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WO2024228131A1 - Solid forms of 8-quinoline sulfonamide, n-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate and its process for preparation thereof - Google Patents

Solid forms of 8-quinoline sulfonamide, n-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate and its process for preparation thereof Download PDF

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WO2024228131A1
WO2024228131A1 PCT/IB2024/054240 IB2024054240W WO2024228131A1 WO 2024228131 A1 WO2024228131 A1 WO 2024228131A1 IB 2024054240 W IB2024054240 W IB 2024054240W WO 2024228131 A1 WO2024228131 A1 WO 2024228131A1
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Prior art keywords
sulfate
mitapivat
solid dispersion
pharmaceutically acceptable
solvents
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Inventor
Manik Reddy Pullagurla
Kiran Kumar Kothakonda
Bhaskar Reddy Pitta
Rajesham Boge
Jagadeesh Babu Rangisetty
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Biophore India Pharmaceuticals Pvt Ltd
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Biophore India Pharmaceuticals Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1). Further, the present invention relates to solid dispersions of 8- quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1) with at least one pharmaceutically acceptable excipient and process for its preparation thereof.
  • the present invention provides process for pure amorphous form of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1). Furthermore, solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1) prepared in the present invention is having purity greater than 99% by HPLC.
  • Mitapivat sulfate is chemically known as 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl]-, sulfate hydrate (2:1:3) (1), represented by the following structural formula
  • Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity.
  • the red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic haemolysis.
  • Mitapivat sulfate (1) is approved by the USFDA and Europe for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.
  • PK pyruvate kinase
  • US patent 11254652 B2 discloses crystalline forms A to J and amorphous form of Mitapivat hemisulfate (1) and their methods for the preparation thereof.
  • US patent publication US2023098234 discloses crystalline forms Ml, M5, M6, Mitapivat hemisulfate-ascorbic acid co-crystal ACC1, Mitapivat hemisulfateadipic acid co-crystal ACC2, Mitapivat hydrochloride salt crystalline from 1 to IV, Mitapivat-Phosphate salt crystalline form Pl and Mitapivat free base form B l and process for its preparation thereof.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid- state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC') which have been used to distinguish polymorphic forms.
  • polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
  • the main objective of the present invention is to provide a solid form of Mitapivat sulfate (1).
  • the present invention provides a process for the preparation of solid forms of Mitapivat sulfate (1).
  • the present invention provides an amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients.
  • the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients. In yet another objective, the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1).
  • the present invention provides solid forms of Mitapivat sulfate (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.
  • the first aspect of the present invention is an amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients.
  • the second aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) preparing a solution of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients in one or more solvents; and b) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
  • the third aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Mitapivat sulfate of formula (1) in one or more solvents, b) adding one or more pharmaceutically acceptable excipients to the solution obtained in step-a), and c) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
  • the fourth aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) heating Mitapivat sulfate (1) with one or more pharmaceutically acceptable excipients in presence of suitable solvent to get a solution, b) cooling the solution, and c) isolating to get solid dispersion of Mitapivat sulfate (1).
  • the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvent, b) optionally, adding one or more anti-solvent(s) to the solution obtained from step a), and c) isolating amorphous form of Mitapivat sulfate (1).
  • the sixth aspect of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvent (s), b) spray drying the solution obtained in step a), and c) isolating the amorphous form of Mitapivat sulfate (1).
  • the seventh aspect of the present invention provides a process for the preparation of amorphous Mitapivat sulfate (1), which comprises: a) milling/grinding Mitapivat sulfate (1) under suitable milling conditions; and b) isolating the amorphous form of Mitapivat sulfate (1).
  • the eighth aspect of the present invention provides a process for the preparation of solid form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) heating the reaction mass to suitable temperature, c) cooling to suitable temperature, d) optionally, combining the mixture obtained in step-c) with one or more antisolvent, and e) isolating solid form of Mitapivat sulfate (1).
  • the nineth aspect of the present invention provides solid forms of Mitapivat sulfate (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.
