DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORMS OF MITAPIVAT SULFATE AND PROCESSES FOR PREPARATION

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of Mitapivat sulfate and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Mitapivat sulfate (Pyrukynd®), chemically known as N-{4-[4-(cyclopropylmethyl) -piperazine-1-carbonyl]phenyl}quinoline-8-sulfonamide Hemisulfate (compound of Formula 1), which is useful for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Pyruvate kinase is an enzyme, which is used by red blood cells. Without this enzyme, red blood cells break down too easily and results into hemolytic anemia.

Formula 1

Mitapivat sulfate (1) was disclosed in US 8,785,450. Moreover, the ‘450 patent also discloses a process for the preparation of Mitapivat.

The US Patent US 11,254,652 disclose crystalline forms of Mitapivat sulfate Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I and Form J.

The PCT application no. WO 2021154987 disclose crystalline forms of Mitapivat sulfate Form M1, Form M5 and Form M6.

Further, the PCT application no. WO2024084501 disclose Crystalline Mitapivat hemi sulfate Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII and Crystalline Mitapivat Form I, Form II, Mitapivat Form III, Form IV. Further discloses crystalline Mitapivat mono sulfate Form I, Form II, Form III, Form IV, Form V and amorphous Mitapivat mono sulfate.

Considering the importance of Mitapivat sulfate, nevertheless, besides the known solid forms of Mitapivat sulfate, there is still the need for further polymorphs, which are, stable in formulation, reproducible, and a process which involves the use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, and/or provide a product of higher purity.

In view of the above, our inventors have developed Crystalline Mitapivat sulfate MIP-1 & Crystalline Mitapivat sulfate MIP-2 of which are, stable, reproducible and process for the preparation thereof.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a crystalline forms of Mitapivat sulfate and a process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention is directed to solid state forms of Mitapivat sulfate, designated as crystalline Mitapivat sulfate Form MIP-1 and crystalline Mitapivat sulfate Form MIP-2.

The present invention further directed to a process for the preparation of crystalline Mitapivat sulfate Form MIP-1 and Form MIP-2.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: PXRD pattern of crystalline Form MIP-1 of Mitapivat sulfate.
Figure 2: DSC pattern of crystalline Form MIP-1 of Mitapivat sulfate.
Figure 3: PXRD pattern of crystalline Form MIP-2 of Mitapivat sulfate.
Figure 4: DSC pattern of crystalline Form MIP-2 of Mitapivat sulfate.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides solid state Mitapivat sulfate, designated as crystalline Mitapivat sulfate Form MIP-1.

In one embodiment, the present invention provides crystalline Mitapivat sulfate, designated as crystalline Mitapivat sulfate Form MIP-1 is a hydrate having water content about 5-10%.

In another embodiment, present invention provides crystalline Mitapivat sulfate Form MIP-1 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 12.2; 13.9; 16.8; 17.6 and 24.0 ± 0.2° 2?.

In another embodiment, the present application crystalline Mitapivat sulfate Form MIP-1 characterized by its PXRD pattern having additional peaks at 13.0; 13.4; 23.0; 25.0 and 25.5± 0.2° 2?.

In another embodiment present application provides crystalline Mitapivat sulfate Form MIP-1 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 10.1; 10.8; 11.0; 12.2; 13.0; 13.4; 13.9; 15.1; 16.8; 17.6; 19.4; 20.1; 20.6; 21.3; 21.7; 22.0; 23.0; 24.0; 25.0; 25.5; 27.0 and 29.3 ± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Mitapivat sulfate Form MIP-1
which comprises;
a) Suspend Mitapivat sulfate in methanol to obtain a suspension;
b) Stir the above suspension; and
c) Obtaining the crystalline Mitapivat sulfate MIP-1.

In another embodiment, the present invention provides a crystalline Mitapivat sulfate having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another embodiment, the present invention provides a crystalline Mitapivat sulfate characterized by DSC thermogram comprising two endothermic Peaks at about 131.38ºC, 150.60ºC, broad endothermic peak at 36.81°C and endothermic peaks above 2200C belong to degradation, as shown in Figure 2.

In another embodiment, the present invention provides solid state Mitapivat sulfate, designated as crystalline Mitapivat sulfate MIP-2.

In one embodiment, the present invention crystalline Mitapivat sulfate, designated as crystalline Mitapivat sulfate Form MIP-1 is a hydrate having water content of 5-10%.

In another embodiment, present application provides crystalline Mitapivat sulfate MIP-2 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.2; 8.4; 11.3; 19.9 and 23.9 ± 0.2° 2?.

In another embodiment, the present application crystalline Mitapivat sulfate MIP-2 characterized by its PXRD pattern having additional peaks at 5.9; 11.9; 13.2; 16.5 and 33.5 ± 0.2° 2?.

