DESC:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No.IN202441000491 filed on Jan 03, 2024.

BACKGROUND OF THE INVENTION
FIELD OF THE DISCLOUSRE
The present disclosure relates to novel crystalline forms of mitapivat hemi sulfate.

DESCRIPTION OF THE RELATED ART
Mitapivat is a Pyruvate kinase R (PKR) activator and is developed by Agios for the treatment of inborn errors of metabolism (IEMs) like Pyruvate kinase deficiencies, thalassemia and sickle cell disease. Mitapivat is marketed under the brand name PYRUKYND in the U.S. The active ingredient of PYRUKYND is mitapivat, present as mitapivat sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-, sulfate and molecular formula is (C24H26N4SO3)2 • H2SO4. The chemical structure of mitapivat sulfate is:

Mitapivat first disclosed in International Publication No. WO2011/002817. International Publication No. WO2019/104134 describes amorphous and different crystalline forms of Mitapivat hemi sulfate of formula.

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; crystalline mitapivat Form I, Form II, Form III, Form IV; crystalline mitapivat monosulfate Form I, Form II, Form III, Form IV, Form V and amorphous form of mitapivat monosulfate are disclosed in co-pending Indian patent application IN202241059196, which is hereby incorporated by reference in their entirety.

Different polymorphs may provide different advantages in a variety of capacities, for example, in ease of formulation, stability of the polymorphic form, stability of the formulation, and in pharmacokinetic profiles. These advantages may arise from the different properties present in each polymorph. The present invention provides novel polymorphic forms of mitapivat hemi sulfate and process for the preparation thereof.

SUMMARY OF THE DISCLOSURE
In one aspect, the present invention is to provide crystalline mitapivat hemi sulfate Form XIII.

Other aspect of the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIII comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture obtained in step (b); and
d) isolating crystalline mitapivat hemi sulfate Form XIII.

Another aspect of the present invention is to provide crystalline mitapivat hemi sulfate Form XIV.

Other aspect of the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding an ester solvent and seeds of mitapivat hemi sulfate Form XI;
c) heating the reaction mixture;
d) cooling and stirring the reaction mixture obtained in step (c); and
e) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

In another aspect the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture;
d) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

Other aspect of the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising drying the crystalline mitapivat hemi sulfate Form XIII.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure. 1 is an X-ray powder diffractogram of crystalline mitapivat hemi sulfate Form XIII.

Figure. 2 is an X-ray powder diffractogram of crystalline mitapivat hemi sulfate Form XIV.

DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The powder X-ray diffraction patterns of said polymorphs of the invention were measured on a PANalytical X’Pert PRO powder diffractometer equipped with a goniometer of ?/? configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°–50.0°, 0.033° step size and 50 seconds step time.

Within the context of the invention, the term “about” when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value. Within the context of the invention, the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.

The present disclosure relates to crystalline forms of mitapivat hemi sulfate. The present disclosure also relates to process for the preparation of crystalline forms of mitapivat hemi sulfate.

In one embodiment, the present disclosure is to provide crystalline mitapivat hemi sulfate Form XIII.

In another embodiment, the present disclosure is to provide crystalline mitapivat hemi sulfate Form XIII, characterized by Powder X-ray diffraction pattern having 2? angle positions at about 7.20, 11.17, 12.55, 15.23, 16.89, 17.40, 18.37 and 20.44 ±0.2°.

In yet another embodiment, crystalline mitapivat hemi sulfate Form XIII is further characterized by Powder X-ray diffraction pattern having 2? angle positions at about 7.20, 7.70, 8.0, 11.17, 12.55, 14.11, 15.23, 16.89, 17.40, 18.37, 19.80, 20.44, 20.84, 21.25, 21.76, 22.9, 28.80 ±0.2°.

In still other embodiment the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIII comprising the steps of:

a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture obtained in step (b); and
d) isolating crystalline mitapivat hemi sulfate Form XIII.

Within the context of this embodiment, the alcoholic solvents employed may include for example, but not limited to ethanol, methanol, n-propanol, n-butanol, 2-butanol, 2-propanol, 3-methyl-1-butanol, 1-pentanol, 2-methyl-1-propanol or mixture thereof. In particular useful embodiments methanol is used.

