterized by 26 values at 5.94, 7.73, 11.44, 11.90, 12.47, 13.50, 14.31, 15.51, 16.53, 17.01, 17.61, 18.36, 18.65, 19.23, 19.62, 20.41, 21.10, 21.66, 22.11, 22.95, 24.22, 24.57, 25.11, 25.90, 26.68, 26.91, 27.31, 27.94, 28.69, 29.70, 30.25, 30.67, 31.14, 31.68, 32.27, 32.87, 33.42, 33.93, 34.12,34.80, 35.39 and 35.64.
A tenth aspect of the present invention provides a process for the preparation of the novel polymorphic Form III of milnacipran hydrochloride, which comprises
a) dissolving milnacipran base in a Ci_3 alkanol,
b) treating the solution obtained in step a) with hydrochloric acid,
c) treating the solution obtained in step b) with a C4-io alkane, and
c) isolating Form III of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran base present in any solid form can be used as a starting material. The starting milnacipran base can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined Publication No 2006-008569 A. The milnacipran base is dissolved in a C-i-3 alkanol, preferably in isopropyl alcohol. The dissolution process may also be accompanied by stirring and/or heating to effect complete dissolution. The solution so obtained is treated with hydrochloric acid. The hydrochloric acid is preferably added as an alcoholic solution. More preferably an isopropyl alcohol solution of hydrochloric acid is used. The treatment with hydrochloric acid is preferably carried out by adding the alcoholic solution of hydrochloric acid to the solution of milnacipran in Ci.3 alkanol at about 0°C to about 30°C. The solution so obtained is treated with a C4.io alkane. The C4.10 alkane is preferably selected from a group consisting of pentane, hexane, heptane and iso-octane. The reaction mixture so obtained is stirred to effect complete precipitation of the
solid. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form III of milnacipran hydrochloride.
A eleventh aspect of the present invention provides a novel polymorphic Form IV of milnacipran hydrochloride having typical XRPD pattern as depicted in Figure 8 of the accompanied drawing. The XRPD of Form IV shows characteristic 26 values at 5.99, 11.53, 11.95, 14.36, 17.94, 18.40, 18.69, 21.13, 21.69, 23.0, 23.39, 23.98, 24.26, 24.50, 26.33, 30.09, 31.70, 33.47, and 33.98. Form IV is further characterized by 26 values at 4.23, 4.98, 5.40, 5.99, 10.78, 11.53, 11.95, 14.36, 15.55, 16.58, 17.04, 17.94, 18.40, 18.69, 19.26, 20.44, 21.13, 21.69, 22.16, 23.0, 23.39, 23.98, 24.26, 24.50, 25.95, 26.33, 26.94, 27.32, 27.98, 28.71, 29.53, 30.09, 31.18, 31.70, 32.28, 33.47, 33.98, 34.83, 35.43 and 35.65.
A twelfth aspect of the present invention provides a process for the preparation of the novel polymorphic Form IV of milnacipran hydrochloride, which comprises
a) dissolving milnacipran base in a Ci-s alkanol,
b) treating the solution obtained in step a) with hydrochloric acid,
c) treating the solution obtained in step b) with an aliphatic ester solvent, and
c) isolating Form IV of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran base present in any solid form can be used as a starting material. The starting milnacipran base can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined Publication No 2006-008569 A. The milnacipran base is dissolved in a C-i-3 alkanol, preferably in isopropyl alcohol. The dissolution process may also be accompanied by stirring and/or heating to effect complete dissolution. The solution so obtained is treated with hydrochloric acid. The hydrochloric acid is preferably added as an alcoholic solution. More preferably an isopropyl alcohol solution of hydrochloric acid is used. The treatment with hydrochloric acid is preferably carried out by adding the alcoholic solution of hydrochloric acid to the solution of milnacipran in C-i-s alkanol at about 0°C to about 30°C. The solution so obtained is treated with an aliphatic ester solvent. The aliphatic ester solvent is preferably ethyl acetate. The reaction mixture so obtained is stirred to effect complete precipitation of the solid. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form IV of milnacipran hydrochloride.
