DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“IVABRADINE CYCLAMATE”

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 particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to novel ivabradine cyclamate salt and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride is marketed as CORLENTOR® or PROCORALAN® which is used to treat the symptoms of long-term stable angina in adults with coronary-artery disease who have a normal heart rhythm. It is also used in patients with long-term heart failure who have a normal heart rhythm but whose heart rate is at least 75 beats per minute.
Various ivabradine salts are known. PCT publication WO2009124940 relates to hydrobromide salt of ivabradine. PCT publications WO2011104723 and WO2008146308 disclose ivabradine tartrate, citrate and hydrogen sulfate and ivabradine oxalate respectively. PCT publication WO2011157720 discloses adipate, S-mandelate, 1-hydroxy-2-naphthanoate, L-aspartate, D-aspartate, ethanesulfonate, L-malate and oxalate salts of ivabradine.
The present invention provides novel cyclamate salt of ivabradine which may be advantageous over known salts and can be easily prepared on industrial scale.
SUMMARY OF THE INVENTION
The present invention provides ivabradine cyclamate salt represented by Formula I
.
I
In one aspect, the present inevention provides ivabradine cyclamate having cyclamic acid content in the range of 25-28 % as measured by Potentiomeric autotitrator method.
In another aspect, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine or a salt thereof with cyclamic acid.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a 1H NMR spectrum of ivabradine cyclamate.
Figure 2 is a 13C NMR spectrum of ivabradine cyclamate.
Figure 3 is a characteristic XRPD of ivabradine cyclamate as obtained in Example 14.
Figure 4 is a characteristic XRPD of ivabradine cyclamate as obtained in Example 11.
Figure 5 is a characteristic XRPD of ivabradine cyclamate as obtained in Example 12
Figure 6 is a DSC thermogram of ivabradine cyclamate as obtained in Example 11.
Figure 7 is a DSC thermogram of ivabradine cyclamate as obtained in Example 12.
Figure 8 is a DSC thermogram of ivabradine cyclamate as obtained in Example 13.
Figure 9 is a TGA thermogram of ivabradine cyclamate as obtained in Example 11.
Figure 10 is a TGA thermogram of ivabradine cyclamate as obtained in Example 12.
Figure 11 is a TGA thermogram of ivabradine cyclamate as obtained in Example 13.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel ivabradine cyclamate salt represented by Formula I
.
I
In one embodiment, the present invention provides ivabradine cyclamate characterized by 1H nuclear magnetic resonance spectrum which is substantially in accordance with Figure 1.

In one embodiment, the novel ivabradine cyclamate salt has ivabradine and cyclamic acid in a ratio of 1:1.
In one embodiment, the present invention provides ivabradine cyclamate characterized by 1H nuclear magnetic resonance spectrum peaks at 1.01-1.18 ppm (5H,m), 1.45-1.58 ppm (3H, m), 1.89 ppm (4H,m), 2.74 ppm(3H,S), 2.80-2.97 ppm (6H,m), 3.18- 3.38 ppm (8H,m), 3.66-3.76 ppm (12H,S), 3.92(4H t), 6.65 ppm (1H,S), 6.69 ppm (1H,S), 6.77 ppm (1H,S), 6.82 ppm (1H, S).
In one embodiment, the present invention provides ivabradine cyclamate characterized by 13C nuclear magnetic resonance spectrum which is substantially in accordance with Figure 2.
In one embodiment, the present invention provides ivabradine cyclamate characterized by 13C nuclear magnetic resonance spectrum peaks at 22.96 ppm (CH2), 24.71 ppm (CH2), 25.48 ppm (CH2), 33.16 ppm (CH2), 35.13(CH2), 38.67 ppm (CH2), 39.95 ppm (CH2). 39.2 ppm (CH), 40.06 ppm (CH), 40.34 ppm (CH2), 41.6 ppm (CH2), 42.92(CH2), 45.36 ppm (CH2), 52.54 ppm (CH), 53.13 ppm (CH2), 55.53 ppm (CH3), 55.64 (CH3), 58.83 (CH3), 55.97(CH3), 107.60 (CH2), 107.93 (CH), 113.90 (CH), 114.36 (CH), 123.45 ppm (CH), 127.90 ppm, 134.20 ppm, 135.28 ppm, 146.76 ppm, 147.53 ppm, 149.40 ppm and 150.35(q), 172.17 (C=O)
In one embodiment, the present invention provides amorphous form of ivabradine cyclamate.
