阅读说明：本技术 罗沙司他的多晶型物和共晶 (Polymorphs and co-crystals of rosuvastatin ) 是由 D·J·卡莱姆 R·提帕拉博伊纳 D·帕蒂瓦达 V·佩蒂 S·P·戈皮 于 2018-08-10 设计创作，主要内容包括：本发明提供罗沙司他的结晶形式-γ,罗沙司他的结晶形式-δ,制备罗沙司他的结晶形式-γ、罗沙司他的结晶形式-δ的方法,及其药物组合物。本发明还提供罗沙司他形式RLP、罗沙司他形式RNM和罗沙司他形式RU的共晶,它们的制备方法及其组合物。(The present invention provides crystalline form-gamma of rosxastat, a process for preparing crystalline form-gamma of rosxastat, crystalline form-of rosxastat, and pharmaceutical compositions thereof the present invention also provides co-crystals of rosxastat form R L P, rosxastat form RNM, and rosxastat form RU, processes for their preparation, and compositions thereof.)

1. Co-crystal of proline from roxasistat.

2. The co-crystal according to claim 1, wherein the proline is L-proline.

3. The co-crystal according to claim 2, the rasagile L-proline co-crystal characterized by an X-ray powder diffraction pattern having peaks at about 3.57, 7.15, 10.17, 10.74, 17.94 and 21.29 ± 0.22 Θ °.

4. The co-crystal according to claim 3, the rasagile L-proline co-crystal characterized by an X-ray powder diffraction pattern having additional peaks at about 9.54, 14.31, 19.17, and 25.22 ± 0.22 θ °.

5. A method of preparing a co-crystal of L-proline to roxasistat comprising:

a) contacting rosxastat with L-proline in solution;

b) optionally, heating the solution of step a);

c) the L-proline co-crystal of roxasistat was isolated.

6. A method of preparing a co-crystal of L-proline to roxasistat comprising:

a) providing L-proline solution with rosxastat;

b) optionally, heating the solution of step a);

c) the L-proline co-crystal of roxasistat was isolated.

7. A process for the preparation of a co-crystal of L-proline from roxasistat, comprising the step of crystallizing roxasistat and L-proline from a solvent or a mixture of solvents comprising water, methanol and acetone.

8. Crystalline form-of rasagiline characterized by an X-ray powder diffraction pattern having peaks at about 6.57, 9.21, 18.10, 19.67, 20.86, 25.10 and 29.47 ± 0.2 ° 2 Θ.

9. The crystalline form according to claim 8, Rosxastat form-, characterized by an X-ray powder diffraction pattern having additional peaks at about 13.02, 13.84, and 22.78 ± 0.2 ° 2 θ.

10. A process for preparing crystalline form-of rosxastat comprising:

a) slurrying crystalline form- γ of rosmarintat in water;

b) optionally, heating the solution of step a);

c) isolating crystalline form-;

d) optionally, the product is dried at a suitable temperature.

11. Crystalline form- γ of rasagiline characterized by an X-ray powder diffraction pattern having peaks at about 6.56, 7.87, 9.22, 13.15, 18.22, 19.80, 20.94, 25.20 and 29.54 ± 0.2 ° 2 Θ.

12. The crystalline form according to claim 11, Rosxastat form- γ, characterized by an X-ray powder diffraction pattern having additional peaks at about 13.95 and 22.85 ± 0.2 ° 2 θ.

13. A process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) isolating crystalline form- γ of rosxastat;

d) optionally, the product is dried at a suitable temperature.

14. A process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) adding an anti-solvent to the solution of rosxastat; or adding a solution of the rosxastat to the anti-solvent;

d) isolating crystalline form- γ of rosxastat;

e) optionally, the product is dried at a suitable temperature.

15. The process according to claim 14, wherein the anti-solvent used in step c) is selected from: n-pentane, n-heptane, n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, diisopropyl ether, petroleum ether, cyclohexane, water or mixtures thereof.

16. The co-crystal of niacinamide with roxasistat characterized by a powder X-ray diffraction pattern having peaks at about 6.24, 10.84, 18.86, 22.20, 23.37, 26.41, and 29.24 ± 0.22 Θ °.

