PROCESSES FOR THE PREPARATION OF IVABRADINE HCl POLYMORPHS

Abstract

Disclosed are new processes for the preparation of known polymorphs of ivabradine HCl, such processes being characterized by robust protocols suitable for industrial production.

Claims

1. A process for the preparation of delta-d crystalline forms of ivabradine HCl, characterized from a powder X-ray diffractogram showing peaks at values of the diffraction angles 2 θ of 14.6, 15.3, 17.2, 18.1 and 21.4, which comprises: a) crystallization of crude ivabradine HCl in a solvent selected from acetonitrile, methyl ethyl ketone, C1-C5 alcohols, to give the respective crystalline solvate; b) removal of the crystallization solvent by exposure of the crystalline solvate obtained in a), optionally subjected to a first drying, to an inert atmosphere with controlled relative humidity, followed by, drying; or alternatively b′) removal of the crystallization solvent by exposure to a supercritical CO.sub.2 flow.

2. The process according to claim 1, wherein the C1-C5 alcohols are ethanol, isopropanol or 2-methyl-2-butanol.

3. The process according to claim 1 wherein the solvent is selected from ethanol and isopropanol.

4. The process according to claim 1, wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C.

5. The process according to claim 1, wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C.

6. The process according to claim 1, wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

7. The process according to claim 1 wherein step b) is carried out on mixtures of delta forms of solvates of acetonitrile, ethanol, 2-methyl-2-butanol, isopropanol, methyl ethyl ketone optionally in mixture with delta-d forms of ivabradine HCl.

8. The process according to claim 1, wherein step b) the delta-hydrated form of ivabradine HCl having KF between 5% and 10% is obtained.

9. The process according to claim 1, wherein the removal of the crystallization solvent is carried out by treatment with supercritical CO.sub.2 at a pressure between 70 bar and 140 bar at a temperature between 40° C. and 1.00° C.

10. The process according to claim 1, wherein the delta-d form of ivabradine HCl is obtained having an acetonitrile content lower than 200 ppm or a content of ethanol or isopropanol or 2-methyl-2-butanol lower than 5000 ppm, and KF<0.5.

11. The process according to claims 2, wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C.

12. The process according to claims 3, wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C.

13. The process according to claim 2, wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C.

14. The process according to claim 3, wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C.

15. The process according to claim 4, wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C.

16. The process according to claim 2, wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

17. The process according to claim 3, wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

18. The process according to claim 4, wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

19. The process according to claim 5, wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

20. The process according to claim 2, wherein step b) is carried out on mixtures of delta forms of solvates of acetonitrile, ethanol, 2-methyl-2-butanol, isopropanol, methyl ethyl ketone optionally in mixture with delta-d forms of ivabradine HCl.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0026] FIG. 1a: XRPD delta-d form of ivabradine HCl

[0027] FIG. 1b: Table with list of peaks related to XRPD of FIG. 1a

[0028] FIG. 2: XRPD delta-d form of ivabradine HCl with peaks indication

[0029] FIG. 3a: XRPD delta-hydrated form of ivabradine HCl

[0030] FIG. 3b: Table with list of peaks related to XRPD of FIG. 3a

[0031] FIG. 4: XRPD delta-hydrated form of ivabradine HCl with peaks indication

DETAILED DESCRIPTION OF THE INVENTION

[0032] We have now found new processes for the preparation of crystalline forms of ivabradine HCl and in particular of the anhydrous delta-d crystalline form, which involve the removal of the crystallization solvent under controlled temperature and humidity conditions or, alternatively, by treatment with supercritical CO.sub.2.

[0033] We therefore found a process for preparing the delta-d form of ivabradine HCl, which includes: [0034] a) crystallization of crude ivabradine HCl in a suitable solvent to yield the corresponding crystalline solvate; [0035] b) the removal of the crystallization solvent by exposure of the crystalline solvate, optionally subjected to a preventive drying, in an inert atmosphere with controlled relative humidity optionally followed by drying; or alternatively [0036] b′) the removal of the crystallization solvent by exposure to a supercritical CO.sub.2 flow.

[0037] Raw ivabradine HCl used in step a) can be obtained according to known processes and in particular according to the processes described in EP 0 534 859 or it can be obtained by salification of ivabradine free base with HCl gas in a suitable solvent.