In one embodiment, the present invention provides amorphous form of ivabradine cyclamate characterized by X-ray powder diffraction pattern which is substantially in accordance with Figure 4.
In one embodiment, the present invention provides amorphous form of ivabradine cyclamate characterized by a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 6.
In one embodiment, the present invention provides amorphous form of ivabradine cyclamate characterized by a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 9.
In one embodiment, the present invention provides a substantially amorphous ivabradine cyclamate.
A used herein, “substantially amorphous ivabradine cyclamate” has less than about 50% crystalline ivabradine cyclamate. In one embodiment, substantially amorphous ivabradine cyclamate has less than about 30% crystalline ivabradine cyclamate. In one embodiment, substantially amorphous ivabradine cyclamate has less than about 20% crystalline ivabradine cyclamate. Preferably, the substantially amorphous ivabradine cyclamate has less than about 15% crystalline ivabradine cyclamate.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by X-ray powder diffraction pattern which is substantially in accordance with Figure 5.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 2? ± 0.2 at about 9.54 and 28.72.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 7.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 10.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 8.
In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 11.
In one embodiment, the present invention provides a solid dispersion of ivabradine cyclamate comprising amorphous ivabradine cyclamate in combination with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and soluplus.
In one embodiment, the present invention provides a solid dispersion of ivabradine cyclamate comprising substantially amorphous ivabradine cyclamate in combination with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and soluplus.
In one embodiment, the present invention provides crystalline form of ivabradine cyclamate.
In one embodiment, the present invention provides ivabradine cyclamate characterized by X-ray powder diffraction pattern which is substantially in accordance with Figure 3.
In one embodiment, the present invention provides a crystalline form of ivabradine cyclamate characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 2? ± 0.2 at about 4.64, 6.45, 7.13, 14.29 and 21.30. In one embodiment, the crystalline form of ivabradine cyclamate is further characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 2? ± 0.2 at about 20.68, 18.37, 20.38, 24.71 and 15.01.
In one embodiment, the crystalline form of ivabradine cyclamate is characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 2? ± 0.2 at about 4.29, 4.64, 5.67, 6.45, 7.13, 7.49, 9.27, 9.52, 10.56, 11.01, 12.04, 12.85, 13.21, 13.42, 13.77, 14.29, 14.57, 14.77, 15.01, 15.88, 16.42, 17.14, 17.39, 17.74, 17.89, 18.37, 18.75, 18.92, 19.39, 19.51, 19.77, 20.04, 20.38, 20.68, 20.85, 21.09, 21.30, 21.52, 22.29, 22.48, 22.92, 23.28, 23.57, 24.71, 25.06, 25.31, 25.59, 26.04, 26.46, 27.03, 27.78, 28.01, 29.48, 30.15, 30.92, 31.32, 31.91, 32.79, 33.93, 35.48, 36.16, 37.09, 38.61, 42.58, 43.25, 43.81, 47.09.

In one embodiment, the present invention provides ivabradine cyclamate having cyclamic acid content in the range of 25-28 % as measured using Potentiometric Autotitrator.
The present invention provides ivabradine cyclamate as characterized and analyzed by following techniques:
A. X-ray powder diffraction profile was obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator [1] ; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV ; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” 1000 seconds.
B. DSC (Mettler Toledo 822e): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at 30-350°C at the rate of 10°C/min.
D. 1H NMR was recorded using Varian Mercury 300 MHz instrument, using DMSO d6.
E. 13C NMR was recorded using Varian Mercury 300 MHz instrument, using DMSO d6.
F. Content of Cyclamic acid by Potentiometric Autotitrator employing the following process:
About 500 mg of sample was accurately weighed and transferred into a 150 ml glass beaker. 50 ml of glacial acetic acid was added into it and mass was sonicated to dissolve the sample. Titration was done against 0.1N perchloric acid, using suitable electrode with autotitrator to the Potentiometric end point. Blank was performed by omitting the sample. The corrected burette reading was obtained by subtracting blank from sample reading. The content of cyclamic acid was determined using the following formula:

A x 17.924 x Actual Normality of 0.1N Perchloric acid
% Cyclamic = ----------------------------------------------------------------------- x 100
Acid content Weight of sample in mg x 0.1
(as such)

A = Corrected burette reading

The present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine or a salt thereof with cyclamic acid.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating a salt of ivabradine with cyclamic acid.