  • Figure 1 Illustrates the X-ray powder diffractogram of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
  • Figure 2 Illustrates the X-ray powder diffractogram of amorphous form of Mitapivat sulfate (1).
  • suitable solvent refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and the like; and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl 20 acetate and the like; "polar- aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N
  • the term “anti- solvent” refers to a solvent which is used to precipitate the solid from a solution.
  • solid dispersion refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer.
  • solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a nonordered way.
  • the two or more components form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
  • excipient refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
  • solid dispersion and premix are used interchangeably to describe solid states disclosed herein.
  • the first embodiment of the present invention provides an amorphous solid dispersion comprising Mitapivat sulfate of formula (1) and one or more pharmaceutically acceptable excipients as well as its process for the preparation.
  • the “excipient “used herein is selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose
  • the ratio of the weight of Mitapivat sulfate to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to about 1:10, preferable ratio 1:1.5.
  • the amorphous solid dispersion of Mitapivat sulfate (1) of the present invention can be further micronized or milled to achieve desired particle size distribution to make suitable formulation.
  • the second embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) preparing a solution of Mitapivat sulfate of formula (1) together with one or more pharmaceutically acceptable excipients in one or more solvents; and b) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
  • the solvent is selected from “polar- aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "polar solvents” such as water or mixtures thereof.
  • the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution.
  • the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) providing a solution of Mitapivat sulfate of formula (1) in one or more solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
  • the solvent is selected from "alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol, and the like; "chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or mixture thereof.
  • alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol, and the like
  • chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or mixture thereof.
  • the fourth embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) heating Mitapivat sulfate (1) with one or more pharmaceutically acceptable excipients in presence of suitable solvent to get a solution, b) cooling the solution to suitable temperature; and c) isolating solid dispersion of Mitapivat sulfate (1).
  • the fifth embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) optionally, adding one or more anti-solvent(s) to the solution obtained from step a), and c) isolating the amorphous form of Mitapivat sulfate (1).
  • the solvent is selected from "alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol, and the like; "polar-aprotic solvents such as N, N- dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; anti-solvent used in step b) is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like.
  • alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methyl
  • the sixth embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvent (s); b) spray drying the solution obtained in step a); and c) isolating the amorphous form of Mitapivat sulfate (1).
  • the seventh embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvent (s), b) lyophilizing the solution obtained in step a); and c) isolating the amorphous form of Mitapivat sulfate (1).
  • the solvent used in the sixth and seventh embodiment is selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-methylpropan-l-ol, 2-butanol, t-butanol, and the like.
  • the eighth embodiment of the present invention provides a process for the preparation of amorphous Mitapivat sulfate (1), which comprising of: a) milling/grinding Mitapivat sulfate (1) under suitable milling conditions; and b) isolating the amorphous form of Mitapivat sulfate (1).
  • the amorphous solid dispersion or amorphous form of Mitapivat sulfate (1) can be isolated by removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.
  • a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to
  • the solvent may be removed optionally under reduced pressures, at temperatures less than about 130°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about -60°C.
  • drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure.
  • the drying may be carried out for any desired times until the required product quality is achieved.
  • the dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or Micronisation may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
  • the nineth embodiment of the present invention provides a process for the preparation of solid forms of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) heating the reaction mass to suitable temperature, c) cooling to suitable temperature, d) optionally, combining the mixture obtained in step-c) with one or more antisolvent; and e) isolating solid form of Mitapivat sulfate (1).
  • step-a) the solvent is selected from acetic acid or ethyl benzene; in step- d), the anti- solvent is selected from hydrocarbon solvents such as n-heptane, n- hexane, xylene, toluene and the like; and ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; in step-d) combining refers to addition of the mixture obtained in step-c) to anti-solvent or addition of an anti-solvent to the mixture obtained in step-c); in step-e), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.
  • hydrocarbon solvents such as n-heptane, n- hexane, xy
  • the present invention provides solid forms of Mitapivat sulfate (1) is having chemical purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.
  • Example-1 Preparation of solid form of Mitapivat sulfate (1).
  • Example-2 Preparation of solid form of Mitapivat sulfate (1).
