WO2017021466A1 - A process for preparation of solid ivabradine hydrochloride - Google Patents
A process for preparation of solid ivabradine hydrochloride Download PDFInfo
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- WO2017021466A1 WO2017021466A1 PCT/EP2016/068577 EP2016068577W WO2017021466A1 WO 2017021466 A1 WO2017021466 A1 WO 2017021466A1 EP 2016068577 W EP2016068577 W EP 2016068577W WO 2017021466 A1 WO2017021466 A1 WO 2017021466A1
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- Prior art keywords
- ivabradine
- process according
- compound
- acid
- water
- Prior art date
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- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 title claims abstract description 96
- 238000000034 method Methods 0.000 title claims abstract description 35
- 229960000504 ivabradine hydrochloride Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000007787 solid Substances 0.000 title abstract description 10
- 229960003825 ivabradine Drugs 0.000 claims abstract description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 49
- 229940125782 compound 2 Drugs 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 238000000605 extraction Methods 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 20
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 17
- 229940011051 isopropyl acetate Drugs 0.000 claims description 17
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 239000001569 carbon dioxide Substances 0.000 claims description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000010410 layer Substances 0.000 description 35
- 229940126214 compound 3 Drugs 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 0 CN(CCC*(CCc(cc1OC)c(C2)cc1OC)C2=O)C[C@@]1c2cc(OC)c(*)cc2C1 Chemical compound CN(CCC*(CCc(cc1OC)c(C2)cc1OC)C2=O)C[C@@]1c2cc(OC)c(*)cc2C1 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Definitions
- the present invention relates to a process for preparation of a solid form of ivabradine hydrochloride preferably in the polymorphic form delta or delta-d.
- the molecule of the formula (I) has one chiral carbon atom in position 7.
- Ivabradine is the single (S) enantiomer.
- ivabradine is present as a hydrochloride salt form.
- Ivabradine hydrochloride was first disclosed in EP 534859. Crystalline ivabradine hydrochloride was obtained therein by treatment of ivabradine base with 0.1 N HC1 and recrystallization of the residual mass after evaporation of the mixture from acetonitrile in 55% yield.
- Alfa-crystalline form is disclosed in US 7176197 and is obtainable by a crystallization of ivabradine hydrochloride from a toluene/ l-methyl-2-pyrrolidone mixture.
- Beta-crystalline form is disclosed in US 2006/0194962 and is obtainable by
- Gamma-crystalline form is disclosed in US 2006/0194963 and is obtainable by a crystallization of ivabradine hydrochloride from 2-ethoxyethanol, a mixture of 2- ethoxyethanol and water or a mixture of ethanol and water. This form is a hydrate and, if heated, it may be converted to the anhydrous gamma-d crystalline form as shown in US 2006/0194964.
- EP 1775288 discloses the delta-form of crystalline ivabradine hydrochloride.
- the product is prepared by a crystallization of the product of EP 534859 from acetonitrile and isolation of the crystalline product from the reaction mixture after 2 days standing by filtration and drying at ambient temperature.
- the crystalline form delta is a hydrate comprising about 2.8% of water.
- EP 1775287 discloses the dehydrated delta form (delta-d form) of crystalline ivabradine hydrochloride.
- the product is prepared by crystallization of the product of EP 534859 from acetonitrile and isolation of the crystalline product from the reaction mixture after 2 days standing by filtration and heating of the solid product at 85°C for 4 hours.
- the crystalline form delta-d is an anhydrous product.
- Ivabradine can be prepared for example by the process as described in EP 534859. The process is depicted in the following scheme:
- the Compound 3 (i.e. (S)-l-(3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl)-N- methylmethanamine) that is not consumed by reaction with 3-(3-halogenopropyl)-7,8- dimethoxy-lH-benzo[d]azepin-2(3H)-one remains in the reaction mixture and if not removed it will subsequently negatively affect the purity of the final ivabradine hydrochloride.
- the removal of the Compound 3 from Compound 2 is not trivial.
- EP 534859 discloses the use of chromatography for ivabradine purification. It is not desirable to use chromatography in production.
- EP 2495237 discloses a purification procedure comprising derivatization of ivabradine and subsequent transformation of the derivative into ivabradine. The drawback of the procedure is the need for the use of additional chemical steps after ivabradine has been prepared.