Salt used may be an inorganic or organic acid salt. Suitable inorganic acid salt of ivabradine may be a salt of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid and the like. Suitable organic acid salt of ivabradine may be a salt of organic acids such as formic acid, oxalic acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, benzoic acid, lactic acid, malic acid, pyruvic acid, ascorbic acid, fumaric acid, succinic acid, gluconic acid, glutaric acid, pamoic acid, camphoric acid, methanesulfonic acid, benzenesulfonic acid and the like.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine hydrochloride with cyclamic acid.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine borate with cyclamic acid.
In one embodiment, treatment of salt of ivabradine with cyclamic acid may be carried out in presence of a base.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising
(a) treating an ivabradine salt with a base to provide ivabradine; and
(b) reacting the ivabradine prepared in (a) with cyclamic acid.
In one embodiment, the salt of ivabradine used in step (a) is ivabradine hydrochloride.
The suitable base used in step (a) includes inorganic and organic bases. Inorganic bases include, but are not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates such as calcium carbonate, magnesium carbonate; alkali metal bicarbonates such as sodium bicarbonate; a source of ammonia such as ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia. Preferably the base selected is aqueous ammonia. Organic bases include, but are not limited to amines such as methylamine, ethylamine, triethylamine, propylamine, isopropylamine, diisopropylamine, tertiary butylamine and the like. An organic base may also include pyridine and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
During treatment of ivabradine salt with base, pH may be between 7.5–10.5, preferably 8–10.
In one embodiment, ivabradine produced in step (a) may be isolated.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising
(a) treating ivabradine hydrochloride with aqueous ammonia to provide ivabradine; and
(b) treating ivabradine produced in (a) with cyclamic acid.
In one embodiment, during treatment of ivabradine salt with base, pH may be between 7.5–10.5, preferably 8–10.
In one embodiment, ivabradine formed in (a) described immediately above is extracted with an organic solvent before treatment with cyclamic acid. The organic solvent used includes, but is not limited to esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is ethyl acetate.
The organic layer containing ivabradine may be washed with water followed by isolation of ivabradine. The process of isolation may be done by process known in the art, preferably by distillation of the organic solvent.
The ivabradine so formed is treated with cyclamic acid, optionally in presence of a solvent to prepare ivabradine cyclamate.
The suitable solvent includes, but is not limited to esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected may be acetonitrile, ethyl acetate or mixture of acetonitrile and ethyl acetate.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine with cyclamic acid in presence of acetonitrile.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine with cyclamic acid in presence of ethyl acetate.
In one embodiment, the present invention provides a process for preparation of ivabradine cyclamate comprising treating ivabradine with cyclamic acid in presence of mixture of acetonitrile and ethyl acetate.

The product is isolated by conventional methods known in the art, preferably, distillation of the organic solvent.
Ivabradine cyclamate so prepared, may be further purified using recrystallization from a solvent. Solvent used includes but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, isopropyl alcohol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent used may be isopropyl alcohol or ethyl acetate.
In one embodiment, the present invention provides purification of ivabradine cyclamate comprising recrystallization from isopropyl alcohol. The process comprises treating ivabradine cyclamate with isopropyl alcohol followed by heating at about 70-85 °C, preferably 75-80 °C. The mass is then cooled to 20-30 °C and isolated by conventional methods known in the art, preferably, by filtration. The wet cake obtained is optionally washed with an organic solvent, preferably ethyl acetate followed by drying to obtain purified ivabradine cyclamate.
In one embodiment, the present invention provides purification of ivabradine cyclamate comprising recrystallization from ethyl acetate. The process comprises treating ivabradine cyclamate with ethyl acetate followed by heating at about 70-85 °C, preferably 75-80 °C. The mass is then cooled to 20-30 °C and isolated by conventional methods known in the art, preferably, by filtration. The wet cake obtained is optionally washed with an organic solvent, preferably ethyl acetate followed by drying to obtain purified ivabradine cyclamate.
Ivabradine cyclamate so obtained may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures from about room temperature to about 100 °C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved.
In one embodiment, the present invention provides ivabradine cyclamate with purity > 99.5%, as determined by HPLC with conditions as described below:
HPLC analysis in the present invention was done by using the following conditions
Column: Inertsil OSD 3V
Column temperature: 35°C
Mobile Phase A: Buffer (100%)
Buffer : 0.1% Perchloric Acid
Mobile Phase B: Methanol (100%)
Time(min.) % Mobile phase A % Mobile phase B
0.01 75 25
40 65 35
55 30 70
65 30 70
68 75 25
75 75 25

Diluent : Water :Acetonitrile: 80:20
Flow Rate: 1.0 ml/min
Detection: 230 nm
Injection Volume: 20µl

In one embodiment, the present invention provides substantially amorphous ivabradine cyclamate characterized by water content of about 0.5-1 % as measured by Karl Fischer method.