17. A co-crystal of urea for troxastat characterized by a powder X-ray diffraction pattern having peaks at about 7.74, 14.79, 17.84, 18.39, 19.41, 20.89, 22.29, 23.22, 24.64, and 29.34 ± 0.22 Θ °.

Technical Field

The present invention provides crystalline forms, solvates and co-crystals of rosuvastatin, methods of their preparation and pharmaceutical compositions thereof.

Background

Rasagiltat (I) or FG-4592 is chemically known as [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid. It is an oral small molecule inhibitor of HIF prolyl hydroxylase or HIF-PH, and is used in phase 3 clinical development to treat and prevent HIF-related conditions, including anemia, ischemia, and hypoxia in chronic kidney disease or CKD.

U.S. Pat. No. 7323475B 2, example D-81(e), by reference to example D-78(D), discloses a process for isolating rasagiline by concentrating the organic phase (EtOAc/methanol) under vacuum.

Us patent No. 8883823B 2 discloses crystalline forms of rasagiline and methods for their preparation. The crystalline forms are designated form a, form B (hemihydrate), form C (hexafluoropropane-2-alcohol solvate) and form D (DMSO: water solvate). It further discloses various salts of rasagile and amorphous rasagile.

U.S. Pat. No. 9206134B2 discloses various crystalline forms of rasagiline and methods for preparing the same. The crystalline forms are designated form I, form II, form III, form IV, form V, form VI and form VII.

Some compounds may exhibit different polymorphs. A single compound may yield a variety of solid forms having different physical properties. Such variations in solid form can be significant and can lead to differences in the pharmaceutical product with respect to solubility, bioavailability, stability, and other properties. Since polymorphic forms may vary in their physical properties, regulatory agencies are demanding that efforts be made to identify all polymorphic forms, e.g., crystalline, solvated forms, etc., of a new drug substance.

The presence and possible number of polymorphic forms of a given compound cannot be predicted and there are no "standard" procedures available to prepare polymorphic forms of a substance. However, the new forms of pharmaceutically useful compounds may provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug may exhibit very different solubilities and dissolution rates. The discovery of new polymorphic forms expands the choice of materials that a formulation scientist can utilize to design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristic. Thus, there is still a need to prepare new and stable polymorphic forms of rasagiline.

Disclosure of Invention

In a first embodiment of the present invention, there is provided crystalline form- γ of rosxastat characterized by a PXRD comprising peaks at about 6.56, 7.87, 9.22, 13.15, 18.22, 19.80, 20.94, 25.20 and 29.54 ± 0.2 ° 2 Θ. In one embodiment, the present invention provides crystalline form- γ of rosxastat characterized by PXRD having additional peaks at about 13.95 and 22.85 ± 0.2 ° 2 Θ.

In a second embodiment of the present invention, there is provided a process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) isolating crystalline form- γ of rosxastat;

d) optionally, the product is dried at a suitable temperature.

In a third embodiment of the present invention, there is provided a process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) adding an anti-solvent to the solution of rosxastat; or adding a solution of the rosxastat to the anti-solvent;

d) isolating crystalline form- γ of rosxastat;

e) optionally, the product is dried at a suitable temperature.

In a fourth embodiment of the invention, there is provided a crystalline form of crystalline rosixatas, characterized by PXRD comprising peaks at about 6.57, 9.21, 18.10, 19.67, 20.86, 25.10 and 29.47 ± 0.2 ° 2 Θ. In one embodiment, the present invention provides crystalline forms of rosxastat characterized by PXRD having additional peaks at about 13.02, 13.84, and 22.78 ± 0.2 ° 2 Θ.

In a fifth embodiment of the invention, there is provided a process for preparing crystalline form-of rosmarinic acid comprising:

a) slurrying crystalline form- γ of rosmarintat in water;

b) optionally, heating the solution of step a);

c) isolating crystalline form-;

d) optionally, the product is dried at a suitable temperature.

