Field of the Invention
The specification discloses a crystalline Alpha-1 form of Mirabegron, has purity more than 99
% when measured by HPLC. In the further aspect of specification describes a process for the
preparation of a crystalline Alpha-1 form of Mirabegron, which holds the moisture content
more than 0.2% over the entire range of relative humidity from 5% to 95%.
Background of the invention
Mirabegron (formerly YM- 178) is an orally active β-3 adrenoceptor agonist developed by
Astellas pharma for the potential treatment of urinary frequency, urinary incontinence, or
urgency associated with overactive bladder.
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-
phenylethyl)amino]ethyl] acetanilide (henceforth "Mirabegron") and has the structural
formula I:
NH
O
S
N
NH2
NH
H OH
Formula-I
Mirabegron or a pharmaceutically acceptable salt thereof was first described in U.S. Patent No.
6,346,532 with its process for the preparation. The other process of Mirabegron is also
elaborated in several patents and applications, e.g. U.S. Patent No. 7,342,117;
WO2015/044965; CN103193730, CN 103232352 and IN 1433/MUM/2014.
U.S. Patent No. 7,342,117 discloses α-form crystal and β-form crystal of Mirabegron and their
process. The US ‘117 also discloses the α-form crystal of the invention has a moisture-holding
amount of not more than 0.2% over the entire range of relative humidity from 5% to 95% and
β-form crystal, an increase in the weight is observed from a relative humidity of about 20%,
and it holds moisture of about 3% and has weak hygroscopicity.
3
Various prior arts, for example, WO2014/132270, US 9,283,210, WO2015/044965A1
WO2015/040605A1, WO2016049749 discloses crystalline forms and amorphous of
Mirabegron and their process.
In view of above, there is an unmet need to develop stable crystalline form of Mirabegron. The
inventors of the present invention found stable crystalline alpha 1 form of mirabegron and its
process, which is simple, cost-effective and commercially viable.
Summary of the Invention
One embodiment of the present invention provides acrystalline Alpha-1 form of Mirabegron,
compound of formula I
NH
O
S
N
NH2
NH
H OH
Formula-I
which holds the moisture content of more than 0.2% and less than 3.0% over the entire range
of relative humidity from 5% to 95%.
Another embodiment of the present invention provides acrystalline Alpha-1 form of
Mirabegron, has the moisture content more than 0.5 % as measured by Karl Fischer titration
method.
Another embodiment of the present invention provides the conversion of crystalline Alpha-1
form of Mirabegron to another crystalline or amorphous form of Mirabegron.
Another embodiment of the present invention provides a process for the preparation of
crystalline Alpha-1 form of Mirabegron, compound of formula I
NH
O
S
N
NH2
NH
H OH
Formula-I
4
has purity more than 99 %, when measured by HPLC, the process includes the steps of
a) providing a solution of Mirabegron free base in 1-butanol or propan-2-ol at suitable
temperature;
b) adding anti-solvent to the reaction mixture of step (a) at suitable temperature;
c) refluxing the reaction mixture for the suitable period at suitable temperature;
d) cooling the reaction mixture at temperature of about 25 °C to 35°C.
Description of the Invention
One embodiment of the present invention provides acrystalline Alpha-1 form of Mirabegron,
compound of formula I
NH
O
S
N
NH2
NH
H OH
Formula-I
which holds the moisture more than 0.2% and less than 3% over the entire range of relative
humidity from 5% to 95%.
The moisture content measurement is carried out by the test method disclosed in US 7,342,117,
result show the crystalline Alpha-1 form of Mirabegron prepared according to present
invention is hygroscopic in nature and holds the moisture more than 0.2% over the entire range
of relative humidity from 5% to 95%.
One embodiment of the present invention provides acrystalline Alpha-1 form of Mirabegron,
has the moisture content more than 0.5 % w/w as measured by Karl Fischer titration method.
Another embodiment of the present invention provides the conversion of crystalline Alpha-1
form of Mirabegron to another crystalline or amorphous form of Mirabegron.
The crystalline Alpha-1 form of Mirabegron, whenstored at temperature 25°C for a period of
3 months did not show contamination of other polymorphic forms.
5
Another embodiment discloses a process for the preparation of crystalline Alpha-1 form of
Mirabegron, compound of formula I,
NH
O
S
N
NH2
NH
H OH
Formula-I
the process comprises the steps of
a) providing a solution of Mirabegron free base in1-butanol at suitable temperature;
b) adding anti-solvent to the reaction mixture of step (a) at suitable temperature;
c) refluxing the reaction mixture for the suitable period at suitable temperature; and
d) cooling the reaction mixture at temperature of about 25 °C to 35°C,
The process involves step a) providing a solution of Mirabegron free base to in 1-butanol at
suitable temperature. The quantity of 1-butanol used for dissolution depends on the temperature
opted for the process. The quantity of 1-butanol may range from 5 to 20 times per gram of
Mirabegron. The solution of Mirabegron obtained by the dissolution of Mirabegron in 1-
butanol or such a solution may be obtained directly from a reaction in which Mirabegron is
formed. Any polymorphic form may be used in the preparation of solution such as crystalline
or semi-crystalline forms, including solvates and hydrates. The dissolution temperature may
range from about 30 to about 100 ◦C or preferably, at about 50◦C to about 80◦C.