Water determination, in the present invention, was done by Karl Fischer methodology using Karl Fischer titrator employing the following process:
The titration vessel was filled with the 15-20 ml of methanol. The start button was pressed. After the display shows ‘drift OK’, parameters were changed to ‘KFT’ mode and started. About 30.0 mg of water was added and the weight was entered and the start button was pressed. Burette reading was noted from the display after completion of the titration. K.F. Factor was calculated using the formula:
K.F. Factor = (weight of water in mg / Burette reading)
The instrument was then changed to ‘KF mode’. The start button was pressed. About 500 mg of the test sample was transferred into the titration vessel and the sample weight was entered. Enter button was pressed. After completion of titration burette reading was noted from the display.
Water content of the test sample was calculated using the following equation:
Burette reading x K.F. Factor
Water Content (%) = -------------------------------------- X 100
Weight of sample in mg
In one embodiment, the present invention provides a composition comprising the novel ivabradine cyclamate salt and a pharmaceutically acceptable carrier.
The composition of the present invention may be used to prepare formulations like tablets or capsules, preferably tablets.
The formulation may be prepared by a method known to a formulator skilled in the art.
The examples that follow 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.
EXAMPLES
EXAMPLE 1: Preparation of 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one
100 g of 7,8-dimethoxy-1,3-dihydro-2H-3-Benzazepin-2-one was charged to dimethyl sulphoxide (700 ml). The reaction mass maintained for about 15 min at about 25-30°C. Potassium hydroxide powder was added to the reaction mass and the reaction mass was stirred for about 60 min at 25-30°C. A mixture of 1- bromo-3- chloropropane ( 86.09 g) and 120 ml of dimethyl sulfoxide cooled to about 10 - 20°C, was added to the stirred reaction mass at about 10-15°C. The reaction mass obtained was stirred for about 180 min at about 20-25°C. After completion of reaction, the reaction mass was quenched into ice water and was stirred for about 5 hrs. The slurry mass was filtered and the wet cake so obtained was washed with water and dried in tray dryer for about 50-55 °C. Yield: 89%, HPLC purity > 95%.
EXAMPLE 2: Purification of 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one
Acetone and water were added to 10 g of 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one and reaction mass was heated to about 50-55 °C for about 30 min. Heating was stopped and the reaction mass was cooled gradually to about 20-25 °C. The reaction mass was maintained at about 20 - 25°C for about 180 min. The reaction mass was filtered and the wet cake obtained was washed with water. The wet cake obtained was suck dried and further dried in vacuum tray dryer at about 50-55°C for about 12 hrs. Yield: 75 %, HPLC Purity > 98.5%
EXAMPLE 3: Purification of 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one
Methanol was added to 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one and reaction mass was heated to about 60-65°C for about 30 min. Heating was stopped and the reaction mass was cooled gradually to about 20-25°C. The reaction mass was maintained at about 20 - 25°C for about 240 min. The reaction mass was filtered and the wet cake obtained was washed with water. The wet cake obtained was suck dried and further dried in vacuum tray dryer at about 50-55°C for about 12 hrs. Yield: 70 %, HPLC Purity > 98.5%

EXAMPLE 4: Preparation of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one
100 g of 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one was added to methyl ethyl ketone (800 ml) and stirred for 10 min to get a clear solution. 101.45 g of sodium iodide was added and the reaction mass was stirred at a temperature of about 25-30°C. The reaction mass was heated to reflux at a temperature of about 70-75°C for about 8 hrs. After completion of the reaction, methyl ethyl ketone was distilled off below 50°C under reduced pressure till no more methyl ethyl ketone distills out. To the reaction mass obtained, acetone and water were added and the reaction mass was stirred. Then acetone and water were distilled off below 50°C under reduced pressure. Acetone and water were added and the reaction mass was heated to about 55-60°C. The reaction mass was maintained under stirring for 60 min at 55-60°C and cooled to 25-30°C. The reaction mass obtained was stirred and filtered. The product obtained was suck dried to obtain a wet cake. The wet cake was washed with water, suck dried and the wet cake obtained was dried at about 55-60°C. Yield 85.0%, HPLC purity > 96%
EXAMPLE 5: Purification of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one