In a sixth embodiment, the present invention provides a co-crystal of rosmarinic acid comprising: rosxastat and proline.

In a seventh embodiment of the invention there is provided a co-crystal of roxarstat comprising roxarstat and L-proline.

In an eighth embodiment of the invention there is provided a co-crystal of rosxastat comprising rosxastat and L-proline, designated crystalline form R L P of rosxastat characterized by a powder X-ray diffraction pattern having peaks at about 3.57, 7.15, 10.17, 10.74, 17.94 and 21.29 ± 0.22 Θ.

In a ninth embodiment of the invention, there is provided a process for preparing a co-crystal (crystalline form R L P) of rosixatas comprising:

a) milling or contacting the rosxastat with L-proline in solution with L-proline;

b) optionally, heating the mixture of step a);

c) the co-crystal of roxasistat (crystalline form R L P) was isolated.

In a tenth embodiment of the invention, there is provided a process for preparing a co-crystal (crystalline form R L P) of rosixatas comprising:

a) providing/dissolving L-proline with a solution of roxarstat;

b) optionally, heating the mixture of step a);

c) the co-crystal of roxasistat (crystalline form R L P) was isolated.

In an eleventh embodiment of the invention there is provided a process for the preparation of co-crystals of rosixastat (crystalline form R L P) comprising the step of crystallizing rosixastat and L-proline from a solvent or solvent mixture comprising water, methanol and acetone.

In a twelfth embodiment of the invention, there is provided a co-crystal of roxarstat, comprising: rosxastat and niacinamide.

In a thirteenth embodiment of the invention, there is provided a co-crystal of rasagiline comprising rasagiline and niacinamide, designated as crystalline form RNM of rasagiline characterized by a powder X-ray diffraction pattern having peaks at about 6.24, 10.84, 18.86, 22.20, 23.37, 26.41 and 29.24 ± 0.22 Θ °.

In a fourteenth embodiment of the present invention, there is provided a process for preparing a co-crystal (crystalline form RNM) of roxarstat, comprising:

a) providing/dissolving a solution of niacinamide and roxaxetil;

b) optionally, heating the mixture of step a);

c) the co-crystal (crystalline form RNM) of roxasistat was isolated.

In a fifteenth embodiment of the present invention, there is provided a co-crystal of roxarstat, comprising: rosemastat and urea.

In a sixteenth embodiment of the invention there is provided a co-crystal of rasagiline comprising rasagiline and urea, designated as crystalline form RU of rasagiline, characterized by a powder X-ray diffraction pattern having peaks at about 7.74, 14.79, 17.84, 18.39, 19.41, 20.89, 22.29, 23.22, 24.64 and 29.34 ± 0.22 Θ °.

In a seventeenth embodiment of the present invention, there is provided a method of preparing a co-crystal (crystalline form RU) of rosixastat comprising:

a) providing/dissolving a solution of urea and rosmarinic acid;

b) optionally, heating the solution of step a);

c) the co-crystal (crystalline form RU) of rasagiline was isolated.

In an eighteenth embodiment of the invention, there is provided a pharmaceutical composition comprising a crystalline form of rosxastat selected from the group consisting of form- γ, form-, form R L P, form RNM and form RU or a mixture thereof, and at least one pharmaceutically acceptable excipient.

Drawings

Figure 1 shows a powder X-ray diffraction ("PXRD") pattern of crystalline form- γ of roxasistat obtained from example 1.

Figure 2 shows the thermogravimetric analysis (TGA) of crystalline form- γ of rosxastat obtained from example 1.

Figure 3 shows a powder X-ray diffraction ("PXRD") pattern of crystalline form of rosxastat obtained from example 5.

Figure 4 shows a thermogravimetric analysis (TGA) of the crystalline form of rosalastat obtained from example 5.

Fig. 5 shows a powder X-ray diffraction ("PXRD") pattern of the co-crystal of roxasistat with L-proline prepared by the method of example 9.

FIG. 6 shows ORTEP of the Rosesarta L-proline (1: 1) cocrystal (form R L P), displacement ellipsoids drawn at the 50% probability level and H atoms shown as small spheres of arbitrary radius.

