DESC: INTRODUCTION

Aspects of the present application relate to a crystalline form of Mirabegron monohydrochloride and a crystalline form of Mirabegron, and process for their preparation and use thereof in the pharmaceutical composition.
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide or 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide. Mirabegron is an orally active beta-3 adrenoceptor agonist and has the structure of Formula I.

Mirabegron is marketed as MYRBETRIQTM (Astellas Pharma Inc, USA), approved by the USFDA for the potential treatment of urinary frequency, urinary incontinence, or urgency associated with overactive bladder. U.S. Patent No. 6,346,532 B1 discloses mirabegron or a salt thereof and process for its preparation. In addition, it also discloses the pharmaceutical compositions and method of treating diabetes mellitus and obesity in a human or animal patient. U.S. Patent No. 7,342,117 B2 describes a-form crystal and ß-form crystal of mirabegron and their process for preparation.

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubilities. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.

The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

There always remains a need to provide the new polymorphic forms of mirabegron which can be used in the pharmaceutical composition.

SUMMARY OF THE INVENTION

In one embodiment, the application provides a crystalline form of Mirabegron monohydrochloride, herein defined as Form R, characterized by a PXRD pattern having three x-ray powder diffraction peaks selected from the following: about 6.6°, 8.8° and 17.6°± 0.2° 2?. The crystalline Form R may be further characterized by x-ray powder diffraction peaks at about 16.6°, 18.6°, 19.8°, 21.1° and 22.9°± 0.2° 2?.

In another embodiment, the application provides a crystalline form of Mirabegron, herein defined as Form S, characterized by a PXRD pattern having x-ray powder diffraction peaks selected from the following: about 9.16°, 10.43°, 12.26°, and 12.66°± 0.2° 2?. The crystalline form S of Mirabegron may be further characterized by a PXRD pattern having x-ray powder diffraction peaks at about 16.85°, 18.43°, 19.57°, 20.42° and 22.78° ± 0.2° 2?.
In another embodiment, the present application provides a process for the preparation of crystalline form R of Mirabegron monohydrochloride, characterized by a PXRD pattern having peaks at about 6.6°, 8.8° and 17.6°± 0.2° 2?; embodiments comprising,

a) providing a solution of Mirabegron monohydrochloride in the mixture of 1-propanol and water;

b) cooling the solution obtained in step (a); and

c) isolating the crystalline form R of Mirabegron monohydrochloride.

In another embodiment, the present application provides a process for the preparation of crystalline form S of Mirabegron, characterized by a PXRD pattern having peaks at about 9.16°, 10.43°, 12.26° and 12.66°± 0.2° 2?; embodiments comprising,

a) providing a solution of Mirabegron in the mixture of methanol and 1-propanol;

b) adding isopropyl acetate to the solution obtained in step (a): and

c) isolating the crystalline form S of Mirabegron.
In another embodiment, the present application also provides pharmaceutical compositions comprising the crystalline form R of Mirabegron monohydrochloride or Form S of Mirabegron as described in the present application and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates an X-ray powder diffraction pattern of crystalline Form R of Mirabegron monohydrochloride obtained according to the procedure of example-1.

Fig. 2 illustrates an X-ray powder diffraction pattern of crystalline Form S of Mirabegron obtained according to the procedure of example-3.

DETAILED DESCRIPTION OF THE INVENTION

The present application provides a crystalline form R of Mirabegron monohydrochloride and a crystalline form S of Mirabegron and process for preparing them and also provides pharmaceutical compositions comprising the crystalline form of Mirabegron monohydrochloride and Mirabegron as described herein and a pharmaceutically acceptable carrier.

In one embodiment, the application provides a crystalline form of Mirabegron monohydrochloride, herein defined as Form R, characterized by a PXRD pattern having three x-ray powder diffraction peaks selected from the following: about 6.6°, 8.8° and 17.6°± 0.2° 2?. The crystalline form may be further characterized by x-ray powder diffraction peaks at about 16.6°, 18.6°, 19.8°, 21.1° and 22.9°± 0.2° 2?. Alternatively, the crystalline form of Mirabegron monohydrochloride may have x-ray powder diffraction peaks at about 6.6°, 8.8° and 17.6°± 0.2° 2?, in which case, the crystalline form of Mirabegron monohydrochloride may be further characterized by x-ray powder diffraction peaks at about 16.6°, 18.6°, 19.8°, 21.1° and 22.9°± 0.2° 2?. In embodiments, the crystalline form may contain water up to 6% (w/w) measured by Karl Fischer titration. XRD pattern of crystalline form R of Mirabegron monohydrochloride is substantially depicted in FIG.1.

