DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“A PREPARATION AND PURIFICATION OF CRYSTALLINE SITAGLIPTIN PHOSPHATE MONOHYDRATE”

HIKAL LIMITED, AN INDIAN COMPANY OF 3A & 3B, INTERNATIONAL BIOTECH PARK, HINJEWADI, PUNE – 411057, MAHARASHTRA, INDIA

The following specification describes the invention and manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation and/or purification of crystalline Sitagliptin phosphate monohydrate of formula (I). The invention further relates to preparation of crystalline Sitagliptin phosphate monohydrate of formula (I) by slurry technique, with good quality and yield, and without recrystallization.

BACKGROUND OF THE INVENTION
Sitagliptin is chemically known as (R)-3-amino-1-[3-(trifluoromethyl)-5,6,dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one and useful as a potent second-generation inhibitor of dipeptidyl-peptidase (DPP) IV inhibitors for the treatment of Type-2 diabetes. It is marketed under the brand name JANUVIA which contains sitagliptin phosphate monohydrate.

Sitagliptin was first disclosed in US Patent 6,699,871 B2 and can be synthesized by different synthetic approaches. The International (PCT) publication no. WO 2003/004498 (henceforth '498) discloses the first synthesis of sitagliptin and its pharmaceutically acceptable salts. WO 2005072530 discloses various salts of Sitagliptin such as phosphate and hydrochloride salts.

The Sitagliptin free base have high solubility due to which its isolation provides lower chemical yield, thus it is advisable to convert directly into suitable salt forms including phosphate salt, hydrochloride salt etc., However, meeting the purity is also a challenge, therefore it is said that the salts undergo further purification(s).

The US patent 7,326,708 B2 disclose the preparation of crystalline sitagliptin phosphate monohydrate by heating a mixture of sitagliptin free base with phosphoric acid using isopropanol and water, seeding with monohydrate, cooling at 4°C to 21°C and further held the mixture for overnight to obtain monohydrate salt.

The prior art disclosed the preparation of crystalline Sitagliptin phosphate monohydrate where the volume ratio of solvent is not defined. The volume ratio plays a critical role which avoids the formation of a solvate form and subsequent anhydrate form on drying. Thus, there is a need for a definite volume ratio in monohydrate preparation.

Although several processes have been reported for the preparation of crystalline sitagliptin phosphate monohydrate, they suffer from one or more drawbacks such as: i) involving tedious purification or recrystallization process; ii) use of multiple solvents; iii) use of high volume of solvent; iv) result of undesired solvate form; v) not meeting regulatory standard purity; vi) lower yield; vii) involving more unit operations and long cycle time; thus, the process does not render economical.

To overcome the limitation of prior art processes, the inventors of the present invention have developed a slurry technique with a unique volume ratio of alcoholic solvent and water for the preparation of crystalline Sitagliptin phosphate monohydrate which avoids the formation of a solvate form and subsequent anhydrate form.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a preparation of crystalline Sitagliptin phosphate monohydrate of formula (I) from Sitagliptin phosphate anhydrate by slurry technique.

In another aspect, the present invention relates to a process for the preparation of crystalline Sitagliptin phosphate monohydrate from Sitagliptin phosphate anhydrate comprising the steps of:
a) adding Sitagliptin phosphate anhydrate in a suitable volume ratio of alcoholic solvent and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.

In another aspect, the present invention relates to a preparation of crystalline Sitagliptin phosphate monohydrate from Sitagliptin phosphate anhydrate comprising the steps of:
a) adding Sitagliptin phosphate anhydrate in a suitable volume ratio of isopropyl alcohol and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.

In another aspect, the present invention relates to a process for purification of crystalline Sitagliptin phosphate monohydrate comprising the steps of:
a) adding crystalline Sitagliptin phosphate monohydrate in a suitable volume ratio of alcoholic solvent and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.
In another aspect, the present invention relates to a process for the purification of crystalline Sitagliptin phosphate monohydrate comprising the steps of:
a) adding crystalline Sitagliptin phosphate monohydrate in a suitable volume ratio of isopropyl alcohol and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffractogram of the crystalline Sitagliptin phosphate monohydrate of formula (I) prepared as per Example 1.
FIG. 2 shows an X-ray powder diffractogram of the crystalline Sitagliptin phosphate monohydrate prepared as per Example 2.
FIG. 3 shows an X-ray powder diffractogram of the mixture of crystalline Sitagliptin phosphate monohydrate and Sitagliptin phosphate anhydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described in more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

Sitagliptin phosphate anhydrate used for the preparation of crystalline Sitagliptin phosphate monohydrate corresponds to Sitagliptin phosphate anhydrate which may contain up to 50% by weight of crystalline Sitagliptin phosphate monohydrate.

Crystalline Sitagliptin phosphate monohydrate used for the purification corresponds to crystalline Sitagliptin phosphate monohydrate which may contain up to 50% by weight of Sitagliptin phosphate anhydrate.

In another embodiment of the present invention, wherein alcoholic solvent is selected methanol, ethanol, isopropanol, isobutanol, n-butanol and the like; more preferably isopropanol.

In another embodiment of the present invention, wherein water used in process is industrial water, distilled water, or demineralized water (DM water).

In another embodiment of the present invention, wherein a suitable volume ratio of alcoholic solvent and water is selected from volume ratio varying from 65:35 to 75:25 respectively, preferably 72:28.

In another embodiment of the present invention, the total volume of alcoholic solvent and water is 3 to 7 volumes per mole equivalent of crystalline Sitagliptin phosphate monohydrate or Sitagliptin phosphate anhydrate.

In another embodiment of the present invention, addition of crystalline Sitagliptin phosphate monohydrate or Sitagliptin phosphate anhydrate is performed at 20°C to 45°C.