In another embodiment present application provides crystalline Mitapivat sulfate MIP-2 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.2; 5.9; 8.4; 11.3; 11.9; 12.6; 13.2; 14.2; 14.7; 15.3; 16.5; 17.6; 19.9; 22.1; 22.7; 23.3; 23.9; 26.1; 28.4; 33.5 and 34.3 ± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Mitapivat sulfate Form MIP-2
Which comprises;
a) suspend Mitapivat sulfate in isobutanol to obtain a suspension;
b) stir the above suspension; and
c) obtaining the crystalline Mitapivat sulfate Form MIP-2.

In another embodiment, the present invention provides a crystalline Mitapivat sulfate Form MIP-2 having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-3.

In another embodiment, the present invention provides a crystalline Mitapivat sulfate MIP-2 characterized by DSC thermogram comprising two endothermic peaks at about 142.08ºC, 163.61°C and broad endothermic peak at about 64.43°C, as shown in Figure 4.

Crystalline Mitapivat Sulfate MIP-1 and Crystalline Mitapivat Sulfate MIP-2 were exposed to different stress conditions like exposure to relative humidity of 20%, 40%, 60% and 80% at room temperature, heating, grinding and open exposer and the product complies with the initial results and found to be stable.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (instrument name Bruker D8 advance-Eco with lynex detector equipped with Cu source ?=1.58Å) measured using CuKa radiation. Methodology of X-ray diffraction is as follows:

Scanning Type: Continuous scan; Scan range: at least 3-40° 2theta; Step size: 0.8°; Time/Step: 0.05 sec; Divergence slit: V20; Rotation: 30 rpm
The Differential Scanning Calorimetry (DSC) thermograms were obtained on a Mettler Toledo DSC3+ or equivalent. Methodology of DSC is as follows:

Nitrogen flow: 50.0 ± 10 mL/min; Range: 25.0°C - 300°C; Ramp: 10.0°C/min., Pan type: Aluminium pan.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:

Example 1: Preparation of crystalline Mitapivat sulfate Form MIP-1.

In a 10mL Round bottom flask, 100mg Mitapivat sulfate (amorphous form) was suspended in pre-cooled methanol (0.8ml) and stirred at -5 °C for 19-20 hours. The obtained solid was filtered and dried at 95°C-65°C for 19-20 hours. Dried material was analyzed by DSC, TGA, & PXRD.

Example 2: Preparation of crystalline Mitapivat sulfate Form MIP-2

In a 10mL Round bottom flask, 1gm Mitapivat sulfate (amorphous form) was suspended in pre-cooled isobutanol (15 ml) and stirred at -5 °C for 19-20 hours. The obtained solid was filtered and dried at 100°C for about 5 hours. Dried material was analyzed by DSC, TGA, PXRD. ,CLAIMS:WE CLAIM:

1. A crystalline Form MIP-1 of Mitapivat Sulfate characterized by XRPD pattern having 2? values 12.2; 13.9; 16.8; 17.6 and 24.0 (± 0.2 degrees 2 theta).

2. The crystalline form according to claim 1, characterized by XRPD pattern having 2? values 13.0; 13.4; 23.0; 25.0 and 25.5 (± 0.2 degrees 2 theta).

3. The crystalline form according to claim 1, characterized by XRPD pattern having 2? values 10.1; 10.8; 11.0; 12.2; 13.0; 13.4; 13.9; 15.1; 16.8; 17.6; 19.4; 20.1; 20.6; 21.3; 21.7; 22.0; 23.0; 24.0; 25.0; 25.5; 27.0 and 29.3 (± 0.2 degrees 2 theta).

4. The crystalline form according to claim 1 characterized by XRPD pattern depicted in Figure 1.

5. A process for the preparation of the crystalline Form MIP-1 of Mitapivat Sulfate, which comprises;
a) Suspending Mitapivat Sulfate in methanol;
b) Stirring the above suspension; and
c) Obtaining the crystalline Mitapivat Sulfate MIP-1.

6. A Crystalline Form MIP-2 of Mitapivat Sulfate characterized by XRPD pattern having 2? values 4.2; 8.4; 11.3; 19.9 and 23.9 (± 0.2 degrees 2 theta).

7. The crystalline form according to claim 6, characterized by XRPD pattern having 2? values 5.9; 11.9; 13.2; 16.5 and 33.5 (± 0.2 degrees 2 theta).

8. The crystalline form according to claim 6, characterized by XRPD pattern having 2? values 4.2; 5.9; 8.4; 11.3; 11.9; 12.6; 13.2; 14.2; 14.7; 15.3; 16.5; 17.6; 19.9; 22.1; 22.7; 23.3; 23.9; 26.1; 28.4; 33.5 and 34.3 (± 0.2 degrees 2 theta).

9. The crystalline form according to claim 6 characterized by XRPD pattern depicted in Figure 3.

10. A process for the preparation of the crystalline Form MIP-2 of Mitapivat Sulfate, which comprises;
a) Suspending Mitapivat Sulfate in isobutanol;
b) Stirring the above suspension; and
c) Obtaining the crystalline Mitapivat Sulfate Form MIP-2.