Figure 7 shows a powder X-ray diffraction ("PXRD") pattern of the co-crystal of roxasistat with niacinamide prepared by the method of example 14.

Figure 8 shows a powder X-ray diffraction ("PXRD") pattern of a co-crystal of roxasistat with urea prepared by the method of example 15.

Detailed Description

Based on the chemical structure, it cannot be predicted with any degree of certainty whether a compound will crystallize, how many crystalline solid forms of the compound may exist under the conditions under which it will crystallize, or the solid state structure of any of these forms.

The present invention arose from the discovery of solid forms of rasagiline. The invention also provides a novel co-crystal of the roxburgh.

Definition of

The following definitions are used in connection with the present invention unless the context indicates otherwise.

By "hydrate" is meant a complex formed by combining rosxastat with water. The term includes stoichiometric as well as non-stoichiometric hydrates.

"solvate" refers to a complex formed by combining the rosxastat and a solvent.

As used herein, "co-crystal" is defined as a crystalline material comprising two or more compounds, wherein at least two compounds are held together, wherein at least one of the compounds is a co-crystal former. As used herein, "co-crystal former" is defined as a component with which the rasagiline is able to form a co-crystal. The eutectic former is part of the crystal lattice.

The terms "about," "approximately," and the like, are to be construed as modifying a term or value such that it is not absolute. These terms will be defined by the context and the terms they modify, as these terms are understood by those skilled in the art. This includes at least the degree of expected experimental, technical, and instrumental error for a given technique of measurement.

The term "crystalline form" means that the rosxatase is present in a substantially crystalline form. By "substantially" crystalline is meant at least 80%, preferably at least 90% or 95% of the crystalline form, more preferably all of the rasagiline is in crystalline form. In other words, "crystalline form" of rasagile means that rasagile does not contain a significant amount of any other crystalline part of rasagile, preferably does not contain an appreciable amount of any other crystalline part of rasagile, such as a part measurable upon X-ray powder diffraction analysis.

The term "optional" or "optionally" is understood to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

In a first embodiment of the present invention, there is provided crystalline form- γ of rosxastat characterized by a PXRD comprising peaks at about 6.56, 7.87, 9.22, 13.15, 18.22, 19.80, 20.94, 25.20 and 29.54 ± 0.2 ° 2 Θ. In one embodiment, the present invention provides crystalline form- γ of rosxastat characterized by PXRD having additional peaks at about 13.95 and 22.85 ± 0.2 ° 2 Θ.

In one embodiment, the present invention provides crystalline form- γ of rosxastat characterized by PXRD substantially as shown in figure 1.

In one embodiment, the present invention provides crystalline form- γ of rosxastat characterized by a TGA substantially as shown in figure 2.

In a second embodiment of the present invention, there is provided a process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) isolating crystalline form- γ of rosxastat;

d) optionally, the product is dried at a suitable temperature.

In embodiments involving step a), the solution may optionally be treated with carbon, flux calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or clarify dissolution. In step a), the rosxastat is dissolved in a solvent comprising formic acid.

The dissolution temperature may be from about 0 ℃ to about the reflux temperature of formic acid, or less than about 120 ℃, less than about 110 ℃, less than about 100 ℃, less than about 70 ℃, less than about 40 ℃, less than about 20 ℃, less than about 0 ℃, or any other suitable temperature, as long as a clear solution of the rasagiline is obtained without affecting its quality.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation or any other suitable technique. The solution may be filtered by passing it through a filter paper, glass fiber or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to avoid premature crystallization.

Step c) involves isolation of crystalline form- γ of rosixastat, which can be achieved by any suitable method including cooling, flash cooling, concentrating the material, adding an anti-solvent, adding seeds to induce crystallization, and the like, if desired. Stirring or other alternative methods such as shaking, agitation, etc. may also be used for separation.

Suitable separation temperatures may be less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 40 ℃, less than about 20 ℃, less than about 10 ℃, less than about 5 ℃, less than about 0 ℃, less than about-10 ℃, less than about-20 ℃, or any other suitable temperature.