[0038] Crude ivabradine HCl can be obtained by treatment of ivabradine HCl with acetonitrile to give an acetonitrile solvate, or by salification of ivabradine free base with gaseous HCl in the presence of C1-C5 alcohols, such as ethanol, isopropanol, 2-methyl-2-butanol methyl ethyl ketone, acetonitrile or mixtures thereof.

[0039] In step a), crude ivabradine HCl is suspended and then dissolved by heating in a suitable solvent equal to or different from the step of preparation of the crude, and preferably selected from acetonitrile, C1-C5 alcohols, methylethylketone or mixtures thereof. The solution thus obtained is left to cool until the solid compound precipitates, which is isolated and possibly subjected to mild drying. Said solid compound is a solvate of ivabradine HCl with the solvent used.

[0040] When the solvent used in step a) is selected from acetonitrile, C1-C5 alcohols, preferably ethanol or isopropanol or 2-methyl-2-butanol, methyl ethyl ketone, the delta forms of solvates of acetonitrile, C1-C5 alcohol are respectively obtained, preferably ethanol solvate, 2-methyl-2-butanol solvate and isopropanol solvate, methyl ethyl ketone solvate optionally mixed with a certain quantity of anhydrous delta-d forms of ivabradine HCl. Said solvates of delta forms of ivabradine HCl optionally in mixture with the delta-d forms of ivabradine HCl can be exposed to an inert atmosphere with controlled relative humidity, leading to the formation of the delta-hydrated form which, after drying under vacuum, is transformed into the anhydrous form delta-d of ivabradine HCl characterized by a content of methyl ethyl ketone, ethanol, 2-methyl-2-butanol or isopropanol lower than 5000 ppm, preferably lower than 2000 ppm; acetonitrile lower than 400 ppm preferably lower than 100 ppm, and relative humidity (Karl Fischer) KF<0.5.

[0041] Alternatively, said delta forms of ivabradine HCl solvates, optionally in admixture with delta-d forms of ivabradine HCl, preferably delta forms of ivabradine HCl solvate of acetonitrile, or C1-C5 alcohols solvates, preferably ethanol, 2-methyl-2-butanol o isopropanol, or methyl ethyl ketone solvates, optionally in admixture with delta-d forms of ivabradine HCl, can be subjected to a supercritical CO.sub.2 flow which leads to the removal of the solvent and the transition to the anhydrous delta-d form of ivabradine HCl.

[0042] It has therefore been shown that if delta forms of ivabradine HCl solvates optionally in admixture with delta-d forms of ivabradine HCl, preferably delta forms of ivabradine HCl acetonitrile solvate, or C1-C5 alcohols solvates, preferably ethanol, 2-methyl-2-butanol or isopropanol, or methyl ethyl ketone solvates, optionally in admixture with delta-d forms of ivabradine HCl, are subjected to a supercritical CO.sub.2 flow under suitable conditions of pressure, flow and time, these are transformed into the anhydrous delta-d form having a content of methyl ethyl ketone, ethanol, 2-methyl-2-butanol or isopropanol lower than 5000 ppm, preferably lower than 2000 ppm; content of acetonitrile lower than 400 ppm preferably lower than 100 ppm even more preferably lower than 40 ppm, and KF<0.5.

[0043] Therefore, an object of the invention is a process for the preparation of delta-d crystalline forms of ivabradine HCl, which includes: [0044] a) crystallization of raw ivabradine HCl in a solvent selected from acetonitrile, methyl ethyl ketone, C1-C5 alcohols, to give the corresponding crystalline solvate; [0045] b) the removal of the crystallization solvent by exposure of the crystalline solvate obtained in step a), optionally subjected to a preventive drying, in an inert atmosphere with controlled relative humidity, followed by drying; or alternatively [0046] b′) the removal of the crystallization solvent by exposure to a supercritical CO.sub.2 flow.

[0047] Preferably, the crystalline solvate of ivabradine HCl prepared in step a) comprises delta forms of acetonitrile solvate, C1-C5 alcohols solvates, methyl ethyl ketone solvate optionally in admixture with delta-d forms of ivabradine HCl. More preferably the crystalline solvate of ivabradine HCl prepared in step a) comprises mixtures of delta forms of acetonitrile solvate, ethanol solvate, 2-methyl-2-butanol solvates, isopropanol solvate optionally in admixture with delta-d forms of ivabradine HCl.

[0048] The optional preventive drying of the crystalline product obtained can be carried out under vacuum at a temperature between room temperature and 80° C., more preferably between 35° C. and 70° C., even more preferably between 40° C. and 60° C.