Within the context of this embodiment, sulfuric acid added is concentrated or diluted with same or different solvents used in the dissolution of mitapivat, preferably same solvent is used.

Within the context of this embodiment, ester solvent employed in step (b) may include, for example, but not limited to ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate or mixtures thereof. In particular useful embodiments ethyl acetate is used.

Within the context of this embodiment, isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation. In particular useful embodiments the solid is isolated by filtration followed by suck-drying.

According to the present disclosure, mitapivat is suspended in alcoholic solvent, added sulfuric acid solution, and heated to elevated temperature of about 60°C. The clear solution was slowly added to the seeds of crystalline mitapivat hemi sulfate Form XIV in ester solvent. Stirred the reaction mixture for about 16 hours, the obtained solid is filtered, washed with ester solvent and then suck-dried, which was identified as crystalline mitapivat hemi sulfate Form XIII.

In another embodiment, the present disclosure is to provide crystalline mitapivat hemi sulfate Form XIV.

Another embodiment, the present disclosure is to provide crystalline mitapivat hemi sulfate Form XIV, characterized by Powder X-ray diffraction pattern having 2? angle positions at about 7.75, 12.60, 13.26, 14.15, 15.53, 17.02, 20.86, 23.40 and 28.86 ±0.2°.

In yet another embodiment, crystalline mitapivat hemi sulfate Form XIV is further characterized by Powder X-ray diffraction pattern having 2? angle positions at about 7.75, 8.12, 12.60, 13.26, 14.15, 15.14, 15.53, 17.02, 17.99, 19.08, 19.82, 20.86, 21.29, 21.80, 23.40, 24.47, 28.86 ±0.2°.

In still another embodiment the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding an ester solvent and seeds of mitapivat hemi sulfate Form XI;
c) heating the reaction mixture;
d) cooling and stirring the reaction mixture obtained in step (c); and
e) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

Within the context of this embodiment, the alcoholic solvents employed may include for example, but not limited to ethanol, methanol, n-propanol, n-butanol, 2-butanol, 2-propanol, 3-methyl-1-butanol, 1-pentanol, 2-methyl-1-propanol or mixture thereof. In particular useful embodiments methanol is used.

Within the context of this embodiment, sulfuric acid added is concentrated or diluted with same or different solvents used in the dissolution of mitapivat, preferably same solvent is used.

Within the context of this embodiment, ester solvent employed in step (b) may include, for example, but not limited to ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate or mixtures thereof. In particular useful embodiments ethyl acetate is used.

Within the context of this embodiment, isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation.

According to the present disclosure, mitapivat is suspended in alcoholic solvent, added sulfuric acid solution, and stirred. To the obtained clear solution ester solvent, the seeds of crystalline mitapivat hemi sulfate Form XI were added and heated the reaction mixture at about 40 °C and stirred for about 12 hours, the obtained solid is filtered, washed with ester solvent and then suck-dried. The obtained material was further dried at about 80 °C for about 16 hours under vacuum to obtain crystalline mitapivat hemi sulfate Form XIV.

In still another embodiment the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:

a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture;
d) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

Within the context of this embodiment, the alcoholic solvents employed may include for example, but not limited ethanol, methanol, n-propanol, n-butanol, 2-butanol, 2-propanol, 3-methyl-1-butanol, 1-pentanol, 2-methyl-1-propanol or mixture thereof. In particular useful embodiments methanol is used.

Within the context of this embodiment, sulfuric acid added is concentrated or diluted with same or different solvents used in the dissolution of mitapivat.

Within the context of this embodiment, ester solvent employed in step (b) may include, for example, but not limited to ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate or mixtures thereof. In particular useful embodiments ethyl acetate is used.

Within the context of this embodiment, isolation can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation.