- the objective of the present invention is to provide an improved process yielding pure crystalline ivabradine hydrochloride, advantageously in delta or delta-d form, without employing toxic crystallization solvents.
- the present invention relates to a process for the preparation of a solid form of ivabradine hydrochloride by reduction of Compound 2 or a salt thereof
- aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
- the process can be followed by crystallization of ivabradine hydrochloride from the water immiscible solvent by adding an ethanolic solution of hydrochloric acid, preferably at room temperature, and optionally isolating solid ivabradine hydrochloride.
- the present invention relates to a process for the preparation of a solid
- aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
- the aqueous solvent used in the reduction is either water or a mixture of water and a water miscible solvent. Preferably, water is used.
- the reduction is performed with a reduction catalyst.
- the reduction catalyst can be for example Pd/C or Pd(OH) 2 /C, preferably
- the concentration of Compound 2 in the aqueous solvent is between 6% (w/w) and 13% (w/w), preferably between 9% (w/w) and 11% (w/w).
- the salt form of Compound 2 is preferably the hydrochloride salt.
- the reduction is performed at a temperature between 30°C and 70°C, preferably between 45 and 55°C. Reduction is preferably done using gaseous hydrogen. The reduction is finished after the most of Compound 2 is transformed into ivabradine. It typically runs for 3-10 hours, preferably for 4-6 hours. After the reduction is finished, the reaction mixture is cooled to 20-35°C and the hydrogenation catalyst is filtrated off.
- ivabradine is also obtained in the form of the salt.
- the obtained salt of ivabradine is treated with a base, preferably a water solution of a base, to obtain a mixture of the free form of ivabradine and the aqueous solvent.
- the mixture is extracted with a water immiscible solvent.
- a base preferably a water solution of a base
- ethyl acetate, isopropyl acetate, toluene or mixtures thereof are used.
- the concentration of ivabradine in the water immiscible solvent is between 0.5 mmol/ml and 5 mmol/ml, preferably 1 mmol/ml and 3 mmol/ml, most preferably 1 mmol/ml.
- the layers are separated and the water layer is disposed.
- the water immiscible layer is washed with an acidic aqueous solution.
- the amount of the acidic aqueous solution is sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2.
- the acid used in the process can be both organic and inorganic acid capable of forming a salt with Compound 3.
- the examples of the acids are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, a solution of carbon dioxide in water (i.e.
- carbonic acid preferably hydrochloric acid or a solution of carbon dioxide in water are used.
- the molar ratio between ivabradine and the acid is between 1:0.001 and 1:0.2 depending on the type of the acid and the reaction scale.
- strong acids for example hydrochloric acid
- the ratio can be between 1:0.001 and 1:0.1, preferably between 1:0.001 and 1:0.06.
- weak acids for example a solution of carbon dioxide in water, i.e. carbonic acid, preferably saturated solution of carbon dioxide in water
- the ratio can be between 1:0.1 and 1:0.2.
- ivabradine remains in the water immiscible solvent layer after the layers are separated.
- the extraction step with a water immiscible solvent solution of ivabradine with the acidic aqueous solution can be optionally repeated.
- the water immiscible solvent layers are mixed and concentrated, using for example distillation, to the final concentration of ivabradine in the solution between 8% (w/w) and 15% (w/w), preferably between 9% (w/w) and 11% (w/w).
- Ivabradine can be optionally isolated from the water immiscible solvent (for example by precipitation or crystallization from the solvent or by distilling off of the solvent) or an ethanolic solution of hydrochloric acid can be added to the solution of ivabradine in the water immiscible solvent and ivabradine hydrochloride is crystallized from the solution.
- the ethanolic solution of hydrochloric acid is added at a temperature between 15°C and 30°C, preferably between 19°C and 21°C.
- the concentration of the ethanolic solution of hydrochloric acid is between 20% (w/w) and 30% (w/w), preferably between 26% (w/w) and 28% (w/w).
- the molar ratio between ivabradine and hydrochloric acid is between 1: 1 and 1:2, preferably between 1: 1 and 1: 1.2.
- the mixture is stirred for 1 to 10 hours, preferably for 2 to 4 hours.