The isolated crystalline form- γ of rosixatas may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for recovering solids under pressure or under reduced pressure. The recovered solids may optionally be dried. The drying may be performed in a tray dryer, vacuum oven, air oven, conical vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, or the like. The drying may be carried out at atmospheric or reduced pressure at a temperature of less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 50 ℃, less than about 30 ℃ or any other suitable temperature. The drying may be carried out any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce the desired particle size. The milling or micronization may be carried out before or after the drying of the product is completed. Techniques that may be used to reduce particle size include, but are not limited to, ball milling, roll and hammer milling, and jet milling.

In a third embodiment of the present invention, there is provided a process for preparing crystalline form- γ of rosxastat comprising:

a) dissolving the rosxastat in formic acid;

b) optionally, heating the solution of step a);

c) adding an anti-solvent to the solution of rosxastat; or adding a solution of the rosxastat to the anti-solvent;

d) isolating crystalline form- γ of rosxastat;

e) optionally, the product is dried at a suitable temperature.

In embodiments involving step a), the solution may optionally be treated with carbon, flux calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or clarify dissolution. In step a), the rosxastat is dissolved in a solvent comprising formic acid.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation or any other suitable technique. The solution may be filtered by passing it through a filter paper, glass fiber or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to avoid premature crystallization.

The dissolution temperature may be from about 0 ℃ to about the reflux temperature of formic acid, or less than about 120 ℃, less than about 110 ℃, less than about 100 ℃, less than about 70 ℃, less than about 40 ℃, less than about 20 ℃, less than about 0 ℃, or any other suitable temperature, as long as a clear solution of the rasagiline is obtained without affecting its quality.

In an embodiment of step c) it is involved adding an anti-solvent to the solution obtained in step b), or adding the solution obtained in step b) to an anti-solvent, wherein in step b) only formic acid is used to prepare the solution. After addition of the anti-solvent, the reaction mass can be held for 15 minutes to 24 hours.

Suitable anti-solvents for use in step c) include, but are not limited to: alkanes (e.g., n-pentane, n-heptane, n-hexane, n-heptane, etc.), ethers (e.g., diethyl ether, methyl tert-butyl ether, diisopropyl ether, petroleum ether), or similar cyclohexanes or mixtures thereof.

If desired, the separation of step d) may be effected by any suitable separation method, for example precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping or by shaking the container, conventional separation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

Suitable separation temperatures may be less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 40 ℃, less than about 20 ℃, less than about 10 ℃, less than about 5 ℃, less than about 0 ℃, less than about-10 ℃, less than about-20 ℃, or any other suitable temperature.

In a fourth embodiment of the invention, there is provided a crystalline form of crystalline rosixatas, characterized by PXRD comprising peaks at about 6.57, 9.21, 18.10, 19.67, 20.86, 25.10 and 29.47 ± 0.2 ° 2 Θ. In one embodiment, the present invention provides crystalline forms of rosxastat characterized by PXRD having additional peaks at about 13.02, 13.84, and 22.78 ± 0.2 ° 2 Θ.

In one embodiment, the present invention provides crystalline forms of rosxastat characterized by PXRD substantially as shown in figure 3. A crystalline form-, which is a hydrate, of rosuvastatin.

In one embodiment, the invention provides a crystalline form-, of rosalastat, characterized by a TGA substantially as shown in figure 4.

In a fifth embodiment of the invention, there is provided a process for preparing crystalline form-of rosmarinic acid comprising:

a) slurrying crystalline form- γ of rosmarintat in water;

b) optionally, heating the solution of step a);

c) isolating crystalline form-;

d) optionally, the product is dried at a suitable temperature.

In embodiments involving step a), the solution may optionally be treated with carbon, flux calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or clarify dissolution. In step a), crystalline form- γ of rosmarintat is slurried in water.

Slurrying the crystalline form- γ of rosixata in water can be less than 24 hours, less than 20 hours, less than 16 hours, less than 12 hours, less than 8 hours, less than 4 hours.