A thirteenth aspect of the present invention provides a process for the preparation of the novel polymorphic Form IV of milnacipran hydrochloride, which comprises
a) treating milnacipran base with an aliphatic ester solvent,
b) treating the reaction mixture obtained in step a) with an alcoholic solution of
hydrochloric acid, and
c) isolating Form IV of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran base present in any solid form can be used as a starting material. The starting milnacipran base can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined Publication No 2006-008569 A. The milnacipran base is treated with an aliphatic ester solvent. The aliphatic ester solvent is preferably ethyl acetate. The reaction mixture so obtained is further treated with hydrochloric acid. The hydrochloric acid is preferably an alcoholic solution. More preferably an isopropyl alcohol solution of hydrochloric acid is used. The reaction mixture so obtained is stirred to effect complete precipitation of the solid. The stirring is carried out at a temperature of about 20°C or less. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form IV of milnacipran hydrochloride.
A fourteenth aspect of the present invention provides a novel polymorphic Form V of milnacipran hydrochloride having typical XRPD pattern as depicted in Figure 9 of the accompanied drawing. The XRPD of Form V shows characteristic 20 values at 5.96, 7.74, 11.44, 11.92, 14.33, 15.52, 16.55, 17.02, 17.92, 18.37, 18.67, 19.23, 20.44, 21.09, 21.67, 22.14, 22.96, 23.96, 24.24, 25.08, 25.93, 26.64, 26.91, 27.29, 27.97, 28.64, 29.70, 30.06, 31.15, 31.64, 32.25, 34.80 and 35.42. Form V is further characterized by absence of peaks between 29 values of 12.00 and 14.00. The novel polymorphic Form V has characteristic FTIR pattern as depicted in Figure 10 of the accompanied drawing. The novel polymorphic Form V has characteristic DSC thermogram as depicted in Figure 11 of the accompanied drawing. The DSC thermogram shows three characteristic endothermic peaks at 90°-100°C, 125°-145°C and 160°-175°C.
A fifteenth aspect of the present invention provides a process for the preparation of the novel polymorphic Form V of milnacipran hydrochloride, which comprises
a) treating milnacipran hydrochloride with a ketone solvent,
b) heating the reaction mixture obtained in step a) to a temperature of about 60°C or
more,
c) cooling the reaction mixture obtained in step b) to a temperature of about 35°C or
less, and
c) isolating Form V of milnacipran hydrochloride from the reaction mixture thereof.
Milnacipran hydrochloride present in any solid form can be used as a starting material. The starting milnacipran hydrochloride can be prepared by following the methods provided in US Patent No 4,478,836, EP Patent No 0,200,638, or JP Unexamined publication No 2006-008569 A. The milnacipran hydrochloride is treated with a ketone solvent and heated to a temperature of about 60°C or above. The ketone solvent is preferably methyl isobutyl ketone or methyl ethyl ketone. The reaction mixture so obtained is subsequently cooled to a temperature of about 35°C or less. The solid so obtained is isolated from the reaction mixture by filtration and/or concentration to obtain Form V of milnacipran hydrochloride.
A sixteenth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form I of milnacipran hydrochloride optionally containing an excipient/diluent.
A seventeenth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form II of milnacipran hydrochloride optionally containing an excipient/diluent.
An eighteenth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form III of milnacipran hydrochloride optionally containing an excipient /diluent.
A nineteenth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form IV of milnacipran hydrochloride optionally containing an excipient/diluent.
A twentieth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form V of milnacipran hydrochloride optionally containing an excipient/diluent.
A twenty first aspect of the present invention provides a method of treating depression and/or chronic pain conditions such as Fibromyalgia and Lupus, which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form I of milnacipran hydrochloride.
A twenty second aspect of the present invention provides a method of treating depression and/or chronic pain conditions such as Fibromyalgia and Lupus, which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form II of milnacipran hydrochloride.
A twenty third aspect of the present invention provides a method of treating depression and/or chronic pain conditions such as Fibromyalgia and Lupus, which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form III of milnacipran hydrochloride.