- the mixture can be cooled before ivabradine hydrochloride is isolated.
- the mixture can be cooled at a temperature between -20 and 20°C.
- the crystallized product is isolated from the mixture by using any conventional technique, e.g. filtering, centrifugation or distillation off the solvent.
- Compound 2 or a salt thereof used as starting material in the process of the present invention can be prepared for example by the process as described in EP 534859, but the invention is not limited to such material.
- the solid forms of ivabradine hydrochloride produced by the process of the present invention have an excellent batch-to-batch uniformity in the size and shape of the formed crystals and preferably comprises less than 10% of other crystalline forms of ivabradine hydrochloride.
- the solid forms of ivabradine hydrochloride obtainable by the described processes may be formulated into pharmaceutical compositions, for instance to tablet compositions for oral administration, and may be used in medicine, for instance in a treatment of angina pectoris.
- Compound 3 Compound 2. HCI 6.46 kg of 10% (w/w) solution of Compound 2.HC1 (containing 1.9% (HPLC IN) of
- Isopropyl acetate solution (containing ivabradine containing 1.9% (HPLC IN) of Compound 3) was extracted with 0.6 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine: HC1 1:0.008). Phases were separated.
- Compound 3 was extracted with 0.41 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine :HC1 1:0.006). Phases were separated.
- the isopropyl acetate layer (containing ivabradine containing 0.66% (HPLC IN) of Compound 3) was extracted with 0.21 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine :HC1 1:0.003). Phases were separated.
- ivabradine in isopropyl acetate 0.8 kg of ethanol, 0.16 kg of 27% (w/w) solution of HC1 in ethanol (molar ratio ivabradine :HC1 1: 1.1) and 0.5 kg of isopropyl acetate were added at 20°C. The mixture was stirred at this temperature for 3 hours. Solid ivabradine hydrochloride was filtered off.
- Example 3 2 g of ivabradine hydrochloride prepared according to Example 1 were dried at 30°C for 4 hours to provide ivabradine hydrochloride form delta in 98% yield.
- Example 3 2 g of ivabradine hydrochloride prepared according to Example 1 were dried at 30°C for 4 hours to provide ivabradine hydrochloride form delta in 98% yield.
- ivabradine hydrochloride prepared according to Example 1 were dried at 50°C for 4 hours to provide ivabradine hydrochloride form delta-d in 98% yield.
- ivabradine content of Compound 3 was 0.06% (HPLC IN)) in yield 80%.
- Compound 3 Compound 2 5 g of Compound 2 (the content of Compound 3 was 0.95 % (HPLC IN)) in 2.5 ml of toluene were treated with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to Compound 2) to provide two-layers system. The layers were separated. The water layer was washed with 0.5 ml of toluene. The toluene layers were mixed and washed with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to Compound 2). The layers were separated and the organic layer was distilled off to provide Compound 2 (the content of Compound 3 was 0.03% (HPLC IN)) in yield 80%.
- Scan step time between 0.2-2.0 seconds
- Antiscatter slit 11.8 mm
Abstract
The present invention relates to a process for the preparation of a solid form of ivabradine hydrochloride by reduction of Compound 2 or a salt thereof in an aqueous solvent followed by extraction of ivabradine wherein the extraction comprises the steps of: 1) adding a water immiscible solvent 2) separating the layers 3) washing the water immiscible solvent layer with an amount of an acidic aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
Description
P1687PC00
A PROCESS FOR PREPARATION OF SOLID IVABRADINE HYDROCHLORIDE
The present invention relates to a process for preparation of a solid form of ivabradine hydrochloride preferably in the polymorphic form delta or delta-d.
BACKGROUND OF THE INVENTION
Ivabradine, chemically 3-[3-({ [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7- yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-2-one of formula (I)
The molecule of the formula (I) has one chiral carbon atom in position 7. Ivabradine is the single (S) enantiomer.
In the marketed products, which are film-coated tablets for oral administration and are sold, e.g., under trade name Procoralan® by Servier, ivabradine is present as a hydrochloride salt form.
Ivabradine hydrochloride was first disclosed in EP 534859. Crystalline ivabradine hydrochloride was obtained therein by treatment of ivabradine base with 0.1 N HC1 and
recrystallization of the residual mass after evaporation of the mixture from acetonitrile in 55% yield.