In another embodiment of the present invention, the temperature is maintained at 20°C to 45°C for 4 to 8 hours under stirring to allow the formation of Crystalline Sitagliptin phosphate monohydrate.

In another embodiment of the present invention, a seeding is performed using seed crystal of crystalline Sitagliptin phosphate monohydrate at 20°C to 45°C under stirring.

In another embodiment of the present invention, wherein isolation of crystalline Sitagliptin phosphate monohydrate is performed using normal isolation techniques such as filtration, washing, and drying.

In another embodiment of the present invention, wherein isolation of crystalline Sitagliptin phosphate monohydrate is performed at 25°C to 45°C.

In another embodiment of the present invention, wherein drying is performed under vacuum at 40°C to 60°C for 4 to 6 hours.

In an embodiment, crystalline Sitagliptin phosphate monohydrate is obtained by the process of the present invention has purity greater than 99.5%, more preferably greater than 99.9% by HPLC.

In an embodiment, crystalline Sitagliptin phosphate monohydrate obtained by the process of the present invention has X-ray powder diffractogram as depicted in FIG. 1 and FIG. 2.

In an embodiment, in the preparation of crystalline Sitagliptin phosphate monohydrate, the Sitagliptin phosphate anhydrate used contains up to 50% by weight of crystalline Sitagliptin phosphate monohydrate and has X-ray powder diffractogram as depicted in FIG. 3.

In another embodiment of the present invention, the crystalline Sitagliptin phosphate monohydrates of formula (I) is characterized by powder X-ray diffraction pattern and recorded on Bruker D8 advance diffractometer using Cu-Ka X-radiation (? = 1.5406 Å) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 2? range 2° to 40° with time per step 0.5(s).

In another embodiment of the present invention, the crystalline Sitagliptin phosphate monohydrate is having an X-ray diffraction pattern that comprises characteristic peaks at 4.7, 9.3, 10.6, 10.9, 11.8, 13.3, 13.9, 15.0, 16.1, 16.9, 17.2, 18.0, 18.5, 18.8, 19.2, 19.7, 20.0, 20.3, 20.9, 21.3, 21.8, 22.4, 23.8, 24.1, 24.5, 25.1, 25.6, 25.8, 26.7, 27.3, 27.9, 28.4, 29.6, 31.1, 32.1, 34.1, 37.5 degrees 2?±0.05 degrees 2?. The X-ray diffraction pattern is shown in FIG. 1; and FIG. 2

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1: Preparation of Crystalline Sitagliptin phosphate monohydrate using Sitagliptin phosphate anhydrate.
To a solution of isopropyl alcohol (3.6 to 4.1 V) and water (1.9 to 1.4 V), a Sitagliptin phosphate anhydrate (1.0 eq) was added at 20°C to 45°C and stirred for 10 minutes. The slurry was maintained at 20°C to 45°C for 4 to 8 hrs under stirring. The slurry was filtered, washed with prechilled mixture of isopropyl alcohol and water, dried under vacuum at 40°C to 60°C for 4-6 hours to obtain crystalline Sitagliptin phosphate monohydrate with X-ray powder diffractogram matching with FIG. 1.
(Yield: 85%, HPLC purity: 99.8%).

Example 2: Purification of Crystalline Sitagliptin phosphate monohydrate.
To a solution of isopropyl alcohol (3.6 to 4.1 V) and water (1.9 to 1.4 V), a crystalline Sitagliptin phosphate monohydrate (1.0 eq) was added at 20°C to 45°C and stirred for 10 minutes. The slurry was maintained at 20°C to 45°C for 4 to 8 hrs under stirring. The slurry was filtered, washed with prechilled mixture of isopropyl alcohol and water, dried under vacuum at 40°C to 60°C for 4-6 hours to obtain crystalline Sitagliptin phosphate monohydrate with X-ray powder diffractogram matching with FIG. 2.
(Yield: 90%, HPLC purity: 99.9%).
,CLAIMS:We Claim:

1) A process for the preparation of crystalline Sitagliptin phosphate monohydrate of formula (I)

from Sitagliptin phosphate anhydrate by slurry technique.

2) The process as claimed in claim 1 comprising the steps of:
a) adding Sitagliptin phosphate anhydrate in a volume ratio ranging from 65:35 to 75:25 of alcoholic solvent and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.

3) A process for purification of crystalline Sitagliptin phosphate monohydrate comprising the steps of:
a) adding crystalline Sitagliptin phosphate monohydrate in a volume ratio ranging from 65:35 to 75:25 of alcoholic solvent and water to obtain a slurry,
b) maintaining a temperature at 20°C to 45°C for 4 to 8 hours under stirring,
c) optionally seeding, and
d) isolating crystalline Sitagliptin phosphate monohydrate.

4) The process as claimed in claim 1, wherein Sitagliptin phosphate anhydrate contain up to 50% by weight of crystalline Sitagliptin phosphate monohydrate.

5) The process as claimed in claim 2, wherein Sitagliptin phosphate monohydrate contain up to 50% by weight of crystalline Sitagliptin phosphate anhydrate.

6) The process as claimed in claim 2 and 3, wherein an alcoholic solvent is selected from methanol, ethanol, isopropanol, isobutanol, and n-butanol.

7) The process as claimed in claim 2 and 3, wherein volume ratio of alcoholic solvent and water is 3 to 7 volumes per mole equivalent of crystalline Sitagliptin phosphate monohydrate or Sitagliptin phosphate anhydrate.

8) The process as claimed in claim 2 and 3, where resulting crystalline Sitagliptin phosphate monohydrate has purity greater than 99.5% by HPLC.