  • Example-3 Preparation of solid form of Mitapivat sulfate (1).
  • Example-4 Preparation of amorphous form of Mitapivat sulfate (1).
  • Example-5 Preparation of amorphous form of Mitapivat sulfate (1).
  • Example-6 Preparation of pure amorphous form of Mitapivat sulfate (1).
  • Example-7 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
  • Mitapivat sulfate 100 mg was dissolved in 25 ml of Methanol at room temperature. To this 300 mg of hydroxypropyl beta cyclodextrin (HPpCD) was added and stirred for 15 to 30 minutes. The obtained clear solution was filtered. This clear solution was taken at room temperature and heated to 45-55°C. Distilled out the solvent using high vacuum. The obtained solid was dried to yield amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD). Yield: 92.5%.
  • HPpCD hydroxypropyl beta cyclodextrin
  • Example-8 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
  • 2.5g of Mitapivat sulfate was dissolved in 60 ml of Methanol at room temperature and stirred for 15 to 30 minutes.
  • To this 2.5 g of hydroxypropyl beta cyclodextrin (HPpCD) was added and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
  • VTD Vacuum air tray dryer
  • Example-9 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with polyvinylpyrrolidone-K-30 (PVP-K-30)
  • VTD Vacuum air tray dryer
  • Example-10 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Soluplus 2.5 g of Mitapivat sulfate (1) was dissolved in 40 ml of methanol at room temperature. To this 2.5 g of Soluplus was added and stirred for 15 to 20 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
  • VTD Vacuum air tray dryer
  • Example- 13 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with (Hydroxypropyl)methyl cellulose E3 (HPMC-E3)
  • Example-14 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Hydroxypropyl cellulose (HPC)
  • Example- 15 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Polyvinylpyrrolidone (PVP)-K-30 (PVP-K-30).
  • VTD Vacuum air tray dryer
  • Example-16 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Copovidone
  • VTD Vacuum air tray dryer
  • Example- 17 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with HPMC-E3
  • Example- 18 Preparation of amorphous solid dispersion of Mitapivat sulfate
  • Example-19 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Polyethylene Glycol 6000 (PEG-6000)
  • VTD Vacuum air tray dryer
  • Example-20 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
  • Example-21 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with maltose.
  • Example-22 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with maltodextrin.
  • Example-23 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with mannitol.
  • Example-24 Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with isomalt.

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Abstract

The present invention relates to solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)-1-piperazinyl] carbonyl] phenyl]-sulfate of formula (1). Further, the present invention relates to solid dispersions of 8- quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)-1-piperazinyl] carbonyl] phenyl]-sulfate of formula (1) with at least one pharmaceutically acceptable excipient and process for its preparation thereof. The present invention provides process for pure amorphous form of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)-1-piperazinyl] carbonyl] phenyl]-sulfate of formula (1). Furthermore, solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)-1-piperazinyl] carbonyl] phenyl]-sulfate of formula (1) prepared in the present invention is having purity at least 99% by HPLC.

Description

"SOLID FORMS OF 8-QUINOLINESULFONAMIDE, N-[4- [[4(CYCLOPROPYLMETHYL)-1-PIPERAZINYL] CARBONYL] PHENYL] -SULFATE AND ITS PROCESS FOR PREPARATION THEREOF"
FIELD OF THE INVENTION
The present invention relates to solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1). Further, the present invention relates to solid dispersions of 8- quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1) with at least one pharmaceutically acceptable excipient and process for its preparation thereof. The present invention provides process for pure amorphous form of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1). Furthermore, solid forms of 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate of formula (1) prepared in the present invention is having purity greater than 99% by HPLC.
BACKGROUND OF THE INVENTION
Mitapivat sulfate is chemically known as 8-quinolinesulfonamide, N- [4- [4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl]-, sulfate hydrate (2:1:3) (1), represented by the following structural formula
Figure imgf000003_0001
Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic haemolysis.
Mitapivat sulfate (1) is approved by the USFDA and Europe for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.