Various crystalline forms (polymorphs) of ivabradine hydrochloride, which are characterized by a certain distinct pattern of signals in the XRPD spectrum, are known in the art.
Alfa-crystalline form is disclosed in US 7176197 and is obtainable by a crystallization of ivabradine hydrochloride from a toluene/ l-methyl-2-pyrrolidone mixture.
Beta-crystalline form is disclosed in US 2006/0194962 and is obtainable by
crystallization of ivabradine hydrochloride from water or an isopropanol- water mixture. This form is a hydrate and, if heated, it may be converted to the anhydrous beta-d crystalline form as shown in US 2006/0194965.
Gamma-crystalline form is disclosed in US 2006/0194963 and is obtainable by a crystallization of ivabradine hydrochloride from 2-ethoxyethanol, a mixture of 2- ethoxyethanol and water or a mixture of ethanol and water. This form is a hydrate and, if heated, it may be converted to the anhydrous gamma-d crystalline form as shown in US 2006/0194964.
EP 1775288 (US 2007/0082885) discloses the delta-form of crystalline ivabradine hydrochloride. The product is prepared by a crystallization of the product of EP 534859 from acetonitrile and isolation of the crystalline product from the reaction mixture after 2 days standing by filtration and drying at ambient temperature. The crystalline form delta is a hydrate comprising about 2.8% of water.
EP 1775287 (US 2007/0082886) discloses the dehydrated delta form (delta-d form) of crystalline ivabradine hydrochloride. The product is prepared by crystallization of the product of EP 534859 from acetonitrile and isolation of the crystalline product from the reaction
mixture after 2 days standing by filtration and heating of the solid product at 85°C for 4 hours. The crystalline form delta-d is an anhydrous product.
Ivabradine can be prepared for example by the process as described in EP 534859. The process is depicted in the following scheme:
Hal: halogen Compound 3 Compound 2
The Compound 3 (i.e. (S)-l-(3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl)-N- methylmethanamine) that is not consumed by reaction with 3-(3-halogenopropyl)-7,8- dimethoxy-lH-benzo[d]azepin-2(3H)-one remains in the reaction mixture and if not removed it will subsequently negatively affect the purity of the final ivabradine hydrochloride. The removal of the Compound 3 from Compound 2 is not trivial.
In the prior art several purification processes are disclosed. EP 534859 discloses the use of chromatography for ivabradine purification. It is not desirable to use chromatography in production. EP 2495237 discloses a purification procedure comprising derivatization of ivabradine and subsequent transformation of the derivative into ivabradine. The drawback of the procedure is the need for the use of additional chemical steps after ivabradine has been prepared.
Thus, the objective of the present invention is to provide an improved process yielding pure crystalline ivabradine hydrochloride, advantageously in delta or delta-d form, without employing toxic crystallization solvents.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a process for the preparation of a solid form of ivabradine hydrochloride by reduction of Compound 2 or a salt thereof
Compound 2
in an aqueous solvent followed by extraction of ivabradine wherein the extraction comprises the steps of:
1) adding a water immiscible solvent
2) separating the layers
3) washing the water immiscible solvent layer with an amount of an acidic
aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
The process can be followed by crystallization of ivabradine hydrochloride from the water immiscible solvent by adding an ethanolic solution of hydrochloric acid, preferably at room temperature, and optionally isolating solid ivabradine hydrochloride.
The process can optionally be followed by the step of drying under vacuum the obtained ivabradine hydrochloride at a temperature between 40°C and 80°C, preferably at a temperature between 45°C and 55°C to obtain ivabradine hydrochloride form delta-d characterized by XRPD pattern comprising, inter alia, peaks at 8.5°, 14.5°, 15.2°, 17.1°, 18.1°, 20.9°, 21.4°, 22.1°, 23.9°, 26.3° theta (+ 0.2) when measured with CuKal radiation ( = 1.54060).