Acetone and water were added to of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one prepared and reaction mass was heated to about 50-55 °C for about 30 min. Heating was stopped and the reaction mass was gradually cooled to about 20-25°C. Reaction mass was maintained at about 20-25 °C for about 3 hrs. Reaction mass was filtered and the wet cake obtained was washed with water. The wet cake obtained was suck dried and dried in vacuum tray dryer 50-55°C for 12 hrs. Yield: 80 %, HPLC Purity > 98.0%
EXAMPLE 6: Purification of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one
Acetonitrile was added to 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one prepared and reaction mass was heated to about 75-80°C for 30 min. Heating was stopped and the reaction mass was gradually cooled to about 20-25°C. Reaction mass was maintained at about 20 -25°C for about 3 hrs. Reaction mass was filtered and the wet cake obtained was washed with acetonitrile. The wet cake obtained was suck dried and dried in vacuum tray dryer 50-55°C for 12 hrs. Yield: 75 %, HPLC Purity > 98.0%
EXAMPLE 7: Preparation of 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3-dihydro-7,8-dimethoxy-2H-3-Benzazepin-2-one
50.36 g of (7S)-3,4-dimethoxy-N-methylm-Bicyclo[4.2.0]octa-1,3,5-triene-7-methanamine hydrochloride was added to 400 ml of dimethyl formamide. The reaction mass was stirred and potassium carbonate powder (178.46 g) was added. The reaction was stirred for about 60 min at about 25-30°C and cooled to about 5-10°C. 100 g of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one was added and the reaction mass was maintained at about 5-10°C. The temperature of the reaction mass was raised to about20-25°C and maintained at same temperature for about 4 hrs. The reaction mass was quenched into water at 5-10°C and pH of the reaction mass was adjusted to about 1 to 2 with conc HCl solution. The reaction mass was extracted by ethyl acetate and organic and aqueous layers were separated. The aqueous layer was basified and pH was adjusted to about 8.0 - 9.5 with 20-25% aqueous ammonia solution. The reaction mass was extracted using ethyl acetate, the organic layer was separated and washed with water. The organic layer was separated and ethyl acetate was distilled off below 50-55°C under reduced pressure to obtain a semi oily mass. Yield 75.0%, HPLC purity > 96%.
EXAMPLE 8: Purification of 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3-dihydro-7,8-dimethoxy-2H-3-Benzazepin-2-one
Ethyl acetate and water were added to 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3-dihydro-7,8-dimethoxy-2H-3-Benzazepin-2-one and pH of the reaction mass was adjusted to about 1 - 2 of the reaction mass with conc HCl solution. The reaction mass was extracted using ethyl acetate and the organic and aqueous layer were separated. The aqueous layer was basified and pH was adjusted to about 8 to 9 with 20-25% with aqueous ammonia solution. The reaction mass was extracted with ethyl acetate. Layers were separated and the organic layer was washed with water. Layers were separated. Organic layer was taken and ethyl acetate was distilled off below a temperature of about 50-55°C under reduced pressure. Product obtained was semi oily mass. Yield 80%, HPLC purity > 96%.
EXAMPLE 9: Preparation of 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-Benzazepin-2-one hydrochloride (Ivabradine hydrochloride)
A mixture of 100 g of 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3-dihydro-7,8-dimethoxy-2H-3-Benzazepin-2-one and 500 ml of ethyl acetate was stirred for about 5 min and activated charcoal (10 g) was added and reaction mass was stirred for about 30 min. The reaction mass was filtered over hyflo and the hyflo bed was washed with ethyl acetate. Ethyl acetate was added to the reaction mass. To the reaction mass, 10% palladium charcoal (17 g) was added and the reaction mixture was charged in an autoclave and heated at about 65-70°C. The reaction mass was hydrogenated in the autoclave under hydrogen pressure of about 8kg/cm3 to about 10kg/cm3 at a temperature of about 65-70°C. The reaction mass was maintained at temp 65-70°C for next 6.0 hrs by maintaining hydrogen pressure at 8.0 -10 kg/cm3. After completion of reaction, the heating was stopped and the reaction mass was cooled to about 20-25°C. Hydrogen gas pressure was released by flushing with nitrogen gas. The reaction mass was unloaded and filtered through the hyflo. The hyflo bed was washed with ethyl acetate. Ethyl acetate was distilled off from the reaction mass below 50°C under reduced pressure to obtain a residue. To the residue 400 ml of acetonitrile and 30 ml of isopropyl alcohol hydrogen chloride (IPA-HCl) was added at 5-10°C. The reaction mass was stirred at a temperature of about 10-15°C for next 180 min. Acetonitrile was distilled off from the reaction mass below 50°C under reduced pressure to obtain crude product. Acetonitrile was added to the crude product and the reaction mass was heated at a temperature of about 80-85°C. The reaction mass was maintained at about 80-85°C for next one hour. The reaction mass was gradually cooled and filtered to obtain a wet cake. The wet cake was washed with acetonitrile and suck dried followed by drying in vacuum tray dryer at about 50-55°C. Yield 70% - 80 %, HPLC purity > 99%.