N- [4-[4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate (1) was disclosed in US8785450 B2 (herein described as US‘45O).US‘45O discloses a process for the preparation of N- [4-[4(cyclopropyl methyl)- 1-piperazinyl] carbonyl] phenyl] -sulfate (1)
US patent 11254652 B2 discloses crystalline forms A to J and amorphous form of Mitapivat hemisulfate (1) and their methods for the preparation thereof.
US patent publication US2023098234 discloses crystalline forms Ml, M5, M6, Mitapivat hemisulfate-ascorbic acid co-crystal ACC1, Mitapivat hemisulfateadipic acid co-crystal ACC2, Mitapivat hydrochloride salt crystalline from 1 to IV, Mitapivat-Phosphate salt crystalline form Pl and Mitapivat free base form B l and process for its preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid- state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC') which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
The discovery of new solid state or crystalline or polymorphic forms of a pharmaceutical compound always provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a significant need in art to develop solid-state forms Mitapivat sulfate (1) which improves the performance characteristics of a pharmaceutical product.
Inventors of the present invention surprisingly found solid forms of Mitapivat sulfate (1) and process for their preparation thereof.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a solid form of Mitapivat sulfate (1).
In another objective, the present invention provides a process for the preparation of solid forms of Mitapivat sulfate (1).
In another objective, the present invention provides an amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients.
In another objective, the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients. In yet another objective, the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1).
In further objective, the present invention provides solid forms of Mitapivat sulfate (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.
SUMMARY OF THE INVENTION
The first aspect of the present invention is an amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients.
The second aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) preparing a solution of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients in one or more solvents; and b) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
The third aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Mitapivat sulfate of formula (1) in one or more solvents, b) adding one or more pharmaceutically acceptable excipients to the solution obtained in step-a), and c) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
The fourth aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, which comprises: a) heating Mitapivat sulfate (1) with one or more pharmaceutically acceptable excipients in presence of suitable solvent to get a solution, b) cooling the solution, and c) isolating to get solid dispersion of Mitapivat sulfate (1).
The fifth aspect, the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvent, b) optionally, adding one or more anti-solvent(s) to the solution obtained from step a), and c) isolating amorphous form of Mitapivat sulfate (1).
The sixth aspect of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvent (s), b) spray drying the solution obtained in step a), and c) isolating the amorphous form of Mitapivat sulfate (1).
The seventh aspect of the present invention provides a process for the preparation of amorphous Mitapivat sulfate (1), which comprises: a) milling/grinding Mitapivat sulfate (1) under suitable milling conditions; and b) isolating the amorphous form of Mitapivat sulfate (1).
The eighth aspect of the present invention provides a process for the preparation of solid form of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) heating the reaction mass to suitable temperature, c) cooling to suitable temperature, d) optionally, combining the mixture obtained in step-c) with one or more antisolvent, and e) isolating solid form of Mitapivat sulfate (1). The nineth aspect of the present invention provides solid forms of Mitapivat sulfate (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Illustrates the X-ray powder diffractogram of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
Figure 2: Illustrates the X-ray powder diffractogram of amorphous form of Mitapivat sulfate (1).
DETAILED DESCRIPTION OF THE INVENTION
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and the like; and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl 20 acetate and the like; "polar- aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chlorinated solvents" such as dichloromethane/ methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyro nitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti- solvent" refers to a solvent which is used to precipitate the solid from a solution. As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a nonordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.
The first embodiment of the present invention provides an amorphous solid dispersion comprising Mitapivat sulfate of formula (1) and one or more pharmaceutically acceptable excipients as well as its process for the preparation.
The “excipient “used herein is selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, Isomaltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, .sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a,P,y-cyclodextrins, sulfo butyl ether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
In the present invention, the ratio of the weight of Mitapivat sulfate to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to about 1:10, preferable ratio 1:1.5.
The amorphous solid dispersion of Mitapivat sulfate (1) of the present invention can be further micronized or milled to achieve desired particle size distribution to make suitable formulation.
The second embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) preparing a solution of Mitapivat sulfate of formula (1) together with one or more pharmaceutically acceptable excipients in one or more solvents; and b) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients. wherein, in step-a) the solvent is selected from "polar- aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "polar solvents" such as water or mixtures thereof.