Step c) involves isolation of the crystalline form of rosxastat-which may be achieved, if desired, by any suitable method, including cooling, flash cooling, concentrating the material, adding an anti-solvent, adding seeds to induce crystallization, and the like. Stirring or other alternative methods such as shaking, agitation, etc. may also be used for separation.

Suitable separation temperatures may be less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 40 ℃, less than about 20 ℃, less than about 10 ℃, less than about 5 ℃, less than about 0 ℃, less than about-10 ℃, less than about-20 ℃, or any other suitable temperature.

The isolated crystalline form of rosixatas-may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for recovering solids under pressure or under reduced pressure. The recovered solids may optionally be dried. The drying may be performed in a tray dryer, vacuum oven, air oven, conical vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, or the like. The drying may be carried out at atmospheric or reduced pressure at a temperature of less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 50 ℃, less than about 30 ℃ or any other suitable temperature. The drying may be carried out any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce the desired particle size. The milling or micronization may be carried out before or after the drying of the product is completed. Techniques that may be used to reduce particle size include, but are not limited to, ball milling, roll and hammer milling, and jet milling.

Cooling crystalline rosixastat from formic acid solvent results in the form- γ of rosixastat. Form gamma is a solvate of a mixture of formic acid and water, with a formic acid content varying from 2% to 3% and a water content between 4% and 5%. When slurried in water, form γ forms as a hydrate of the form rosixastat. The water content of the form is between 4.5% and 5.5%, i.e. equivalent to the monohydrate and formic acid content < 5000 ppm.

In a sixth embodiment of the present invention, there is provided a co-crystal of rosmarin comprising: rosxastat and proline.

The term "eutectic", as used herein, means that a crystalline material comprises two or more distinct solids at room temperature, each solid containing different physical properties, such as structure, melting point, and heat of fusion. The co-crystal of the present invention comprises a co-crystal former (proline) hydrogen bonded to roxasistat.

The rasagilate feed may be in crystalline or amorphous form. The co-crystals herein may be anhydrous; it may also be present as a co-crystal hydrate or solvate thereof.

In a seventh embodiment of the invention there is provided a co-crystal of roxarstat comprising roxarstat and L-proline.

In an eighth embodiment of the invention there is provided a co-crystal of rosxastat comprising rosxastat and L-proline, designated crystalline form R L P of rosxastat characterized by a powder X-ray diffraction pattern having peaks at about 3.57, 7.15, 10.17, 10.74, 17.94 and 21.29 ± 0.22 Θ.

In one embodiment, the present invention provides crystalline form R L P of rosxastat characterized by PXRD substantially as shown in figure 5.

In a ninth embodiment of the invention, there is provided a process for preparing a co-crystal (crystalline form R L P) of rosixatas comprising:

a) milling or contacting the rosxastat with L-proline in solution with L-proline;

b) optionally, heating the mixture of step a);

c) the co-crystal of roxasistat (crystalline form R L P) was isolated.

The milling process includes dry or wet milling of rosalata with L-proline, in which process rosalata and L-proline are milled in a mortar, mill or mill to obtain co-crystals, in which process physical milling involving rosalata and co-crystals is milled in a mortar, mill or mill, in which process rosalata and L-proline are milled with a solvent or mixture of solvents followed by drying to obtain co-crystals.

The amount of solvent used for wet milling is in the range of up to about 10 weight percent (w/w) of the solid component. For example, weight percentages of less than or equal to about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1,2, 3, 4, 5, 6, 7, 8, and 9 may be used.

The co-crystals may be formed by contacting roxasistat with L-proline in solution the process comprises a) dissolving roxasistat and L-proline in a suitable solvent, b) cooling the solution, and c) isolating the co-crystals formed.

In the process according to the invention, contacting the rosxastat with L-proline involves solubilizing the rosxastat and adding L-proline, or solubilizing L-proline and adding the rosxastat thereto.

Suitable solvents that can be used to prepare the solution include, but are not limited to, water; alcohol solvents such as methanol, ethanol, isopropanol, and the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and the like; polar aprotic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, and the like; ethers including tetrahydrofuran, 1, 4-dioxane, and the like; halogenated hydrocarbons including dichloromethane, trichloromethane and the like.