EXAMPLE 10 Purification of 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-Benzazepin-2-one hydrochloride (Ivabradine hydrochloride)
Acetonitrile was added to ivabradine hydrochloride and the reaction mass was heated and stirred at a temperature of about 80-85°C. The reaction mass became a clear solution and the reaction mass was maintained at a temperature of about 80-85°C for about 30 min. Heating and stirring was stopped and the reaction mass was gradually cooled to about 25-30°C and the reaction mass was maintained at about 25-30°C for about 3 hrs. The reaction mass was stirred and filtered. The wet cake obtained was washed with acetonitrile and dried under vaccum at a temperature of about 45-50°C. Yield 70% - 80 %, HPLC purity > 99.5%.
EXAMPLE 11: Preparation of ivabradine cyclamate
96 ml water was added to ivabradine hydrochloride (9.60 g) and the reaction mass was cooled. pH of the reaction mass was adjusted to about 8.0 to 9.5 with 20-25% aqueous ammonia solution (about 4 ml). Reaction mass was extracted with ethyl acetate. Organic and aqueous layers were separated. Organic layer was washed with water. Layers were separated. Ethyl acetate was distilled off from the organic layer below 50-55°C under reduced pressure. Semi oily mass compound obtained.
To the oily mass obtained (8.45 g), acetonitrile (45 ml) was added and the reaction mass was stirred at about 20-30°C. To the reaction mass 3.23 g of cyclamic acid was added and the reaction mass was stirred at about 20-30°C for about 1 hr. Acetonitrile was distilled off below 45-50°C under reduced pressure. The reaction mass was degassed under reduced pressure for about 22 hrs at 45-50°C. Yield 80- 90%, HPLC purity >99.5%). Acetonitrile content NMT 100 ppm.
MASS: [M+H]+: 469.30
1H NMR: (DMSO 300 MHZ) 1.01-1.18 ppm (5H,m), 1.45-1.58 ppm (3H, m), 1.89 ppm (4H,m), 2.74 ppm (3H,S), 2.80- 2.97 ppm (6H,m), 3.18- 3.38 ppm (8H,m), 3.66-3.76 ppm (12H,S), 3.92(4H t), 6.65 ppm(1H,S), 6.69 ppm (1H ,S), 6.77 ppm(1H,S), 6.82 ppm (1H, S).
13CNMR (DMSO 300 MHZ) : peaks at 22.96 ppm (CH2), 24.71 ppm (CH2), 25.48 ppm (CH2), 33.16 ppm (CH2), 35.13(CH2), 38.67 ppm (CH2), 39.95 ppm (CH2). 39.2 ppm (CH), 40.06 ppm (CH), 40.34 ppm (CH2), 41.6 ppm (CH2), 42.92 ppm (CH2), 45.36 ppm (CH2), 52.54 ppm (CH), 53.13 ppm (CH2), 55.53 ppm (CH3), 55.64 (CH3), 58.83 (CH3), 55.97(CH3), 107.60 (CH2), 107.93 (CH), 113.90 (CH), 114.36 (CH), 123.45 ppm (CH), 127.90 ppm, 134.20 ppm, 135.28 ppm, 146.76 ppm, 147.53 ppm,149.40 ppm and 150.35(q), 172.17 (C=O)
EXAMPLE 12: Preparation of ivabradine cyclamate
Water (140 ml) was added to 14 g of ivabradine HCl and the reaction mass was cooled and pH was adjusted to about 8.0 to 9.5 with about 20-25% aqueous ammonia solution (about10 ml). The reaction mass was extracted using ethyl acetate and the organic and aqueous layers were separated. The organic layer was washed with water and the layers were separated. Ethyl acetate was distilled off from organic layer below a temperature of about 50-55°C under reduced pressure. Semi oily mass was obtained.