A twenty fourth aspect of the present invention provides a method of treating depression and/or chronic pain conditions such as Fibromyalgia and Lupus, which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form IV of milnacipran hydrochloride.
A twenty fifth aspect of the present invention provides a method of treating depression and/or chronic pain conditions such as Fibromyalgia and Lupus, which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form V of milnacipran hydrochloride.
Figure 1 depicts XRPD of Form I of milnacipran hydrochloride. Figure 2 depicts FTIR of Form I of milnacipran hydrochloride. Figure 3 depicts DSC of Form I of milnacipran hydrochloride. Figure 4 depicts XRPD of Form II of milnacipran hydrochloride. Figure 5 depicts FTIR of Form II of milnacipran hydrochloride. Figure 6 depicts DSC of Form II of milnacipran hydrochloride.
Figure 7 depicts XRPD of Form III of milnacipran hydrochloride. Figure 8 depicts XRPD of Form IV of milnacipran hydrochloride. Figure 9 depicts XRPD of Form V of milnacipran hydrochloride. Figure 10 depicts FTIR of Form V of milnacipran hydrochloride. Figure 11 depicts DSC of Form V of milnacipran hydrochloride.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A .
FTIR of the samples were determined by using Instrument: Perkin Elmer,16 PC, SCAN: 16scans, 4.0 cm'1, according to the DSP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
DSC thermograms were recorded using DSC821 e, Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-250° C, Heating rate: 10°C/min, Nitrogen 50.0 mL/min, Number of holes in the crucible: 1
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF MILNACIPRAN HYDROCHLORIDE: METHOD A:
(Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (50 g) was added into denaturated spirit (250 ml) at 25° to 30°C. The reaction mixture was heated to 60°C and hydrazine hydrate (7.35 g) was added. The reaction mixture was subsequently heated to reflux at 80°C and stirred at reflux temperature for 3 h. The denaturated spirit was recovered at 50° to 55°C under reduced pressure, followed by the addition of deionised water (2 X 50 ml) and the recovery of denaturated spirit was continued under reduced pressure. The mixture obtained was cooled to 10° to 15°C, stirred for 30 minutes at 10° to 15°C and filtered. The solid was washed with deionised
water (10° to 15°C, 2 x 10 ml) and subjected to suction under vacuum. The wet material obtained was suspended in deionised water (450 ml), cooled to 10° to 15°C and acidified with concentrated hydrochloric acid (11.4 ml) to about pH 2. The reaction mixture was filtered on Celite bed and washed with deionised water (10° to 15°C, 2 x 50 ml). The mother liquor and washings were combined and basified with aqueous sodium hydroxide solution (about 25 % w/v) to attain a pH of about 12 at 10° to 15°C. The reaction mixture was extracted with dichloromethane (3 x 50 ml) and combined organic layers were stirred with activated carbon (1.0 g at 25° to 30°C for 1 h). The contents were filtered over Celite bed and washed with dichloromethane (2x10 ml). The mother liquor and washings were combined and the solvent was removed under reduced pressure to obtain a residue. Isopropyl alcohol (5 ml) was added to the residue, followed by the addition of ethyl acetate (250 ml) at 25° to 30°C. Isopropyl alcohol hydrochloride (15 g) was added to the reaction mixture in 1 h at 25° to 40°C to obtain a pH of about 2. The reaction mixture was heated to reflux (about 80°C) and stirred for 2 h. The slurry obtained was cooled to 10° to 15°C and stirred for 1 h at 10° to 15°C. The slurry was filtered, washed with ethyl acetate (2 x 30 ml, 10° to 15°C), and further washed with ethyl acetate (30 ml, 10 - 15°C) at faster rate. The wet solid (28.5 g) obtained was dried at 50° to 55°C under vacuum to obtain the title compound.