In another embodiment, the present application provides a process for the preparation of crystalline Form R of Mirabegron monohydrochloride, characterized by a PXRD pattern having peaks at about 6.6°, 8.8° and 17.6°± 0.2° 2?; embodiments comprising,

a) providing a solution of Mirabegron monohydrochloride in the mixture of 1-propanol and water;

b) cooling the solution obtained in step (a): and

c) isolating the crystalline form R of Mirabegron monohydrochloride.

In embodiments, Mirabegron monohydrochloride can be dissolved in the mixture of 1-propanol and water to provide a solution. In embodiments, the solution can be obtained by first dissolving Mirabegron monohydrochloride in 1-propanol and then water is added. In embodiments, the premix of 1-propanol and water can also be used for preparing the solution of Mirabegron monohydrochloride. In embodiments, the ratio of 1-propanol to water used for making the solution can be from about 1:10 or 10:1.

In embodiments, a solution of Mirabegron monohydrochloride can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature of the solvent used. Mixing may be used to reduce the time required for the dissolution process. Mirabegron monohydrochloride solution can also be obtained from reaction mixtures of the previous stage during the synthesis of Mirabegron. In embodiments, a solution of
Mirabegron monohydrochloride may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In an embodiment, the precipitation of Mirabegron monohydrochloride form R can be obtained by cooling the solution obtained in step a). In embodiments, the solution obtained in step a) can be cooled to room temperature to -10°C preferably about 15°C to 0°C. In embodiments, the slurry comprising precipitated mirabegron monohydrochloride can be maintained at any suitable temperatures, such as from about room temperature to about 0°C. In general, yields of the crystalline product will be improved by maintaining the reaction mass at lower temperatures that are above the freezing point of the solvents and/or by increasing the solute content of the solution. In embodiments, the slurry comprising precipitated mirabegron monohydrochloride can be maintained for about 10 minutes to about 10 hours, or longer.

In embodiments, optionally the desired seed material can also be used for the preparation of the crystalline form R of Mirabegron monohydrochloride. In embodiments, the seed material can be crystalline Form R of Mirabegron monohydrochloride.

In embodiments, crystalline Form R of Mirabegron monohydrochloride can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline form R of Mirabegron monohydrochloride can be isolated by filtration.

In embodiments, crystalline form R of Mirabegron monohydrochloride that is isolated can be dried at suitable temperatures such as room temperature to about 80°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.

Fig. 1 provides the PXRD pattern of crystalline form R of Mirabegron monohydrochloride obtained by the process of the present application.

In one embodiment, the application provides a crystalline form of Mirabegron, herein defined as Form S, characterized by a PXRD pattern having x-ray powder diffraction peaks selected from the following: about 9.16°, 10.43°, 12.26°, and 12.66°± 0.2° 2?. The crystalline form of Mirabegron may be further characterized by a PXRD pattern having x-ray powder diffraction peaks at about 16.85°, 18.43°, 19.57°, 20.42° and 22.78° ± 0.2° 2?.

Alternatively, the crystalline form of Mirabegron may have x-ray powder diffraction peaks at about 9.16°, 10.43°, 12.26°, and 12.66°± 0.2° 2?, in which case, the crystalline form of Mirabegron may be further characterized by x-ray powder diffraction peaks at about 16.85°, 18.43°, 19.57°, 20.42° and 22.78° ± 0.2° 2?. XRD pattern of crystalline form S is substantially depicted in FIG.3. This crystalline form may be considered an isopropyl acetate solvate of Mirabegron. The isopropyl acetate solvate of Mirabegron may have about 5 percent to 30 percent isopropyl acetate, preferably about 10 percent to 20 percent isopropyl acetate.