To the oily mass obtained (12 g) acetonitrile (60 ml) was added and reaction mass was stirred at about 20-30°C. To the reaction mass cyclamic acid (4.59 g) was added and the reaction mass was stirred at about 20-30°C for about 1 hr. Acetonitrile was distilled off from the reaction mass below a temperature of about 45-50°C under reduced pressure. The reaction mass was degassed under reduced pressure for 14 hrs at a temperature of about 45-50°C.
Water content : 0.74 %, Yield 80- 90% , HPLC purity >99.5%, Residual solvent Acetonitrile NMT 100 ppm. (XRD as per Figure 5, DSC as per Figure 7, TGA as per figure 10)
EXAMPLE 13: Preparation of ivabradine cyclamate
Water (140 ml) was added to 14 g of ivabradine HCl and the reaction mass was cooled and pH was adjusted to about 8.0 to 9.5 with about 20-25% aqueous ammonia solution (about10 ml). The reaction mass was extracted using ethyl acetate and the organic and aqueous layers were separated. The organic layer was washed with water and the layers were separated. Ethyl acetate was distilled off from organic layer below a temperature of about 50-55°C under reduced pressure. Semi oily mass was obtained.
To the oily mass obtained (12 g) acetonitrile (60 ml) was added and reaction mass was stirred at about 20-30°C. To the reaction mass cyclamic acid (4.59 g) was added and the reaction mass was stirred at about 20-30°C for about 1 hr. Acetonitrile was distilled off from the reaction mass below a temperature of about 45-50°C under reduced pressure. The reaction mass was degassed under reduced pressure for 12 hr at a temperature of about 45-50°C.
Water content: 0.96%, Yield 80- 90% , HPLC purity >99.5%, Residual solvent Acetonitrile NMT 100 ppm (DSC as per Figure 8, TGA as per figure 11 )
EXAMPLE 14: Preparation of ivabradine cyclamate
To 5.0 g of ivabradine hydrochloride water (50 ml) was added and the reaction mass was basified with 20-25% with aqueous ammonia solution (1.5 ml) to adjust the pH to about 9 to 10. The reaction mass was extracted with ethyl acetate. Layers were separated. The organic layer was washed with water. Layers were separated. Ethyl acetate was distilled off from the organic layer below 50-55°C under reduced pressure. To the semi oily mass obtained, ethyl acetate (25 ml) and cyclamic acid (1.77 g) were added. The reaction mass stirred and heated to about 50-55°C and maintained at the same temperature for about 60 min. Acetonitrile was added and the reaction mass was stirred for about 60 min at about 50-55°C. The reaction mass was cooled to about 20-30°C and maintained at same temperature for about 1 hr. The reaction mass was filtered and the wet cake obtained was washed with acetonitrile. The wet cake obtained was suck dried and dried in Vacuum Tray Dryer at about 50-55°C for about 12 hrs. (Yield 60-70.0 %, HPLC purity > 99.5%).
EXAMPLE 15: Preparation of ivabradine cyclamate
To 28 g of ivabradine hydrochloride water (280 ml) was added and the reaction mass was basified with 20-25% with aqueous ammonia solution (12 ml) to adjust the pH to about 8 to 9. The reaction mass was extracted with ethyl acetate. Layers were separated. The organic layer was washed with water. Layers were separated. Ethyl acetate was distilled off from the organic layer below 50-55°C under reduced pressure. To the semi oily mass obtained, ethyl acetate (150 ml) and cyclamic acid (10.51 g) were added. The reaction mass stirred and heated to about 70-75°C and maintained at the same temperature for about 60 min. The reaction mass was cooled to about 20-30°C and maintained at same temperature for about 12 hr. The reaction mass was filtered and the wet cake obtained was washed with ethyl acetate. The wet cake obtained was suck dried and dried in Vacuum Tray Dryer at about 50-55°C for about 12 hrs. (Yield 80-90 %, HPLC purity > 99.5%)
EXAMPLE 16: Purification of ivabradine cyclamate
Isopropyl alcohol was added to ivabradine cyclamate and the reaction mass was heated to about 75-80°C for about 30 min. The reaction mass was cooled to about 20-30°C and maintained at the same temperature for about 12 hrs. Reaction mass was filtered and the wet cake obtained was washed with ethyl acetate. Wet cake obtained was suck dried followed by drying in in Vacuum Tray Dryer at about 50-55°C for about 12 hrs. Yield 75-85 %, HPLC purity >99.5%
EXAMPLE 17: Purification of ivabradine cyclamate
Ethyl acetate was added to ivabradine cyclamate and the reaction mass was heated to about 75-80°C for about 30 min. The reaction mass was cooled to about 20-30°C and maintained at the same temperature for about 12 hrs. Reaction mass was filtered and the wet cake obtained was washed with ethyl acetate. Wet cake obtained was suck dried followed by drying in Vacuum Tray Dryer at about 50-55°C for about 12 hrs. Yield 75-85 %, HPLC purity >99.5%
EXAMPLE 18: Various ivabradine salts worked upon

Name of Acid Structure of acid Remark
2,5-Dihydroxybenzoic acid or
No solid obtained
Gentisic acid No solid obtained
2-Oxobutyric acid
No solid obtained
Lauric acid
No solid obtained
Oleic acid
No solid obtained