Yield: 21.2g
METHOD B:
(Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (2.5 Kg) was added into denaturated spirit (12.5 L) stirred at about 25°C. The reaction mixture was further stirred for 10 minutes, followed by the addition of hydrazine hydrate (0.375 Kg). The reaction mixture was heated at reflux temperature (80°C) for 3 h. The denaturated spirit was removed at 50° to 55°C under reduced pressure, followed by the addition of deionised water (2.5 L) and the recovery of denaturated spirit was continued at 50° to 55°C under reduced pressure. The mixture obtained was cooled to 10° to 15°C, stirred for 30 minutes at 10° to 15°C and filtered. The solid obtained was washed with cooled deionised water (10° to 15°C, 2 x 0.5 L) and subjected to suction under vacuum. The wet material was added to deionised water (7.5 L) and cooled to 10° to 15°C. Concentrated hydrochloric acid (about 0.57 L) was added to the reaction mixture to obtain a pH of about 2, and stirred for 15 minutes at 10° to 15°C. The mixture obtained was filtered over Celite bed and washed with cooled deionised water (10° to 15°C, 2 x
2.5 L) The filtrate and washings were combined and aqueous sodium hydroxide
solution (prepared by dissolving sodium hydroxide (0.25 Kg) in deionised water (1 L) and cooling the solution to 10°C) was added at 10° to 15°C to obtain a pH of about 12. Dichloromethane (2.5 L) was added to the reaction mixture at 10° to 15°C and stirred for 10 minutes at 10° to 15°C. The reaction mixture was filtered through Celite bed, washed with dichloromethane (2 x 0.5 L) and the layers were allowed to settle. The organic layer (OL-1) and the aqueous layer (AL-1) were separated. Dichloromethane (2.5 L) was added to the aqueous layer (AL-1), stirred for 10 minutes at 10° to 15°C and the layers were allowed to settle. The organic layer (OL-2) and the aqueous layer (AL-
2) were separated. Dichloromethane (2.5 L) was added to the aqueous layer (AL-2),
stirred for 10 minutes at 10° to 15°C and the layers were allowed to settle. The organic
layer (OL-3) and the aqueous layer (AL-3) were separated and the aqueous layer (AL-
3) was discarded. The organic layers (OL-1 + OL-2 + OL-3) were combined and
activated carbon (0.05 Kg) was added to the combined organic layer. The reaction
mixture was stirred for 1 h at 25° to 30°C. The mixture obtained was filtered through
Celite bed, washed with dichloromethane (2 x 0.5 L). The filtrate and the washings were
combined. Dichloromethane was recovered initially at atmospheric pressure up to 50%
of volume and subsequently under reduced pressure at 35° to 40°C. Ethyl acetate (2 .5
L) was added to the residue and stirred for 15 minutes. Ethyl acetate was recovered at
40° to 45°C under reduced pressure. Ethyl acetate (12.5 L) was added to the residue,
and stirred at 25° to 30°C. Isopropyl alcohol hydrochloride (0.8 Kg) was added to the
reaction mixture in 1 h at 25° to 40°C and stirred for 30 minutes at 25° to 30°C. The
reaction mixture was cooled to 10° to 15°C and stirred for 1 hr at 10° to 15°C. The
reaction mixture was filtered, washed with pre-cooled ethyl acetate (2 x 1.5 L, 10° to
15°C) and further washed with ethyl acetate (1.5 L, 10 - 15°C) at faster rate. The wet
solid was dried at 45° to 55°C under vacuum to obtain the title compound.
