Field of Invention :
The present invention relates to a novel crystalline Mirabegron which is a solvate of pentan-3-one. The present invention also provides a process for its preparation.
Background of the Invention :
Mirabegron is a beta-3-adrenergic agonist useful in the treatment of overactive urinary bladder with symptoms of urinary incontinence, urgency and frequency. It was developed by Astellas Pharma and is approved in USA and Europe in 2012. Mirabegron is chemically, (R)-2-(2-aminothiazol-4-yI)-4'-[2-[(2-hydroxy-2-phenylethyl) amino] ethyl]-acetanilide, represented by Formula I.
Mirabegron as its dihydrochloride salt was first disclosed in the in US. 6,346,532. However, the dihydrochloride salt was found to be strongly hygroscopic and unstable limiting its use as medicine. Later, two crystalline forms were disclosed in US.7,342,117 B2, referred to as a- form crystal and P-form crystal. Both of these two crystals are of free base and are distinguished from each other by powder X-ray diffraction spectrum and DSC analysis. The P-form crystal has about 3% moisture content and has been used to prepare a- form crystal. The marketed formulation of Mirabegron contains a- form crystal. However, the a- form crystal has very low solubility in water. It is sparingly soluble in solutions at pH 1.0 to 7.0. An amorphous form of Mirabegron is reported in US. 9,283,210 B2, which also describes solid dispersion of amorphous Mirabegron together with one or more pharmaceutical^ acceptable carriers such as povidone.
Despite the existence of various polymorphs of Mirabegron, there remains a need for a new polymorphic form with an improved solubility.

Summary of the Invention :
The present invention describes a novel crystalline form of Mirabegron which is a 1:1 solvate of pentan-3-one having the structure as shown in Formula II.
The new crystalline form exhibits higher solubility, compared to the marketed a-form in water. It also shows higher solubility at pH 1.2 which is the pH of the simulated gastric fluid and at pH 6.8 which is the pH of the simulated intestinal fluid pH.
Brief Description of the Figure :
Figure 1: Infra-Red Spectrum of Mirabegron pentan-3-one solvate of Formula II.
Figure 2: X-ray Powder Diffraction (XRPD) pattern of Mirabegron pentan-3-one solvate of Formula II.
Figure 3: Differential Scanning Calorimetry (DSC) thermogram of Mirabegron pentan-3-one solvate of Formula II.
Detailed Description of the Invention :
The present invention describes a novel crystalline Mirabegron which is a solvate of pentan-3-one in 1:1 ratio having the Formula II. The preparation of Mirabegron pentan-3-one solvate of Formula II comprises suspending Mirabegron in pentan-3-one and heating the suspension to about 90 °C,

to obtain a clear solution. Subsequently, the clear solution is cooled to room temperature resulting in crystalline Mirabegron pentan-3-one solvate.
The solvate can also be prepared by stirring Mirabegron with pentan-3-one at room temperature. The solid Mirabegron will first becomes a gummy material and on continuous stirring turns into crystalline Mirabegron pentan-3-one solvate. The isolation of the Mirabegron pentan-3-one solvate may involve further washing the solvate with other solvent to remove the traces of pentan-3-one followed by drying. The drying may be accomplished by any suitable methods such as drying under reduced or normal pressure at a temperature between 20 to 40°C for about 30 minutes to 5 hours.
The starting material, Mirabegron can be prepared according to the process described in Patents US. 6,346,532 or US 7,342,117.
The IR spectrum of crystalline Mirabegron pentan-3-one solvate shows signals for both Mirabegron and pentan-3-one (Figure 1). In addition to the amide carbonyl peak of Mirabegron at about 1687 cm"1, another carbonyl peak at about 1712 cm"1 for pentan-3-one is observed (Figure 1)..Other characteristic infra-red peaks observed are: 3311, 3274, 3124, 2974, 2935, 1712, 1687, 1610, 1546, 1515, 1460, 1413, 1329, 1297, 1261, 1207, 1117, 1090, 1070, 1058, 1025,978,949, '826, 752, 703 and 649 (± 2) cm"1.
The Proton NMR of Mirabegron pentan-3-one solvate also shows signals for both Mirabegron and pentan-3-one. The methylene signals of Mirabegron appears at 2.59 to 2.79 ppm whereas the methyl groups of 3-Pentanone appears at 0.83-1.01 ppm. The integration values for protons show that Mirabegron and pentan-3-one are in 1:1 ratio in the solvate.
The Thermogravimetric Analysis (TGA) showed a relative weight loss of about 18% at a temperature range of about 150°C, which accounts for about 1:1 ratio between Mirabegron and pentan-3-one in the solvate.
The HPLC analysis of the solvate further confirms that it is a mono solvate.

The crystalline Mirabegron pentan-3-one obtained shows the following X-ray powder diffraction pattern expressed in terms of d-spacing, 29 value and relative intensity are summarized in Table

The peaks at 20 values at 10.06, 16.99, 18.71,19.46, 19.81, 20.22, 22.61 and 22.92 (± 0.2) degrees are characteristic of this polymorph. The X-ray powder diffraction diagram of the crystalline Mirabegron pentan-3-one solvate is given in Figure 2.
The crystalline Mirabegron pentan-3-one is further characterised by Differential Scanning Calorimetry (DSC). The DSC thermogram shows a minor broad endotherm between 85° to 103°C, with a peak at 98.37°C, and a main endotherm at 108°C to 118°C, with a peak at 114.44°C due to melting of the sample. The DSC thermogram of the crystalline Mirabegron pentan-3-one solvate is given in Figure 3.
One of the most important aspects of the invention is the good aqueous solubility of the crystalline Mirabegron pentan-3-one solvate at physiological conditions.