According to the present disclosure, mitapivat is suspended in alcoholic solvent, added sulfuric acid solution, and heated to elevated temperature of about 60°C. The clear solution was slowly added to the seeds of crystalline mitapivat hemi sulfate Form XIV in ester solvent. Stirred the reaction mixture for about 16 hours, the obtained solid is filtered, washed with ester solvent and then suck-dried. The material obtained was further dried at about 80 °C under vacuum for about 16 hours to get crystalline mitapivat hemi sulfate Form XIV.

In still another embodiment the present invention is to provide a process for the preparation of crystalline mitapivat hemi sulfate Form XIV by drying crystalline mitapivat hemi sulfate Form XIII under reduced pressure at 70-90°C for 10-20 hours.

Stability Study
In yet another embodiment, the physical and chemical stability of Mitapivat sulfate Form XIV were determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% RH conditions for six months as shown in Table 1. The samples were analyzed by PXRD and HPLC. Mitapivat sulfate Form XIV was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for up to six months.

Table 1. Summary of stability studies on Form XIV
Conditions Mitapivat sulfate Form XIV
PXRD Purity (%)
at 40°C/75% RH
Initial Form XIV 99.82
1 month Stable 99.82
2 months Stable 99.86
3 months Stable 99.83
6 months Stable 99.83
at 25°C/60% RH
1 month Stable 99.82
2 months Stable 99.87
3 months Stable 99.83
6 months Stable 99.85

According to the present invention, the input mitapivat is prepared by any prior-art process for example PCT publication No. WO2011/002817.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1: Crystalline Mitapivat hemi sulfate Form XIII
Mitapivat (3 g) was suspended in methanol (9 mL) at 28±2 °C. Conc. H2SO4 (0.339 g, 0.52 mole eq.) diluted with 3 mL methanol was slowly added to the suspension at 28±2 °C. The resulting suspension was heated to 60±2 °C and maintained under stirring for 15min at 60±2 °C. Methanol (6 mL) was added to the resulting hazy solution and continued stirring for 15min at 60±2 °C. Then filtered the hazy solution through hyflo to remove any undissolved particulate matter. Charged in separate RBF ethyl acetate (45 mL) and mitapivat hemi sulfate Form XIV (5 mg) seeds at 28±2 °C. Added slowly above methanolic reaction mass solution into ethyl acetate at 28±2 °C for 10 minutes and maintained under stirring for 16 hours. The resulting reaction mass was filtered, washed with ethyl acetate (2 mL) and suck-dried for 10 minutes. The wet material was identified by PXRD as Mitapivat hemi sulfate Form XIII.
Yield: 2.6g

Example 2: Crystalline Mitapivat hemi sulfate Form XIV
Mitapivat base (5g) was suspended in methanol (15 mL) at 27±2 °C. Conc. H2SO4 (0.56 g, 0.52 mole eq.) diluted with 10 mL methanol was slowly added to the suspension and maintained under stirring at 27±2 °C for 20-30 minutes. To the resulting suspension added 30 mL methanol and the hazy solution thus obtained was filtered through Whatman filter paper to remove any undissolved particulate matter. Ethyl acetate (50 mL) was added to the resulting clear solution, added mitapivat hemi sulfate Form XI seeds (0.1g) at 25-30 °C, heated to 40-45 °C, stirred for 60 minutes at 40-45 °C, added 40 mL ethyl acetate at 40-45 °C. Cooled to 27±2 °C and maintained under stirring for 12 hours. The resulting reaction mass was filtered, washed with ethyl acetate (10 mL) and suck-dried for 10 minutes. The wet material was dried at 85 °C under vacuum for 16 hours. The solid obtained was identified by PXRD as Mitapivat hemi sulfate Form XIV.
Yield: 2.5g