After dissolving Mitapivat sulfate (1) and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution.
The third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) providing a solution of Mitapivat sulfate of formula (1) in one or more solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients. wherein, in step a) the solvent is selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol, and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or mixture thereof.
The fourth embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Mitapivat sulfate (1) and one or more pharmaceutically acceptable excipients, comprising of: a) heating Mitapivat sulfate (1) with one or more pharmaceutically acceptable excipients in presence of suitable solvent to get a solution, b) cooling the solution to suitable temperature; and c) isolating solid dispersion of Mitapivat sulfate (1).
The fifth embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) optionally, adding one or more anti-solvent(s) to the solution obtained from step a), and c) isolating the amorphous form of Mitapivat sulfate (1). wherein, in step-a) the solvent is selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol, and the like; "polar-aprotic solvents such as N, N- dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; anti-solvent used in step b) is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like.
The sixth embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvent (s); b) spray drying the solution obtained in step a); and c) isolating the amorphous form of Mitapivat sulfate (1).
The seventh embodiment of the present invention provides a process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvent (s), b) lyophilizing the solution obtained in step a); and c) isolating the amorphous form of Mitapivat sulfate (1). In an embodiment, the solvent used in the sixth and seventh embodiment is selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n- butanol, 2-methylpropan-l-ol, 2-butanol, t-butanol, and the like.
The eighth embodiment of the present invention provides a process for the preparation of amorphous Mitapivat sulfate (1), which comprising of: a) milling/grinding Mitapivat sulfate (1) under suitable milling conditions; and b) isolating the amorphous form of Mitapivat sulfate (1).
In another embodiment, the amorphous solid dispersion or amorphous form of Mitapivat sulfate (1) according to the second, third and fourth embodiments, can be isolated by removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.
The solvent may be removed optionally under reduced pressures, at temperatures less than about 130°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about -60°C.
Moreover, drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or Micronisation may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
The nineth embodiment of the present invention provides a process for the preparation of solid forms of Mitapivat sulfate (1), which comprises: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) heating the reaction mass to suitable temperature, c) cooling to suitable temperature, d) optionally, combining the mixture obtained in step-c) with one or more antisolvent; and e) isolating solid form of Mitapivat sulfate (1). wherein in step-a) the solvent is selected from acetic acid or ethyl benzene; in step- d), the anti- solvent is selected from hydrocarbon solvents such as n-heptane, n- hexane, xylene, toluene and the like; and ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; in step-d) combining refers to addition of the mixture obtained in step-c) to anti-solvent or addition of an anti-solvent to the mixture obtained in step-c); in step-e), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.
In another embodiment, the present invention provides solid forms of Mitapivat sulfate (1) is having chemical purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC. The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples
Example-1: Preparation of solid form of Mitapivat sulfate (1).
1.0 g of Mitapivat sulfate was dissolved in 5 ml of acetic acid at room temperature. The reaction mass was heated to 60-65 °C and stirred for 10-15 minutes at the same temperature. The obtained clear solution was filtered. The reaction mass was cooled to 0-5°C. To this 20 ml of n-heptane was added and stirred for 12 to 15 hours at room temperature, then 20 ml of methyl tert-butyl ether was added at the same temperature and stirred for 1 to 2 hours. The solid was filtered and dried at below 55°C to get solid form of Mitapivat sulfate (1). Yield: 65%.
Example-2: Preparation of solid form of Mitapivat sulfate (1).
500 mg of Mitapivat sulfate was dissolved in 4 ml of acetic acid at room temperature. The reaction mass was heated to 60-65°C and stirred for 10-15 minutes at the same temperature. The obtained clear solution was filtered. The reaction mass was cooled to room temperature and stirred for 22 to 24 hours. Filtered the solid and dried the obtained solid at below 55°C to get solid form of Mitapivat sulfate (1). Yield: 93%. Purity: 99.98%.
Example-3: Preparation of solid form of Mitapivat sulfate (1).