[0049] Preferably, step b) is carried out in an inert atmosphere with relative humidity between 15 and 65%, more preferably between 20 and 55%, even more preferably between 30 and 45%, for a time between 5 and 36 hours, preferably between 10 and 24 hours, at a temperature between 10 and 40° C., preferably between 20 and 30° C.

[0050] Preferably, step b) is carried out on mixtures of Ivabradine HCl delta forms of solvates of acetonitrile, ethanol, isopropanol, 2-methyl-2-butanol or of methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl.

[0051] Preferably, step b′) is carried out at a supercritical CO2 flow at a pressure between 70 bar and 140 bar, preferably between 85 bar and 120 bar; at a temperature between 40° C. and 100° C., preferably between 70° C. and 90° C., with a flow suitably chosen according to the equipment used.

[0052] For example, for a reactor having internal dimensions 7 mm×150 mm and filling≥70%, the flow is between 1 and 20 mL/min, preferably between 2 and 10 mL/min, even more preferably between 2 and 5 mL/min.

[0053] In step b′) ivabradine HCl is obtained in delta-d form with an acetonitrile content lower than 200 ppm, preferably lower than 100 ppm, more preferably lower than 40 ppm, even more preferably lower than 10 ppm; or a content of ethanol, 2-methyl-2-butanol or isopropanol lower than 5000 ppm, preferably lower than 2000 ppm and KF<0.5.

[0054] The process of the invention allows to obtain ivabradine HCl in delta-d form starting from a raw solvate of ivabradine HCl which can be crystallized from a solvent selected from C1-C5 alcohols, preferably selected from ethanol, 2-methyl-2-butanol and isopropanol; acetonitrile and methyl ethyl ketone to give the corresponding crystalline solvate which, subjected to an optional drying, and subsequent exposure to controlled relative humidity, provides a hydrated form which can be optionally dried to give the anhydrous form.

[0055] Surprisingly, the crude solvate of ivabradine HCl can be converted to a delta form of a solvate of ivabradine HCl derived from the crystallization of the crude ivabradine HCl with C1-C5 alcohols, preferably ethanol, 2-methyl-2-butanol or isopropanol, methyl ethyl ketone or acetonitrile and subsequently transformed into a hydrated form using controlled relative humidity, said hydrated form when suitably dried leads to the formation of the anhydrous delta-d polymorph of ivabradine HCl with purity requirements and residual solvent content well below the limits set by the ICH guidelines.

[0056] Alternatively, said crude crystalline solvate of ivabradine HCl can be subjected to drying and subsequently to a supercritical CO.sub.2 flow which allows to remove the crystallization solvent and to provide the anhydrous delta-d form of ivabradine HCl with residual acetonitrile content up to less than 5 ppm, content of methyl ethyl ketone, ethanol, 2-methyl-2-butanol or isopropanol lower than 5000 ppm, preferably lower than 2000 ppm.

[0057] In order to better illustrate the present invention, the following examples are now provided.

Analytical

[0058] X-ray diffractometric analysis—powder process (XRPD)

[0059] The samples, before being analyzed, were subjected to a gentle grinding in an agate mortar and then analyzed by X-ray diffractometry, with the following instrumental characteristics: [0060] Philips diffractometer model PW1800/10 [0061] X′Pert High Score data processing software—v. 2.0a (PANalytical) [0062] Radiation Cu Kα (Kα1=1.54060 Å Kα2=1.54439 Å) [0063] graphite monochromator [0064] diverging automatic slide [0065] generator power: 45 Kv, 35 mA [0066] scan interval: 2°-65° 2 θ [0067] scan speed (step): 0.02° 2 θ/sec [0068] counting time per step: 1.0 sec

[0069] The samples are analyzed in the scan interval: 2°-65° 2 θ.

DSC Analysis (Differential Scanning Calorimetry)

[0070] DSC analyzes were conducted using METTLER TOLEDO's DSC 822e instrument. The experiments were conducted with a heating ramp of 10.0° C./min in the range 30-350° C. and with a nitrogen flow of 40 ml/min. 40 μL aluminum crucibles with perforated lid were used.

IR Analysis

[0071] The IR spectra were recorded using a JASCO FT-IR 460 Plus spectrophotometer. The samples were prepared by grinding about 5 mg of sample with about 500 mg of KBr and analyzed in the range 4000-400 cm.sup.−1 with a resolution of 4 cm.sup.−1.