The process can also optionally be followed by the step of drying under vacuum the obtained ivabradine hydrochloride at a temperature below 40°C, preferably below 30°C, to
obtain ivabradine hydrochloride form delta characterized by XRPD pattern comprising, inter alia, peaks at 4.1°, 11.0°, 14.7°, 15.3°, 16.9°, 17.8°, 18.0°, 21.6°, 21.9°, 22.1°, 25.8° theta (+ 0.2) when measured with CuKal radiation k= 1.54060).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of a solid
ivabradine hydrochloride by reduction of Compound 2 or a salt thereof
Compound 2
in an aqueous solvent followed by extraction of ivabradine wherein the extraction comprises the steps of:
1) adding a water immiscible solvent
2) separating the layers
3) washing the water immiscible solvent layer with an amount of an acidic
aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
The aqueous solvent used in the reduction is either water or a mixture of water and a water miscible solvent. Preferably, water is used. The reduction is performed with a reduction catalyst. The reduction catalyst can be for example Pd/C or Pd(OH)2/C, preferably
Pd(OH)2/C. The concentration of Compound 2 in the aqueous solvent is between 6% (w/w) and 13% (w/w), preferably between 9% (w/w) and 11% (w/w). The salt form of Compound 2 is preferably the hydrochloride salt. The reduction is performed at a temperature between 30°C and 70°C, preferably between 45 and 55°C. Reduction is preferably done using gaseous
hydrogen. The reduction is finished after the most of Compound 2 is transformed into ivabradine. It typically runs for 3-10 hours, preferably for 4-6 hours. After the reduction is finished, the reaction mixture is cooled to 20-35°C and the hydrogenation catalyst is filtrated off. In case Compound 2 was reduced in the form of a salt, ivabradine is also obtained in the form of the salt. The obtained salt of ivabradine is treated with a base, preferably a water solution of a base, to obtain a mixture of the free form of ivabradine and the aqueous solvent. The mixture is extracted with a water immiscible solvent. Preferably ethyl acetate, isopropyl acetate, toluene or mixtures thereof are used. The concentration of ivabradine in the water immiscible solvent is between 0.5 mmol/ml and 5 mmol/ml, preferably 1 mmol/ml and 3 mmol/ml, most preferably 1 mmol/ml. The layers are separated and the water layer is disposed. The water immiscible layer is washed with an acidic aqueous solution. The amount of the acidic aqueous solution is sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2. The acid used in the process can be both organic and inorganic acid capable of forming a salt with Compound 3. The examples of the acids are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, a solution of carbon dioxide in water (i.e.
carbonic acid), preferably hydrochloric acid or a solution of carbon dioxide in water are used.
The molar ratio between ivabradine and the acid is between 1:0.001 and 1:0.2 depending on the type of the acid and the reaction scale. For strong acids (for example hydrochloric acid) the ratio can be between 1:0.001 and 1:0.1, preferably between 1:0.001 and 1:0.06. For weak acids (for example a solution of carbon dioxide in water, i.e. carbonic acid, preferably saturated solution of carbon dioxide in water) the ratio can be between 1:0.1 and 1:0.2.
Using the correct ratio between ivabradine and the acid assures that Compound 3 remains in the water layer after the layers are separated. On the other hand, ivabradine remains in the water immiscible solvent layer after the layers are separated.
Depending on the level of Compound 3 in ivabradine the extraction step with a water immiscible solvent solution of ivabradine with the acidic aqueous solution can be optionally repeated. After the extractions are finished, the water immiscible solvent layers are mixed and concentrated, using for example distillation, to the final concentration of ivabradine in the solution between 8% (w/w) and 15% (w/w), preferably between 9% (w/w) and 11% (w/w).
Ivabradine can be optionally isolated from the water immiscible solvent (for example by precipitation or crystallization from the solvent or by distilling off of the solvent) or an ethanolic solution of hydrochloric acid can be added to the solution of ivabradine in the water immiscible solvent and ivabradine hydrochloride is crystallized from the solution.
The ethanolic solution of hydrochloric acid is added at a temperature between 15°C and 30°C, preferably between 19°C and 21°C. The concentration of the ethanolic solution of hydrochloric acid is between 20% (w/w) and 30% (w/w), preferably between 26% (w/w) and 28% (w/w). The molar ratio between ivabradine and hydrochloric acid is between 1: 1 and 1:2, preferably between 1: 1 and 1: 1.2. After the ethanolic solution of hydrochloric acid is added, the mixture is stirred for 1 to 10 hours, preferably for 2 to 4 hours. The mixture can be cooled before ivabradine hydrochloride is isolated. The mixture can be cooled at a temperature between -20 and 20°C.