We claim
1. Ivabradine cyclamate salt.
2. The ivabradine cyclamate salt as claimed in claim 1 characterized by 1H nuclear magnetic resonance spectrum peaks at 1.01-1.18 ppm, 1.45-1.58 ppm, 1.89 ppm, 2.74 ppm, 2.80- 2.97 ppm, 3.18-3.38 ppm, 3.66-3.76 ppm, 3.92, 6.65 ppm, 6.69 ppm, 6.77 ppm, 6.82 ppm.
3. The ivabradine cyclamate salt as claimed in claim 1 which is characterized by 13C nuclear magnetic resonance spectrum peaks at 22.96 ppm, 24.71 ppm, 25.48 ppm, 33.16 ppm, 35.13, 38.67 ppm, 39.95 ppm, 39.2 ppm, 40.06 ppm, 40.34 ppm, 41.6 ppm, 42.92, 45.36 ppm, 52.54 ppm, 53.13 ppm, 55.53 ppm, 55.64, 58.83, 55.97, 107.60, 107.93, 113.90, 114.36, 123.45 ppm, 127.90 ppm, 134.20 ppm, 135.28 ppm, 146.76 ppm , 147.53 pm,149.40 ppm and 150.35, 172.17.
4. Ivabradine cyclamate having cyclamic acid content in the range of 25-28 % as measured using Autotitrator Potentiometric method.
5. A process for preparation of ivabradine cyclamate comprising treating ivabradine or a salt thereof with cyclamic acid.
6. A process for preparation of ivabradine cyclamate as claimed in claim 5 wherein the salt of ivabradine used is ivabradine hydrochloride.

Dated this (11th) day of August, 2015

(Signed)____________________
Dr. Madhavi Karnik
General Manager-IPM
Glenmark Pharmaceuticals Limited
,CLAIMS:1. Ivabradine cyclamate salt.
2. The ivabradine cyclamate salt as claimed in claim 1 characterized by 1H nuclear magnetic resonance spectrum peaks at 1.01-1.18 ppm, 1.45-1.58 ppm, 1.89 ppm, 2.74 ppm, 2.80- 2.97 ppm, 3.18-3.38 ppm, 3.66-3.76 ppm, 3.92, 6.65 ppm, 6.69 ppm, 6.77 ppm, 6.82 ppm.
3. The ivabradine cyclamate salt as claimed in claim 1 which is characterized by 13C nuclear magnetic resonance spectrum peaks at 22.96 ppm, 24.71 ppm, 25.48 ppm, 33.16 ppm, 35.13, 38.67 ppm, 39.95 ppm, 39.2 ppm, 40.06 ppm, 40.34 ppm, 41.6 ppm, 42.92, 45.36 ppm, 52.54 ppm, 53.13 ppm, 55.53 ppm, 55.64, 58.83, 55.97, 107.60, 107.93, 113.90, 114.36, 123.45 ppm, 127.90 ppm, 134.20 ppm, 135.28 ppm, 146.76 ppm , 147.53 pm,149.40 ppm and 150.35, 172.17.
4. Ivabradine cyclamate having cyclamic acid content in the range of 25-28 % as measured using Autotitrator Potentiometric method.
5. A process for preparation of ivabradine cyclamate comprising treating ivabradine or a salt thereof with cyclamic acid.
6. A process for preparation of ivabradine cyclamate as claimed in claim 5 wherein the salt of ivabradine used is ivabradine hydrochloride.