Example 1: Treatment with Supercritical CO.SUB.2

[0072] Ivabradine HCl (delta solvated form of acetonitrile) is loaded into the extraction chamber which is then connected to the plant. The extraction phase is started at 80° C. by varying the parameters of temperature, CO.sub.2 flow and time as shown in Table 1 below.

TABLE-US-00002 TABLE 1 Weight Pressure Flow Temperature Time Acetonitrile N. (g) (bar) (mL/min) (° C.) (h) (ppm) Delta form of ivabradine HCl acetonitrile solvate 67118.5 A 1.391 85 5 80 6 134.9 B 1.364 120 2 80 6 40.5 C 1.373 85 2 80 12 <1.5 D 1.317 120 5 80 12 3.6

Example 2: Delta-d form of Ivabradine HCl

[0073] In a flask, 1 g of acetonitrile solvated of ivabradine HCl (2 mmol) is suspended in 6 mL of acetonitrile and 0.2 mL of water. The suspension is heated to reflux until it is completely dissolved. Subsequently the solution is cooled to 20-25° C. observing precipitation of the product. The obtained suspension is left under stirring for at least 1 hour. The desired product is then isolated by filtration and washed with 0.5 mL of acetonitrile (delta form).

[0074] The product obtained is kept for 20 hours at a relative humidity of 43% (in the presence of a saturated solution of potassium carbonate) and subsequently dried under vacuum at 40° C. for 15 hours, so as to obtain the desired delta-d form (yield 90,0%).

Example 3: Delta-d form of Ivabradine HCl

[0075] In a flask, 1 g of ivabradine HCl ethanol solvate (2 mmol) is suspended in 5 mL of absolute ethanol. The suspension is heated to reflux until it is completely dissolved. Subsequently the solution is cooled to 20-25° C. observing precipitation of the product. The obtained suspension is left under stirring for at least 1 hour. The desired product is then isolated by filtration and washed with 0.5 mL of ethanol (delta form).

[0076] The product obtained is kept 8-10 hours at a relative humidity of 43% (in the presence of a saturated solution of potassium carbonate) and subsequently dried under vacuum at 40° C. for 15 hours, so as to obtain the desired delta-d form (yield 90.0%).

Example 4: Delta-d form of Ivabradine HCl

[0077] In a flask, 1 g of ivabradine HCl isopropanol solvate (2 mmol) is suspended in 5 mL of isopropanol. The suspension is heated to reflux until it is completely dissolved. Subsequently the solution is cooled to 20-25° C. observing precipitation of the product. The obtained suspension is left under stirring for at least 1 hour. The desired product is then isolated by filtration and washed with 1 mL of isopropanol (delta form).

[0078] The product obtained is kept 8-10 hours at a relative humidity of 43% (in the presence of a saturated solution of potassium carbonate) and subsequently dried under vacuum at 40° C. for 15 hours, so as to obtain the desired delta-d form (yield 85.0%).

Example 5: Delta-d form of Ivabradine HCl

[0079] In a flask, 1 g of Ivabradine HCl (2 mmol) is suspended in 5 mL of absolute ethanol. The suspension is heated to reflux until it is completely dissolved. Subsequently the solution is cooled to 20-25° C. observing precipitation of the product. The suspension is left under stirring for at least 1 hour. The desired product is then isolated by filtration after adding 3 mL of ethanol and washed with 0.5 mL of ethanol (delta form).

[0080] The product obtained is dried under vacuum at 55° C. for 15 hours, kept for 12 hours at a relative humidity of 43% (in the presence of a saturated solution of potassium carbonate) and subsequently kept for 15 hours under a flow of dry nitrogen, so as to obtain the desired delta-d form (yield 90.0%).

Example 6: Delta-d form of Ivabradine HCl

[0081] In a flask 1 g of Ivabradine HCl (2 mmol) is suspended in 5 mL of absolute ethanol. The suspension is heated to reflux until it is completely dissolved. Subsequently the solution is cooled to 20-25° C. observing precipitation of the product. The suspension is left under stirring for at least 1 hour. The desired product is then isolated by filtration after adding 3 mL of ethanol and washed with 0.5 mL of ethanol (delta form).

[0082] The obtained product is kept 15 hours under nitrogen flow at a relative humidity of 43% (in the presence of a saturated solution of potassium carbonate) and subsequently dried under vacuum at 40° C. for 15 hours, so as to obtain the delta-d form desired (yield 90.0%).