The crystallized product is isolated from the mixture by using any conventional technique, e.g. filtering, centrifugation or distillation off the solvent.
The process can also be followed by the step of drying the obtained ivabradine hydrochloride at a temperature below 40°C, preferably below 30°C for 2-15 hours, preferably for 4-8 hours, to obtain ivabradine hydrochloride form delta characterized by XRPD pattern comprising, inter alia, peaks at 4.1°, 11.0°, 14.7°, 15.3°, 16.9°, 17.8°, 18.0°, 21.6°, 21.9°, 22.1°, 25.8° theta (+ 0.2) when measured with CuKal radiation ( = 1.54060).
The process can be followed by further drying the obtained ivabradine hydrochloride at a temperature between 40°C and 80°C, preferably between 45°C and 55°C, for 2-15 hours, preferably for 4-8 hours, to obtain ivabradine hydrochloride form delta-d characterized by XRPD pattern comprising, inter alia, peaks at 8.5°, 14.5°, 15.2°, 17.1°, 18.1°, 20.9°, 21.4°, 22.1°, 23.9°, 26.3° theta (+ 0.2) when measured with CuKal radiation ( = 1.54060).
Compound 2 or a salt thereof used as starting material in the process of the present invention can be prepared for example by the process as described in EP 534859, but the invention is not limited to such material.
The solid forms of ivabradine hydrochloride produced by the process of the present invention have an excellent batch-to-batch uniformity in the size and shape of the formed crystals and preferably comprises less than 10% of other crystalline forms of ivabradine hydrochloride.
The solid forms of ivabradine hydrochloride obtainable by the described processes may be formulated into pharmaceutical compositions, for instance to tablet compositions for oral administration, and may be used in medicine, for instance in a treatment of angina pectoris.
The invention will be further described with reference to the following non-limiting examples.
EXAMPLES
Example 1
Compound 3 Compound 2. HCI
6.46 kg of 10% (w/w) solution of Compound 2.HC1 (containing 1.9% (HPLC IN) of
Compound 3) in water was mixed with 0.04 kg of 20% Pd(OH)2/C catalyst and the mixture was reduced under hydrogen atmosphere (110 - 140 kPa) at 50°C for 5 hours. Reaction mixture was cooled to 30°C and the catalyst was filtered off. To the filtrate a solution of 0.06 kg of NaOH in 0.15 kg of water was added. The mixture was washed with 4.7 kg of isopropyl acetate. Layers were separated, water layer was washed with 2.4 kg of isopropyl acetate. Isopropyl acetate layers were mixed together. Isopropyl acetate solution (containing ivabradine containing 1.9% (HPLC IN) of Compound 3) was extracted with 0.6 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine: HC1 1:0.008). Phases were separated.
Isopropyl acetate layer (containing ivabradine containing 1.27% (HPLC IN) of
Compound 3) was extracted with 0.41 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine :HC1 1:0.006). Phases were separated. The isopropyl acetate layer (containing ivabradine containing 0.66% (HPLC IN) of Compound 3) was extracted with 0.21 kg of 0.07% (w/w) water solution of HC1 (molar ratio ivabradine :HC1 1:0.003). Phases were separated. The ivabradine solution in isopropyl acetate (containing 0.19% (HPLC IN) of
Compound 3) was concentrated to the final concentration 10% (w/w) solution of ivabradine in isopropyl acetate.
To the 10% (w/w) solution of ivabradine in isopropyl acetate 0.8 kg of ethanol, 0.16 kg of 27% (w/w) solution of HC1 in ethanol (molar ratio ivabradine :HC1 1: 1.1) and 0.5 kg of isopropyl acetate were added at 20°C. The mixture was stirred at this temperature for 3 hours. Solid ivabradine hydrochloride was filtered off.
Example 2
2 g of ivabradine hydrochloride prepared according to Example 1 were dried at 30°C for 4 hours to provide ivabradine hydrochloride form delta in 98% yield.