In another embodiment, the present application provides a process for the preparation of crystalline form S of Mirabegron, characterized by a PXRD pattern having peaks at about 9.16°, 10.43°, 12.26° and 12.66° ± 0.2° 2?; embodiments comprising,

a) providing a solution of Mirabegron in the mixture of methanol and 1-propanol;

b) adding isopropyl acetate to the solution obtained in step (a): and

c) isolating the crystalline form S of Mirabegron.

In embodiments, Mirabegron can be dissolved in the mixture of methanol and 1-propanol to provide a solution. In embodiments, the Mirabegron solution can be obtained by first dissolving Mirabegron in methanol and then 1-propanol is added. In embodiments, the premix of methanol and 1-propanol can also be used for preparing the solution of Mirabegron.

In embodiments, a solution of Mirabegron can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature of the solvent used. Mixing may be used to reduce the time required for the dissolution process. Mirabegron solution can also be obtained from reaction mixtures of the previous stage during the synthesis of Mirabegron. In embodiments, a solution of Mirabegron may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In embodiments, isopropyl acetate is added to the solution obtained in step a) to precipitate the product at a temperature from about room temperature to -10°C preferably about 15°C to 0°C. In embodiments, isopropyl acetate may be added to the solution obtained in step a) drop wise or in one lot or in many lots. In embodiments, isopropyl acetate may be added in one lot.

In an embodiment, the precipitation of crystalline form S of Mirabegron can be obtained during the addition of isopropyl acetate to the solution obtained in step a). In an embodiment, the precipitation of Mirabegron can be obtained by cooling the solution or suspension obtained in step b). In embodiments, the solution or suspension obtained in step b) can be cooled to room temperature to 0°C. In embodiments, the slurry comprising precipitated mirabegron can be maintained at any suitable temperatures, such as from about room temperature to about 0°C. In general, yields of the crystalline product will be improved by maintaining the reaction mass at lower temperatures that are above the freezing point of the solvent or anti-solvent, and/or by increasing the solute content of the solution. In embodiments, the slurry comprising precipitated mirabegron can be maintained for about 10 minutes to about 10 hours, or longer.

In embodiments, crystalline form S of Mirabegron can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline form S of Mirabegron can be isolated by filtration.

In embodiments, crystalline form S of Mirabegron that is isolated can be dried at suitable temperatures such as room temperature to about 80°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.

Fig. 2 provides the PXRD pattern of crystalline form S of Mirabegron obtained by the process of the present application as described herein.

In embodiments, crystalline Mirabegron or Mirabegron hydrochloride obtained by a method of the present disclosure having a chemical purity greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC). In embodiments, the process described in this application can also be useful to enhance the chemical purity of the Mirabegron.

The crystalline form R of Mirabegron monohydrochloride or form S of Mirabegron according to the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.

In embodiments, Mirabegron hydrochloride or Mirabegron which is used as the starting material for the preparation of crystalline forms can be prepared by any method, including methods known in the art. In embodiments, Mirabegron hydrochloride or Mirabegron which is used as the starting material can be in any known or unknown crystalline form, anhydrous form, hydrated form, solvate or amorphous form.

X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.6°" means "having a diffraction peak at a diffraction angle (2?) of 6.4° to 6.8°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks can vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors can slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).

An aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of crystalline form R of Mirabegron monohydrochloride or form S of Mirabegron described herein in the present application, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions comprising crystalline form R of Mirabegron monohydrochloride or form S of Mirabegron together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization.

Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS

As used throughout herein, the term room temperature refers to a temperature of from about 18°C to about 28°C., preferably about 20°C to about 25°C.

A “decolorizing agent” removes colored impurities by adsorption on the surface of the “decolorizing agent” particles. Examples of a “decolorizing agent” include, decolorizing carbon, activated alumina, activated clay, or silica gel.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Examples

Example-1: Preparation of crystalline Form R of Mirabegron monohydrochloride:
Mirabegron monohydrochloride (2 g), 1-propanol (8 mL) and water (12 mL) were charged in to a round bottom flask at 28°C. The obtained suspension was stirred and heated to 43°C to get a clear solution. The solution was cooled to 8°C in 45 minutes and maintained for 2 hours at the same temperature. The precipitated solid was collected by filtration and washed with 1-propanol (2 mL) and dried under suction for 10 minutes. The product was further dried under vacuum at 55°C for 4 hours. Yield: 1.1g; HPLC purity: 99.57%. Water content: 4.34%. The PXRD pattern of the obtained product was same as shown in Fig. 1.