The dissolution temperature may be about 20 to 120 ℃ depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution is obtained.

For separation to occur, the reaction mass may be further maintained at a temperature below the dissolution temperature (e.g., below about 10 ℃ to about 25 ℃) for a period of time necessary for the product to more completely separate. The exact cooling temperature and time required for complete crystallization can be readily determined by one skilled in the art and will also depend on parameters such as the concentration and temperature of the solution or slurry.

Optionally, separation may be initiated or enhanced by methods such as cooling, seeding, partial removal of solvent from solution, use of an anti-solvent, or a combination thereof.

The method of recovering the solid material from the final mixture, whether or not cooling below the operating temperature is required, may be any of a number of techniques such as filtration by gravity or by suction, decantation, centrifugation, and the like.

Optionally, the obtained product may be further dried. The drying may be carried out under reduced pressure. The drying may be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, agitated film dryer, spin flash dryer, or the like.

In a tenth embodiment of the invention, there is provided a process for preparing a co-crystal (crystalline form R L P) of rosixatas comprising:

a) providing/dissolving L-proline with a solution of roxarstat;

b) optionally, heating the solution of step a);

c) the co-crystal of roxasistat (crystalline form R L P) was isolated.

Suitable solvents that may be used in step a) include, but are not limited to: water; alcohol solvents such as methanol, ethanol, isopropanol, and the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and the like; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, and the like; aromatic hydrocarbon solvents such as toluene, xylene, chlorobenzene, tetralin, and the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or mixtures thereof.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation or any other suitable technique. The solution may be filtered by passing it through a filter paper, glass fiber or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to avoid premature crystallization.

The above steps may be carried out at a temperature of between about 20 ℃ and about 100 ℃, preferably between about 25 ℃ and about 50 ℃.

In an eleventh embodiment of the invention there is provided a process for the preparation of co-crystals of rosixastat (crystalline form R L P) comprising the step of crystallizing rosixastat and L-proline from a solvent or solvent mixture comprising water, methanol and acetone.

In one embodiment of the invention, an ORTEP plot of the roxasita L-proline (1: 1) co-crystal is provided as shown in fig. 6, displacement ellipsoids are drawn at the 50% probability level and the H atoms are shown as small spheres of arbitrary radius.

Troxastat L-proline co-crystal (crystalline form R L P):

eutectic of rosisastat and L-proline crystallizes from acetone, methanol and water in the monoclinic space group P21 the asymmetric unit consists of one molecule of rosisastat and one molecule of L-proline the eutectic involves O-H (carboxyl) O (carboxylate) hydrogen bonds between the carboxylic acid group of rosisastat and the carboxylate of proline.

Table 1 crystallization data and structural details of the roxasistat L-proline (1: 1) co-crystal:

TABLE 2 hydrogen bonding of the Rosesarta L-proline (1: 1) cocrystal (form-R L P):

the crystalline form R L P of rosisita L-proline co-crystal was found to be stable for three months under all three ICH conditions the following data demonstrate that form R L P has high storage stability.

Pack-1 (normal L DPE bag with 1g of silica gel packed in HDPE container):

pack-2 (black L DPE bag with 1g of silica gel packed in HDPE container):

in a twelfth embodiment of the invention, there is provided a co-crystal of roxarstat, comprising: rosxastat and niacinamide.

The term "eutectic", as used herein, means that a crystalline material comprises two or more distinct solids at room temperature, each solid containing different physical properties, such as structure, melting point, and heat of fusion. The co-crystal of the present invention comprises a co-crystal former (niacinamide) hydrogen bonded to the roxasistat.

The rasagilate feed may be in crystalline or amorphous form. The co-crystals herein may be anhydrous; it may also be present as a co-crystal hydrate or solvate thereof.

In a thirteenth embodiment of the invention, there is provided a co-crystal of rasagiline comprising rasagiline and niacinamide, designated as crystalline form RNM of rasagiline characterized by a powder X-ray diffraction pattern having peaks at about 6.24, 10.84, 18.86, 22.20, 23.37, 26.41 and 29.24 ± 0.22 Θ °.