Example 3
2 g of ivabradine hydrochloride prepared according to Example 1 were dried at 50°C for 4 hours to provide ivabradine hydrochloride form delta-d in 98% yield.
Example 4
10 g of 8% (w/w) solution of ivabradine (containing 1.8% (HPLC IN) of Compound 3) in isopropyl acetate was extracted with 1.3 g 0.035% (w/w) of aqueous solution of hydrochloric acid (i.e. 0.007 equivalents on ivabradine), to provide two-layers system. The layers were separated. The isopropyl acetate layer was washed with 1.1 g of 0.035% (w/w) aqueous hydrochloric acid solution (i.e. 0.003 equivalents on ivabradine). The isopropyl acetate solution was distilled off to provide ivabradine in yield 85% (content of Compound 3 was 0.11% (HPLC IN)).
Example 5
5 g of 8 % (w/w) solution of ivabradine (content of Compound 3 was 1.8% (HPLC IN)) in isopropyl acetate was treated with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to ivabradine) to provide two-layers system. The layers were separated. The water layer was washed with 0.5 ml of isopropyl acetate. The isopropyl layers were mixed and washed with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to
ivabradine). The organic layer was distilled off to provide ivabradine (content of Compound 3 was 0.06% (HPLC IN)) in yield 80%.
Example 6
Compound 3 Compound 2
5 g of Compound 2 (the content of Compound 3 was 0.95 % (HPLC IN)) in 2.5 ml of toluene were treated with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to Compound 2) to provide two-layers system. The layers were separated. The water layer was washed with 0.5 ml of toluene. The toluene layers were mixed and washed with 2.5 g of saturated water solution of carbon dioxide (0.1 equivalent to Compound 2). The layers were separated and the organic layer was distilled off to provide Compound 2 (the content of Compound 3 was 0.03% (HPLC IN)) in yield 80%.
Example 7
10 g of Compound 2 (the content of Compound 3 was 1.6 % (HPLC IN)) in 5 ml of toluene were treated with 1.3 g of 0.035% (w/w) of aqueous solution of hydrochloric acid (0.007 equivalent to Compound 2) to provide two-layers system. The layers were separated. The water layer was washed with 1 ml of toluene. The toluene layers were mixed and washed with 1.1 g of 0.035% (w/w) of aqueous solution of hydrochloric acid (0.003 equivalent to Compound 2) to provide two-layers system. The layers were separated and the organic layer was distilled off to provide Compound 2 (the content of Compound 3 was 0.11% (HPLC IN)) in yield 80%.
In the above examples, the X-Ray Powder Diffraction patterns were recorded on Bruker-AXS D8 vario (Θ/2Θ geometry, reflection mode, Vantec PSD detector) at the following settings:
Start angle (2 Θ): 2.0 °
End angle (2 Θ): 35.0 °
Scan step width: 0.02 0
Scan step time: between 0.2-2.0 seconds
Radiation type: Cu
Radiation wavelengths: 1.54060 A (Kcci), primary monochromator used Exit slit: 6.0 mm
Focus slit: 0.2 mm
Divergence slit: Variable (V20)
Antiscatter slit: 11.8 mm
Receiving slit: 20.7 mm
Claims
1. A process for the preparation of ivabradine hydrochloride by reduction of
Compound 2 or a salt thereof
Compound 2
in an aqueous solvent followed by extraction of ivabradine wherein the extraction comprises the steps of:
1) adding a water immiscible solvent
2) separating the layers
3) washing the water immiscible solvent layer with an amount of an acidic aqueous solution sufficient to obtain a molar ratio ivabradine to acid between 1:0.001 and 1:0.2
2. The process according to claim 1 wherein the aqueous solvent in the reduction is water.
3. The process according to claim 1 or 2 wherein the reduction is performed with a reduction catalyst.
4. The process according to claim 3 wherein the reduction catalyst is Pd/C or
Pd(OH)2/C.
5. The process according to any one of claims 1 to 4 wherein the concentration of Compound 2 in the aqueous solvent is between 6% (w/w) and 13% (w/w).
6. The process according to any one of claims 1 to 5 wherein the reduction is
performed at a temperature between 30°C and 70°C.