Example 3: Crystalline Mitapivat hemi sulfate Form XIV
Mitapivat base (0.5 g) was suspended in methanol (1.5 mL) at 28±2 °C. Conc. H2SO4 (0.56g, 0.52 mole eq.) diluted with 0.5 mL methanol was slowly added to the suspension at 28±2 °C. The resulting suspension was heated to 60±2 °C and maintained under stirring for 15 minutes at 60±2 °C. The resulting clear solution was cooled to 28±2 °C and filtered through Whatman filter paper to remove any undissolved particulate matter. Charged in separate RBF ethyl acetate (7.5 mL) and mitapivat hemi sulfate Form XIV (5 mg) at 28±2 °C. Added slowly above methanolic reaction mass solution into ethyl acetate at 28±2 °C for 10 minutes and maintained under stirring for 16 hours. The resulting reaction mass was filtered, washed with ethyl acetate (2 mL) and suck-dried for 10 minutes. The wet material was further dried at 85 °C under vacuum for 16 hours. The solid obtained was identified by PXRD as Mitapivat hemi sulfate Form XIV.
Yield: 370mg

Example 4: Crystalline Mitapivat hemi sulfate Form XIV
The wet material obtained as per example 1 was dried at 85 °C under vacuum for 16 hours. The solid obtained was identified by PXRD as Mitapivat hemi sulfate Form XIV.

Example 5: Crystalline Mitapivat hemi sulfate Form XIV
Mitapivat base (10 g) was suspended in methanol (50 mL) at 27±2 °C. Conc. H2SO4 (1.13 g, 0.52 mole eq.) diluted with 10 mL methanol was slowly added to the suspension and maintained under stirring at 27±2 °C for 20-30 minutes. Heated to 52±2°C and stirred for 30 minutes to get clear solution. The clear solution was filtered through hyflo bed to remove any undissolved particulate matter. Charge ethyl acetate (150 mL) into another RBF and heated to 45±2 °C. Added above reaction mass solution to pre-heated ethyl acetate at 45±2 °C for 45 minutes and stirred for 30minutes at 45±2°C. The resulting suspension was cooled to 28±2°C and maintained for 16h. Cooled to 0-5°C and stir for 60min. The resulting reaction mass was filtered, washed with mixture of methanol (6 mL) and ethyl acetate (15 mL) and suck-dried for 30 minutes. The wet material was dried at 110 °C under vacuum for 15 hours. The solid obtained was identified by PXRD as Mitapivat hemi sulfate Form XIV.
Yield: 9.0g
,CLAIMS:
1. A crystalline mitapivat hemi sulfate Form XIII, which has a powder X-ray diffraction pattern having 2? angles positions at about 7.20, 11.17, 12.55, 15.23, 16.89, 17.40, 18.37 and 20.44 ±0.2°.

2. A crystalline mitapivat hemi sulfate Form XIII, characterized by Powder Xray diffraction pattern as depicted in FIG. 1.

3. The process for the preparation of crystalline mitapivat hemi sulfate Form XIII comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture obtained in step (b); and
d) isolating crystalline mitapivat hemi sulfate Form XIII.

4. A crystalline mitapivat hemi sulfate Form XIV, which has a powder X-ray diffraction pattern having 2? angles positions at about 7.75, 12.60, 13.26, 14.15, 15.53, 17.02, 20.86, 23.40 and 28.86 ± 0.2°.

5. A crystalline mitapivat hemi sulfate Form XIV, characterized by Powder Xray diffraction pattern as depicted in FIG. 2.

6. The process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding an ester solvent and seeds of mitapivat hemi sulfate Form XI;
c) heating the reaction mixture;
d) cooling and stirring the reaction mixture obtained in step (c); and
e) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

7. The process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising the steps of:
a) dissolving mitapivat in an alcoholic solvent and adding sulfuric acid;
b) adding the reaction mixture obtained in step (a) to the seeds of mitapivat hemi sulfate Form XIV in an ester solvent;
c) stirring the reaction mixture; and
d) filtering, drying to isolate crystalline mitapivat hemi sulfate Form XIV.

8. The process as claimed in above claims wherein alcoholic solvent is selected from ethanol, methanol, n-propanol, n-butanol, 2-butanol, 2-propanol, 3-methyl-1-butanol, 1-pentanol, 2-methyl-1-propanol or mixture thereof.

9. The process as claimed in above claims wherein ester solvent is selected from ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate or mixtures thereof.

10. The process for the preparation of crystalline mitapivat hemi sulfate Form XIV comprising drying of crystalline mitapivat hemi sulfate Form XIII under reduced pressure at a temperature of 70-90°C.