Yield: 1.18kg HPLC Purity: 99.98%
EXAMPLE 2
PREPARATION OF FORM I OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (5 g) obtained from Example 1 (B) was dissolved in methanol (50 ml) at 25° to 30°C to obtain a clear solution. Methanol was recovered under vacuum to obtain a solid. The solid was further dried under vacuum to obtain the title compound. Yield: 4.3 g
EXAMPLE 3
PREPARATION OF FORM I OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (5 g) obtained from Example 1 (B) was dissolved in 1,4-dioxane (350 ml) at 80° to 85°C to obtain a clear solution. The solution was cooled to 25° to 30°C. The reaction mixture was filtered and washed with 1,4-dioxane (10 ml). The solid was dried under vacuum to obtain the title compound. Yield: 2.5 g
EXAMPLE 4
PREPARATION OF FORM I OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (5 g) obtained from Example 1 (B) was suspended in toluene (50 ml). The mixture was refluxed at 110°C for 4 h. The slurry was cooled to 25° to 30°C and stirred for 1 h. The reaction mixture was filtered and washed with toluene (2 x 10 ml). The solid was dried under vacuum to obtain the title compound. Yield: 4.3 g
EXAMPLE 5
PREPARATION OF FORM I OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (50 g) obtained from Example 1 (B) was added to ethyl acetate (250 ml) and stirred at 25° to 30°C. Isopropyl alcohol (5 ml) was added to the reaction mixture, followed by the addition of isopropyl alcohol hydrochloride (3 ml) to attain the pH of about 2 in 15 minutes at 25° to 30°C. The slurry was heated to reflux temperature (about 80°C) and stirred under reflux for 2 h. The slurry was cooled to 10° to 15°C and stirred for 1 h at 10° to 15°C. The mixture was filtered and washed with ethyl acetate (2 x 30 ml, 10° to 15°C) followed by running wash with ethyl acetate (30 ml, 10° to 15°C). The wet solid (61 g) was dried at 50° to 55°C under vacuum to obtain the title compound. Yield: 48.9 g

EXAMPLE 6
PREPARATION OF FORM I OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (5 g) was dissolved in methanol (5 ml) to obtain a clear solution. The solution so obtained was added to stirred diisopropyl ether (200 ml) at 25° to 30°C in about 20 minutes. The mixture was stirred for about 1 h at 25° to 30°C, filtered and washed with diisopropyl ether (2x10 ml). The solid obtained was dried under vacuum to obtain the title compound. Yield: 4.5 g
EXAMPLE 7
PREPARATION OF FORM II OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran Hydrochloride (20 g) was dissolved in deionised water (200 ml) at 25° to 30°C to obtain a clear solution. The solution so obtained was spray dried in spray dryer (Model: Lab plant SD-05; Carrier gas: compressed air; Atomizer type: pressure/spray nozzle; Feed rate: 3 ml/minute; Inlet temperature: 95°C). The solid obtained was dried to get the title compound. Yield: 8.5 g
EXAMPLE 8
PREPARATION OF FORM III OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran base (10 g) was dissolved in isopropyl alcohol (10 ml) by stirring. Isopropyl alcohol hydrochloride (10 ml) was added into said solution at 25° to 30°C followed by stirring for 5 minutes. Hexane (200 ml) was subsequently added into said solution at 20° to 25°C. The reaction mixture was stirred for half an hour at 20° to 25°C and filtered. The solid was washed with hexane (20 ml) and dried under vacuum over night at 40° to 45°C to obtain the title compound. Yield: 9.3 g
EXAMPLE 9
PREPARATION OF FORM IV OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran base (10 g) was dissolved in isopropyl alcohol (10 ml) by stirring. Isopropyl alcohol hydrochloride (10 ml) was added into said solution at 20° to 25°C and stirred for 10 minutes. Ethyl acetate (250 ml) was subsequently added into said solution and stirred for 1 h at 20° to 25°C. The solid obtained was filtered and washed with ethyl
acetate (2 x 40 ml). The wet material (9.2 g) was dried under suction and further dried overnight at 45° to 50°C under vacuum to obtain the title compound. Yield: 8.2 g
EXAMPLE 10
PREPARATION OF FORM IV OF MILNACIPRAN HYDROCHLORIDE:
(Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (50 g) was added into denaturated spirit (250 ml) at about 25°C, followed by the addition of hydrazine hydrate (7.50 g). The reaction mixture was heated to reflux at 80°C and stirred at reflux temperature for 3 h. The denaturated spirit was recovered at 50° to 55°C under reduced pressure. The deionised water (2 X 50 ml) was added to the reaction mixture and the recovery of denaturated spirit was continued under reduced pressure. The reaction mixture was cooled to 10° to 15°C, stirred for 30 minutes at 10° to 15°C and filtered. The solid was washed with deionised water (10° to 15°C, 2x10 ml) and subjected to suction under vacuum. The wet material obtained was suspended in deionised water (150 ml), cooled to 10° to 15°C and acidified with concentrated hydrochloric acid (11.2 ml) to obtain a pH of about 2. The reaction mixture was filtered on Celite bed and washed with deionised water (10° to 15°C, 2 x 50 ml). The mother liquor and the washings were combined and basified with aqueous sodium hydroxide solution (about 25 % w/v) to obtain a pH of about 12 at 10° to 15°C. The mixture was extracted with dichloromethane (3 x 50 ml) and the combined organic layers were stirred with activated carbon (1.0 g, 25° to 30°C, 1 h). The reaction mixture was filtered over Celite bed and washed with dichloromethane (2x10 ml). The mother liquor and the washings were combined and the solvent was recovered under reduced pressure to obtain an oily residue. Ethyl acetate (250 ml) was added to the residue and stirred at 25° to 30°C. Isopropyl alcohol hydrochloride (15 g) was added to the reaction mixture in 1 h at 25° to 40°C. The reaction mixture was stirred for 30 minutes at 25° to 30°C, cooled to 10° to 15°C and stirred for 1 h at 10° to 15°C. The reaction mixture was filtered and the slurry was washed with ethyl acetate (2 x 30 ml, 10° to 15°C) and running wash was carried out with ethyl acetate (30 ml, 10° to 15°C). The wet solid was dried at 45° to 55°C under vacuum to obtain the title compound. Yield: 21.7 g
EXAMPLE 11
PREPARATION OF FORM V OF MILNACIPRAN HYDROCHLORIDE:
Milnacipran hydrochloride (5 g) obtained from Example 1 (B) was suspended in methyl isobutyl ketone (50 ml). The reaction mixture was refluxed at 118°C for 4 h. The slurry was cooled to 25° to 30°C and stirred for 1 h. The reaction mixture was filtered and washed with methyl isobutyl ketone (2x10 ml). The solid was dried under vacuum to obtain the title compound. Yield: 4.3 g

WE CLAIM:
1. Polymorphic Form I of milnacipran hydrochloride having characteristic XRPD pattern,
wherein 26 values are obtained at 5.97, 7.75, 11.46, 11.93, 12.48, 13.52, 14.32, 15.52,
16.56, 17.03, 17.63, 18.37, 18.67, 19.26, 19.63, 20.54, 21.11, 21.68, 22.15, 22.96,
24.24, 24.38, 24.58, 25.12, 25.91, 26.69, 26.93, 27.31, 27.98, 28.70, 29.51, 30.25,
30.70, 31.15, 31.84, 32.29, 32.87, 34.13, 34.83 and 35.64.
2. Polymorphic Form I of milnacipran hydrochloride according to claim 1 having
characteristic DSC pattern, wherein one characteristic endothermic peak is obtained at
177°-179°C.
3. A process for the preparation of polymorphic Form I of milnacipran hydrochloride,
which comprises

a) dissolving milnacipran hydrochloride in a Ci-3 alkanol,
b) treating the solution obtained in step a) with an ether solvent, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
4. A process for the preparation of polymorphic Form I of milnacipran hydrochloride,
which comprises
a) dissolving milnacipran hydrochloride in a Ci_3 alkanol,
b) partially or completely removing the solvent from the solution obtained in step a), and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
5. A process for the preparation of polymorphic Form I of milnacipran hydrochloride,
which comprises
a) dissolving milnacipran hydrochloride in a water miscible aliphatic ether at a
temperature of about 50°C or above,
b) cooling the solution obtained in step a) to a temperature of about 35°C or less, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
6. A process for the preparation of polymorphic Form I of milnacipran hydrochloride,
which comprises
a) treating milnacipran hydrochloride with an aromatic hydrocarbon solvent,

b) heating the reaction mixture obtained in step a) to a temperature of about 60°C or
more,
c) cooling the reaction mixture obtained in step b) to a temperature of about 35°C or
less, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
7. A process for the preparation of polymorphic Form I of milnacipran hydrochloride, which comprises
a) treating milnacipran hydrochloride with an aliphatic ester solvent and optionally a C-i-3
alkanol,
b) treating the reaction mixture obtained in step a) with an acid, and
c) isolating Form I of milnacipran hydrochloride from the reaction mixture thereof.