7. The process according to anyone of claims 1 to 6 wherein the water immiscible solvent is ethyl acetate, isopropyl acetate, toluene or a mixture thereof.
8. The process according to any one of claims 1 to 7 wherein the acid is hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or a solution of carbon dioxide in water.
9. The process according to claim 8 wherein the acid is hydrochloric acid and the
molar ratio between ivabradine and the acid is between 1:0.001 and 1:0.1.
10. The process according to claim 9 wherein the molar ratio between ivabradine and the hydrochloric acid is between 1:0.01 and 1:0.06.
11. The process according to any one of claims 1 to 10 followed by crystallization of ivabradine hydrochloride from the water immiscible solvent by adding an ethanolic solution of hydrochloric acid.
12. The process according to claim 11 wherein the concentration of the ethanolic
solution of hydrochloric acid is between 20% (w/w) and 30% (w/w).
13. The process according to claim 12 wherein the molar ratio between ivabradine and hydrochloric acid is between 1: 1 and 1:2.
14. The process according to any one of claims 11 to 13 performed at room temperature and further comprising the step of drying the obtained ivabradine hydrochloride at a temperature below 40°C to obtain ivabradine hydrochloride form delta
characterized by XRPD pattern comprising peaks at 4.1°, 11.0°, 14.7°,
15.3°,
16.9°,
17.8°, 18.0°, 21.6°, 21.9°, 22.1°, 25.8° theta (+ 0.2) when measured with CuKal radiation ( = 1.54060).
15. The process according to any one of claims 11 to 13 performed at room temperature and further comprising the step of drying the obtained ivabradine hydrochloride at a temperature between 40°C and 80°C to obtain ivabradine hydrochloride form delta- d characterized by XRPD pattern comprising peaks at 8.5°, 14.5°, 15.2°, 17.1°,
18.1°, 20.9°, 21.4°, 22.1°, 23.9°, 26.3° theta (+ 0.2) when measured with CuKal radiation ( = 1.54060).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16745772.0A EP3331862A1 (en) | 2015-08-04 | 2016-08-03 | A process for preparation of solid ivabradine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15179744.6 | 2015-08-04 | ||
| EP15179744 | 2015-08-04 |
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| WO2017021466A1 true WO2017021466A1 (en) | 2017-02-09 |
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| EP (1) | EP3331862A1 (en) |
| WO (1) | WO2017021466A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107200710A (en) * | 2017-05-22 | 2017-09-26 | 苏州华健瑞达医药技术有限公司 | Novel ivabradine hydrochloride crystal form, preparation method and the composition containing it |
| IT202000025312A1 (en) * | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | PROCESSES FOR THE PREPARATION OF IVABRADINE HCL POLYMORPHS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (en) * | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substituted 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases |
| WO2014114341A1 (en) * | 2013-01-24 | 2014-07-31 | Synthon Bv | Process for making ivabradine |
| WO2014188248A1 (en) * | 2013-05-22 | 2014-11-27 | Laboratorio Chimico Internazionale S.P.A. | A process for preparing ivabradine |
-
2016
- 2016-08-03 WO PCT/EP2016/068577 patent/WO2017021466A1/en active Application Filing
- 2016-08-03 EP EP16745772.0A patent/EP3331862A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (en) * | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substituted 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases |
| WO2014114341A1 (en) * | 2013-01-24 | 2014-07-31 | Synthon Bv | Process for making ivabradine |
| WO2014188248A1 (en) * | 2013-05-22 | 2014-11-27 | Laboratorio Chimico Internazionale S.P.A. | A process for preparing ivabradine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107200710A (en) * | 2017-05-22 | 2017-09-26 | 苏州华健瑞达医药技术有限公司 | Novel ivabradine hydrochloride crystal form, preparation method and the composition containing it |
| IT202000025312A1 (en) * | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | PROCESSES FOR THE PREPARATION OF IVABRADINE HCL POLYMORPHS |
| WO2022090138A1 (en) * | 2020-10-26 | 2022-05-05 | Cambrex Profarmaco Milano S.R.L. | PROCESSES FOR THE PREPARATION OF IVABRADINE HCl POLYMORPHS |
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|---|---|
| EP3331862A1 (en) | 2018-06-13 |
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