DESC:Field of the Invention:
The present application relates to novel crystalline forms for Mitapivat sulfate hydrate and processes thereof, is represented by the following structural formula-I.

Formula-I

Background of the Invention:
Mitapivat, is a pyruvate kinase activator, as a sulfate salt is approved in USA for the treatment of hemolytic anemia and is available in the market with the brand name PYRUKYND® developed by Agio pharmaceutical in the form of tablet. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl]phenyl]-, sulfate, hydrate (2:1:3).
The US patent US8785450B2 first disclosed mitapivat free base and pharmaceutically acceptable salts. The US’450 disclosed various processes for preparation of mitapivat. The said patent reported purification of mitapivat by using column chromatography in a mixture of methanol and dichloromethane.
The US11254652B2 reported mitapivat sulfate, hemi sulfate hydrate and their polymorphs. Additionally, the said patent reported alternative process for preparation of mitapivat sulfate salt and its polymorphs and processes thereof.
The PCT application publication WO2020237047A1 reported various salts of mitapivat and polymorphs and processes thereof.
The PCT application publication WO2021154987A1 reported various crystalline forms for mitapivat sulfate and mitapivat-cocrystals and processes thereof.
Discovering new solid-state forms, hydrates, co-crystals and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid-state forms (including solvated forms) of mitapivat sulfate.
The present invention provides polymorphs for 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl]phenyl]-, sulfate, hydrate and processes for thereof.
Brief Description:
The first aspect of the present invention is to provide novel crystalline form of 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl]phenyl]-sulfate, hydrate compound of formula-I, herein after designated as crystalline form-P of Mitapivate sulfate hydrate.
The second aspect of the present invention is to provide process for the preparation of crystalline form-P of 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]- sulfate, hydrate compound of formula-I.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form-P of 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl]phenyl]-,sulfate, hydrate compound of formula-I.

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminum hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel.

The first aspect of the present invention provides a stable crystalline form-P of 8-quinolinesulfonamide, N-[4-[[4(cyclopropyl methyl)-1-piperazinyl] carbonyl] phenyl]-, sulfate, hydrate compound of formula-I. The crystalline form-P of the present invention is characterized by its powder X-Ray diffraction pattern having characteristic peaks at about 13.8, 14.6, 21.7 and 24.0. The said crystalline form-P is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-1. Further, the crystalline form-P of mitapivat sulfate may be characterized by the PXRD pattern having peaks at 4.4, 8.3, 8.9, 10.8,11.1, 11.9, 12.3, 13.4, 14.9, 16.1, 17.1, 17.5, 18.0, 18.4, 19.7, 20.3, 20.6, 21.4, 22.5, 22.7, 23.7, 24.5, 25.5, 26.2, 27.4, 27.8, 28.5, 28.9, 29.3, 32.0, 32.2, 33.0, and 33.5 ± 0.2° 2?. The crystalline form-P of mitapivat sulfate is hydrate form.
The second aspect of the present invention is to provide process for the preparation of crystalline form-P of 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-, sulfate hydrate compound of formula-I.
Comprising of
a) Stirring mitapivat in a suitable solvent at suitable temperature,
b) adding sulfuric acid solution and stirring at suitable temperature,
c) isolating and drying to get the crystalline form-P of mitapivat sulfate hydrate.
Wherein in step-a to c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvents, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-100°C.
The preferred embodiment of the aspect of the present invention is to provide process for the preparation of crystalline form-P of 8-quinolinesulfonamide, N- [4-[[4(cyclopro pylmethyl)-1-piperazinyl] carbonyl] phenyl]-, sulfate hydrate compound of formula-I.
Comprising of
a) dissolving mitapivat in a mixture of toluene, isopropanol, water at 80-90°C,
b) adding sulfuric acid to the solution obtained in step b) and stirring at 20-30°C,
c) filtering the compound obtained in step-b) to get the crystalline form-P of mitapivat sulfate hydrate.
8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate, hydrate compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. milling or micronization may be performed before drying, or after the completion of drying of the product.
The particle size of the compound of formula-I obtained as per the present invention D90< 300 µm, D50 <200 µm. D10 < 100 µm.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
PXRD analysis of 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate, hydrate compound of formula-I was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate, hydrate compound of formula-I used in the present invention is synthesized by the prior known processes.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of crystalline form-P of compound of formula-1
A round bottom flask was charged N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl) phenyl) quinoline-8-sulfonamide (200 g) and a pre-mixed solvents of isopropanol (2950 mL), toluene (1088 mL) and water (600 g) and the suspension was heated to 80-90°C to dissolve the solid compound. Filtered the reaction mixture at 70-80°C, and the resulting filtrate solution was cooled to 40-50°C and stirred for 20 min. The reaction solution was charged with aqueous solution of sulfuric acid (2.4 M, 22.6 g in 96 mL of water) about 45 min and stirred at 20-30° for 4 hr. The solid compound was filtered and washed with a mixture of isopropanol and toluene to get wet title compound. The wet compound was charged with pre-mixed solvents of isopropanol (2950 mL), toluene (1088 mL) and water (600 g) and heated to 40-50°C and stirred for 30 min. Then cooled to 25-35°C and stirred for 4 hr at same temperature. Filtered the solid compound and washed with a mixture of isopropanol and toluene and dried to get the title compound.
The PXRD of the obtained compound depicted in figure-1.
Yield: 200 g; Water content: about 10 %
particle size distribution of D90 <80 µm, D50 <36 µm. D10 <15 µm.

,CLAIMS:We claim:

1. A crystalline form-P of mitapivat sulfate characterized by the PXRD pattern having peaks at 4.4, 8.3, 8.9, 10.8,11.1, 11.9, 12.3, 13.4, 14.9, 16.1, 17.1, 17.5, 18.0, 18.4, 19.7, 20.3, 20.6, 21.4, 22.5, 23.7, 24.5, 25.5, 26.2, 27.4, 27.8, 28.5, 28.9, 29.3, 32.0, 32.2, 33.0, and 33.5 ± 0.2° 2?.
2. The crystalline form-P of mitapivat sulfate according to claim 1, is in hydrate form.
3. A process for the preparation of crystalline form-P of 8-quinolinesulfonamide, N-[4-[[4(cyclo propylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate hydrate compound of formula-I.
Comprising of
a) dissolving mitapivat in a mixture of toluene, isopropanol, water,
b) adding sulfuric acid to the solution obtained in step-a) and stirring at 20-30°C,
c) filtering the compound obtained in step b) to get crystalline form-P of mitapivat sulfate hydrate.
4. Mitapivat sulfate according to the preceding claims is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
5. Mitapivat sulfate according to the preceding claims has purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99% as measured by HPLC.