Example-2: Preparation of crystalline Form R of Mirabegron monohydrochloride:
Mirabegron monohydrochloride (2 g) and 1-propanol (20 mL) were charged in to a round bottom flask at 28°C. The obtained suspension was stirred and heated to 75°C to get a clear solution. Water (5 mL) was added to the obtained clear solution at 75°C and maintained for 10 minutes at the same temperature. The clear solution was allowed to cool to 35°C in about 30 minutes and further cooled to 7°C and maintained for 2 hours. The precipitated solid was collected by filtration and washed with 1-propanol (4 mL) and dried under suction for 10 minutes. The product was further dried under vacuum at 55°C for 6 hours. HPLC purity: 99.50%. The PXRD pattern of the obtained product was same as shown in Fig. 1.

Example-3: Preparation of crystalline Form S of Mirabegron

Mirabegron (1 g), methanol (10 mL) and 1-propanol (30 mL) were charged into a round bottom flask at 25°C and stirred to get clear solution. Isopropyl acetate (120 mL) was added to the clear solution and stirred for 2 hours at 25°C. The precipitated solid was collected by filtration and dried at 55°C for 1 hour. The PXRD pattern of the obtained product was same as shown in Fig. 2.

Example-4 Preparation of Mirabegron monohydrochloride

Mirabegron (5 g), methanol (50 mL) were charged into a round bottom flask at 26°C and stirred to get clear solution. The solution was cooled to 15°C and concentrated hydrochloric acid (1.3 mL) was added drop wise to the solution. The solution was stirred for 25°C. The solvent was evaporated from the solution on rotavapour to obtain the solid compound which was slurried in methanol (25 mL) at 28°C. The solid was obtained by filtration and dried under vacuum at 50°C to obtain the title compound. Hydrochloric acid content: 9.55% (w/w).

CLAIMS:

We Claim:

1. A crystalline Form R of Mirabegron monohydrochloride, characterized by a PXRD pattern having peaks at about 6.6°, 8.8° and 17.6°± 0.2°2?.

2. The crystalline Form R of Mirabegron monohydrochloride as claimed in claim 1, further characterized by a PXRD pattern having peaks at about 16.6°, 18.6°, 19.8°, 21.1° and 22.9°± 0.2°2?.

3. The crystalline Form R of Mirabegron monohydrochloride as claimed in claims 1 and 2, characterized in that it provides PXRD pattern substantially in accordance with Fig.1.

4. A process for preparation of crystalline Form R of Mirabegron monohydrochloride as claimed in claims 1 to 3 comprising:

a) providing a solution of Mirabegron monohydrochloride in the mixture of 1-propanol and water;

b) cooling the solution obtained in step (a); and

c) isolating the crystalline form R of Mirabegron monohydrochloride.

5. A crystalline Form S of Mirabegron, characterized by a PXRD pattern having peaks at about 9.16°, 10.43°, 12.26°, and 12.66°± 0.2°2?.

6. The crystalline Form S of Mirabegron as claimed in claim 5, further characterized by a PXRD pattern having peaks at about 16.85°, 18.43°, 19.57°, 20.42° and 22.78° ± 0.2° 2?.

7. The crystalline Form S of Mirabegron as claimed in claims 5 and 6, is an isopropylacetate solvate.

8. The crystalline Form S of Mirabegron as claimed in claims 5 to 7, characterized in that it provides PXRD
pattern substantially in accordance with Fig.2.

9. A process for preparation of crystalline Form S of Mirabegron as claimed in claims 5 to 8 comprising;

a) providing a solution of Mirabegron in the mixture of methanol and 1-propanol;

b) adding isopropyl acetate to the solution obtained in step (a); and

c) isolating the crystalline form S of Mirabegron.

10. A pharmaceutical composition comprising the crystalline form R of Mirabegron monohydrochloride as claimed in claims 1 to 4 or crystalline Form S of Mirabegron as claimed in claims 5 to 9 and one or more pharmaceutically acceptable carrier.