In one embodiment, the present invention provides crystalline form RNM of rosxastat characterized by PXRD substantially as shown in figure 7.

In a fourteenth embodiment of the present invention, there is provided a process for preparing a co-crystal (crystalline form RNM) of roxarstat, comprising:

a) providing/dissolving a solution of niacinamide and roxaxetil;

b) optionally, heating the solution of step a);

c) the co-crystal (crystalline form RNM) of roxasistat was isolated.

Suitable solvents that may be used in step a) include, but are not limited to: water; alcohol solvents such as methanol, ethanol, isopropanol, and the like; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and the like; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, and the like; aromatic hydrocarbon solvents such as toluene, xylene, chlorobenzene, tetralin, and the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or mixtures thereof.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation or any other suitable technique. The solution may be filtered by passing it through a filter paper, glass fiber or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to avoid premature crystallization.

The above steps may be carried out at a temperature of between about 20 ℃ and about 100 ℃, preferably between about 25 ℃ and about 60 ℃.

If desired, the separation of step c) may be effected by any suitable separation method, for example precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping or by shaking the container, conventional separation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

The co-crystal of roxasistat nicotinamide (crystalline form RNM) was found to be stable for three months under all three ICH conditions. The following data demonstrate that form RNM has high storage stability.

Pack-1 (L DPE bag with 1g molecular sieve packed in HDPE container):

pack-2 (L DPE bag with 1g of silica gel packed in HDPE container):

in a fifteenth embodiment of the invention, there is provided a co-crystal of rasagiline comprising rasagiline and urea.

In a sixteenth embodiment of the invention there is provided a co-crystal of rasagiline comprising rasagiline and urea, designated as crystalline form RU of rasagiline, characterized by a powder X-ray diffraction pattern having peaks at 7.74, 14.79, 17.84, 18.39, 19.41, 20.89, 22.29, 23.22, 24.64 and 29.34 ± 0.22 Θ °.

In one embodiment, the present invention provides crystalline form RU of rosxastat characterized by PXRD substantially as shown in figure 8.

In a seventeenth embodiment of the present invention, there is provided a method of preparing a co-crystal (crystalline form RU) of rosixastat comprising:

a) providing/dissolving a solution of urea and rosmarinic acid;

b) optionally, heating the solution of step a);

c) the co-crystal (crystalline form RU) of rasagiline was isolated.

The solvent and reaction conditions of steps (a) to (c) may be selected from one or more suitable solvents and process conditions as described in the step of the fourteenth embodiment of the invention.

The drying in the embodiment of the present invention may be suitably performed by using any of an air tray dryer, a vacuum tray dryer, a fluidized bed dryer, a spin flash dryer, a flash dryer, and the like. Drying may be carried out at or above atmospheric pressure, or under reduced pressure, particularly at temperatures below about 80 ℃, and more particularly below about 60 ℃. Drying may be carried out for any period of time required to achieve the desired product quality, for example, from about 30 minutes to about 24 hours, or longer.

All PXRD data reported herein were obtained using a PANalytical X-ray diffractometer with copper K α radiation and a Bruker D8 advanced X-ray diffractometer.

The rasagiline used as starting material for the preparation of any solid form of the present application may be purified prior to use by applying any purification technique known in the art, such as recrystallization, pulping or chromatography, or according to the procedures described or exemplified in the present application. The starting material may be in a crystalline or amorphous state, or an alternative crystalline form to that of roxasistat known in the art.

In an eighteenth embodiment of the invention, there is provided a pharmaceutical composition comprising a crystalline form of rosxastat selected from the group consisting of form- γ, form-, form R L P, form RNM and form RU, or a mixture thereof, and at least one pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention may be formulated according to conventional methods, and may be prepared in the form of oral preparations such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions and the like, or in the form of preparations for parenteral injection such as intramuscular, intravenous or subcutaneous administration.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the present application in any way. Reasonable variations of the described procedure are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.