Table 2: The aqueous Solubility of Mirabegron pentan-3-one solvate and the a-form crystal of Mirabegron
The solubility of Mirabegron.pentan-3-one solvate in water is about 18.4 mg/mL compared to the poor solubility of about 0.41 mg/mL exhibited by the a-form crystal which is the marketed form. Similarly, at pH 1.2 which is the pH of the simulated gastric fluid, the pentan-3-one solvate shows very high solubility, about 55 mg/mL compared to 19 mg/mL for a-form crystal. Higher solubility at acidic pH is mainly due to the basic nature of Mirabegron which can undergo ionization to form salt. At pH 6.8 which is the pH of the simulated intestinal fluid, the solubility of the pentan-3-one solubility is about 32 mg/mL and that of a-form crystal is about 4.3 mg/mL. The corresponding values at pH 4.5 are about 32.2 mg/mL for pentan-3-one solvate and 11.33 mg/mL for the a-form crystal.
Mirabegron pentan-3-one solvate is also soluble in methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl formamide, and dimethyl sulfoxide and partially soluble in acetonitrile. It shows poor solubility in ethyl acetate, 2-methyl tetrahydrofuran, dichloromethane, chloroform, methyl terf-butyl ether, toluene, and n-hexane.
The daily dose of Mirabegron is about 25 mg. As a Mirabegron pentan-3-one solvate, 25 mg Mirabegron is associated with about 5.4 mg of pentan-3-one. The acute oral toxicity (LD50) of pentan-3-one is about 2140 mg/kg in rat. Thus the daily dose of 5.4 mg of pentari-3-one is about 396 times less than its LD50 value. Also, it is not listed as carcinogen by ACG1H, IARC, or NTP. Furthermore, pentan-3-one is a natural product present in many plants. For example, it is present in the fruits such as Kiwi (JAgric Food Chem. 1989, 37: 1023-25) and nactarines (JAgric Food

Chem. 1988, 36: 553-60.). Thus pentan-3-one is safe at the dose at which it will be consumed as solvate of Mirabegron.
The embodiments of the present invention are illustrated in the following examples.
EXAMPLES:
The measurement of the X-ray powder diffraction (XRPD) was carried out using a PANalytical® X'pert PRO with X'celerator as the detector under the following conditions: Tube: Cu, tube current: 40 mA, tube voltage: 45 kV, Scan mode: Continues scan; Scan axis: Gonio; step size: 0.017 deg, Time/step: 10.16 S; wavelength: 1.540 A, measurement diffraction angle range (29): 2.5 to 50°.
The DSC was recorded using a Mettler Toledo DSC 3, from 25° C to 250° C. (10° C/min), N2 (20 mL/min), aluminum made sample pan.
The TGA was recorded using a Perkin-Elmer, from 30° C to 250° C. (10° C/min), N2 (20 mL/min), aluminum-made sample pan.
Nuclear magnetic resonance (NMR) spectra were recorded using Bruker® 300 MHz, and tetramethylsilane (TMS) was used as an internal standard.
Infrared (IR) spectrum was recorded on Perkin Elmer Spectrum One, Software: Spectrum VJ 0.1, Scan begin: 450 cm1, Scan end: 4000 cm1, Resolution: 4.00 cm-1.
HPLC: Cosmicsil Agate RPC18 (250x4.6 mm, 5 |im), Elution: Gradient, Flow rate: 1.0 mL/min, Column temperature: 45°C, Injection volume: 5 jal, Run Time: 45 min, X: 210 nm, Mobile Phase A: Buffer : MeOH (70: 30 v/v), Mobile Phase B: Buffer : Acetonitrile (30: 70 v/v), Buffer is prepared by mixing di potassium hydrogen phosphate and sodium salt of 1-octane sulfonic acid.

Example 1: Preparation of mirabegron pentan-3-one solvate
Method A:
A suspension of Mirabegron (5.0 g) in pentan-3-one (50 mL) was heated to about 90°C to yield a clear solution. The clear solution was stirred for another 30 minutes at this temperature. Subsequently, the solution was cooled to about 25°C and stirred for 3 hours. The resulting suspension was filtered and the solid was stirred in n-hexane (50 mL) for 30 minutes to remove any traces of pentan-3-one. After filtration, the solid was washed with n-hexane (10 mL) and dried under vacuum at 25 to 30 °C for 3 hours to yield Mirabegron pentan-3-one solvate, 5.60 g (92.1 %).
Method B:
Mirabegron (1.0 g) was suspended in pentan-3-one (10 mL) and stirred at about 25 °C for 4 to 5 hours. The initial suspension first turns gummy and later Mirabegron pentan-3-one solvate crystallizes out. The obtained solid was filtered and suspended in n-hexane (10 mL). After filtration, the solid was washed with n-hexane (5 mL) and dried under vacuum at 25 to 30 °C for 3 hours to yield Mirabegron pentan-3-one solvate, 1.10 g (90.4 %).
FT-IR(KBr): v max 3311,3274,3124,2974,2935, 1712, 1687, 1610, 1546, 1515, 1460, 1413, 1329, 1297, 1261, 1207, 1117, 1090, 1070, 1058, 1025, 978, 949, 826, 752, 703 and 649 (±2) cm"1.
'HNMR(DMSO-