The obtained clear solution optionally treated with activated charcoal to enhance the color of
the compound and filtered through an inert medium such as Hyflo.
The quantity of anti-solvent that may be used frequently is from 5 to 30 or more times on the
weight of Mirabegron.
The prepared crystalline Alpha-1 form of Mirabegron free base has purity more than 99 %
when measured by HPLC and moisture content more than 0.5 % w/w as measured by Karl
Fischer titration method.
6
The suitable anti-solvent is selected from the group comprising one or more of toluene, n-hexane, benzene, heptane and the like. The hydrocarbon solvent also functions to remove non-polar impurities in the compound.
In an embodiment, the solution of step a) may be added to anti-solvent.
The suitable temperature for the addition of anti-solvent may be in the range of about 25 to 100 °C, or preferably at 70 to 80 °C.
The reaction mixture thus obtained may be maintained/refluxed at the 70-80 °C for a period of 10 minutes to 1 hour or more without affecting on the degradation of the product.
The reaction mixture may be allowed to cool to ambient temperature or below 25 °C and maintained for a period of 15 minutes to 2 hours or more to enhance the crystallization and quality of the product.
The solid may be isolated by conventional techniques such as filtering, centrifuging and the like, or by filtering under an inert atmosphere using gases such as for example nitrogen and the like. The wet cake may be dried at a temperature of about 30 to about 70 °C for any desired time period until the desired product purity and quality is obtained.
The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.
Example
Example-1: Preparation of crystalline Alpha-1 form of Mirabegron
To a mixed solution of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol mono- hydrochloride (10g), 2-aminothiazole-4-yl-acetic acid hydrochloride (6.6 g) and water (150 ml), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono-hydrochloride (EDC.HCl) (7.2 g) was added at temperature of about 25 °C to 35°C and the reaction mixture was stirred for 1
7
hour at temperature of about 25 °C to 35°C. After completion of the reaction, 20% aqueous sodium hydroxide solution (20 ml) was charged drop wise to the reaction mixture. The obtained suspension was stirred for 1-2 hours at RT, followed by filtration to get the Mirabegron. Dried the product at 40-50°C to get dried product (11.5 g). The product (1 g) obtained above was dissolved in n-butanol (12 ml) or propan-2-ol at 70-80°C. Toluene (24 ml) was charged to the clear solution at 70-80°C. The reaction mixture was allowed to cool to RT slowly. The obtained suspension was stirred at RT for ~1 hour and then filtered the suspension to get a titled compound as solid. The obtained solid was subjected to XRPD. Figure 1 shows the XRPD of Alpha-1 form of Mirabegron.
HPLC Purity:99.92%
Moisture content:<3 % w/w (Karl Fischer titration method)
Powder X-ray Diffraction (PXRD): The measurements were carried out with a Bruker powder X-ray diffractometer using Cu Ka radiation in the Bragg-Brentano reflection geometry. Generally, the 2Θ values are accurate within an error of ±0.1 -0.2°.
Figure 1 shows the XRPD of Alpha-1 form of Mirabegron.

We Claim:
1. A crystalline Alpha-1 form of Mirabegron compound of formula I
NH
O
S
N
NH2
NH
H OH
Formula-I
which holds the moisture content of more than 0.2% and less than 3.0% over the
entire range of relative humidity from 5% to 95%.
2. A crystalline Alpha-1 form of Mirabegron according to claim 1, holds the moisture
more than 0.2% over the entire range of relative humidity from 5% to 95%.
3. A crystalline Alpha-1 form of Mirabegron according to claim 1, has the moisture
content more than 0.5 % as measured by Karl Fischer titration method.
4. A process for the preparation of crystalline Alpha-1 form of Mirabegron, the process
comprises the steps of
a) providing a solution of Mirabegron free base in1-butanol or propan-2-ol at
suitable temperature;
b) adding anti-solvent to the reaction mixture of step (a) at suitable temperature;
c) refluxing the reaction mixture for the suitable period at suitable temperature;
and
d) cooling the reaction mixture at temperature of about 25 °C to 35°C.
e)
5. The process according to claim 4, wherein the anti-solvent is selected from the group
comprising one or more of toluene, n-hexane, benzene and heptane.
6. The process according to claim 4, wherein the suitable temperature period is about -
65°C to 80 °C.
7. The process according to claim 4, wherein the suitable time period is about 1 hour to 2
hours.
9
8. The process according to claim 4, wherein Mirabegron free base has purity more than 99 %, when measured by HPLC.
9. The process according to claim 4, wherein Mirabegron free base is further converted to hydrochloride salt thereof.