9. Polymorphic Form II of milnacipran hydrochloride having characteristic XRPD
pattern, wherein 26 values are obtained at 5.95, 11.45, 11.91, 14.32, 18.37, 18.66,
21.11, 21.67, 22.96, 24.23, 24.38, 24.57, 25.39 and 27.67.
10. Polymorphic Form II of milnacipran hydrochloride according to claim 9 having
characteristic DSC pattern, wherein one characteristic endothermic peak is obtained at
175°-177°C.
11. A process for the preparation of polymorphic Form II of milnacipran hydrochloride,
which comprises
a) dissolving milnacipran hydrochloride in an aqueous solvent,
b) spray drying the solution obtained in step a) in a spray dryer, and
c) isolating Form II of milnacipran hydrochloride from said spray dryer.
12. Polymorphic Form III of milnacipran hydrochloride having characteristic XRPD
pattern, wherein 20 values are obtained at 5.94, 11.44, 11.90, 14.31, 18.36, 18.65,
21.10, 21.66, 22.95, 24.22, 24.57, 29.70, 31.68, 33.42, 33.93, and 35.39.
13. A process for the preparation of polymorphic Form III of milnacipran hydrochloride,
which comprises
a) dissolving milnacipran base in a Ci_3 alkanol,

b) treating the solution obtained in step a) with hydrochloric acid,
c) treating the solution obtained in step b) with a C4.io alkane, and
c) isolating Form III of milnacipran hydrochloride from the reaction mixture thereof.
14. Polymorphic Form IV of milnacipran hydrochloride having characteristic XRPD
pattern, wherein 26 values are obtained at 5.40, 5.99, 10.78, 11.53, 11.95, 14.36,
17.94, 18.40, 18.69, 21.13, 21.69, 23.0, 23.39, 23.98, 24.26, 24.50, 26.33, 30.09,
31.70,33.47, and 33.98.
15. A process for the preparation of polymorphic Form IV of milnacipran hydrochloride,
which comprises
a) dissolving milnacipran base in a Ci-s alkanol,
b) treating the solution obtained in step a) with hydrochloric acid,
c) treating the solution obtained in step b) with an aliphatic ester solvent, and
c) isolating Form IV of milnacipran hydrochloride from the reaction mixture thereof.
16. A process for the preparation of polymorphic Form IV of milnacipran hydrochloride,
which comprises
a) treating milnacipran base with an aliphatic ester solvent,
b) treating the reaction mixture obtained in step a) with an alcoholic solution of
hydrochloric acid, and
c) isolating Form IV of milnacipran hydrochloride from the reaction mixture thereof.
17. Polymorphic Form V of milnacipran hydrochloride having typical XRPD wherein
characteristic 26 values are obtained at 5.96, 7.74, 11.44, 11.92, 14.33, 15.52, 16.55,
17.02, 17.92, 18.37, 18.67, 19.23, 20.44, 21.09, 21.67, 22.14, 22.96, 23.96, 24.24,
25.08, 25.93, 26.64, 26.91, 27.29, 27.97, 28.64, 29.70, 30.06, 31.15, 31.64, 32.25,
34.80 and 35.42.
18. Polymorphic Form V of milnacipran hydrochloride according to claim 17 having
characteristic DSC thermogram wherein three characteristic endothermic peaks are
obtained at 90°-100°C, 125°-145°C and 160°-175°C.
19. A process for the preparation of polymorphic Form V of milnacipran hydrochloride,
which comprises

a) treating milnacipran hydrochloride with a ketone solvent,
b) heating the reaction mixture obtained in step a) to a temperature of about 60°C or
more,
c) cooling the reaction mixture obtained in step b) to a temperature of about 35°C or
less, and
c) isolating Form V of milnacipran hydrochloride from the reaction mixture thereof.