500 mg of Mitapivat sulfate was dissolved in 5 ml of ethyl benzene at room temperature. The reaction mass was heated to 60-65°C and stirred for 22-24 hrs at the same temperature. The obtained reaction mass was cooled to room temperature and stirred for 1 to 2 hours. Filtered the solid and dried the obtained solid at below 55°C to get solid form of Mitapivat sulfate (1). Yield: 95%. Purity: 99.98%.
Example-4: Preparation of amorphous form of Mitapivat sulfate (1).
500 mg of Mitapivat sulfate (1) was dissolved in 20 ml of methanol at room temperature and stirred for 15 to 30 minutes. Filtered the obtained solution to make it particle free. The total reaction mixture was then transferred to a beaker and spray dried with the below settings: Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
Reaction mass was transferred into petri dish. The solid was further dried in vacuum tray dryer (VTD) below 40°C to yield amorphous form of Mitapivat sulfate (1).
Yield: 65 %.
Example-5: Preparation of amorphous form of Mitapivat sulfate (1).
500 mg of Mitapivat sulfate (1) was dissolved in 20 ml of methanol at room temperature and stirred for 15 to 30 minutes at 55 to 60°C. The obtained clear solution was filtered. This solution was added to 60 ml of methyl tert-butyl ether at -15°C to -20°C and stirred for 15 to 30 minutes. Filtered the solid and dried in vacuum tray dryer (VTD) below 50°C to yield amorphous form of Mitapivat sulfate (1). Yield: 91 %.
Example-6: Preparation of pure amorphous form of Mitapivat sulfate (1).
500 mg of Mitapivat sulfate was dissolved in 5 ml of dimethyl sulfoxide (DMSO at room temperature) and stirred for 15 to 30 minutes. The obtained reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.
Example-7: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
100 mg of Mitapivat sulfate was dissolved in 25 ml of Methanol at room temperature. To this 300 mg of hydroxypropyl beta cyclodextrin (HPpCD) was added and stirred for 15 to 30 minutes. The obtained clear solution was filtered. This clear solution was taken at room temperature and heated to 45-55°C. Distilled out the solvent using high vacuum. The obtained solid was dried to yield amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD). Yield: 92.5%.
Example-8: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD). 2.5g of Mitapivat sulfate was dissolved in 60 ml of Methanol at room temperature and stirred for 15 to 30 minutes. To this 2.5 g of hydroxypropyl beta cyclodextrin (HPpCD) was added and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion of Mitapivat sulfate (1) with HPpCD. Yield: 60%.; PXRD: Figure-1.
Example-9: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with polyvinylpyrrolidone-K-30 (PVP-K-30)
2.5 g of Mitapivat sulfate (1) was dissolved in 50 ml of methanol at room temperature. To this 2.5 g of polyvinylpyrrolidone-K-30 (PVP-K-30) was added and stirred for 15 to 20 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with polyvinylpyrrolidone- K-30 (PVP-K-30). Yield: 58%.
Example-10: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Soluplus 2.5 g of Mitapivat sulfate (1) was dissolved in 40 ml of methanol at room temperature. To this 2.5 g of Soluplus was added and stirred for 15 to 20 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Soluplus. Yield: 62%. Example-11: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Eudragit
2.5 g of Mitapivat sulfate (1) was dissolved in 80 ml of methanol at room temperature. To this 2.5 g of Eudragit was added and stirred for 15 to 20 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Eudragit. Yield: 56%. Example-12: Preparation of amorphous solid dispersion of Mitapivat sulfate
(1) with sulfobutylether-p-cyclodextrin (SBCED)
2.5 g of Mitapivat sulfate (1) was dissolved in 60 ml of methanol at room temperature. To this 2.5 g of sulfobutylether-P-cyclodextrin (SBCED) was added and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings: Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with sulfobutylether-P- cyclodextrin (SBCED). Yield: 58%.
Example- 13: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with (Hydroxypropyl)methyl cellulose E3 (HPMC-E3)
2.5 g of Mitapivat sulfate (1) was dissolved in 60 ml of methanol at room temperature and stirred for 15 to 30 minutes. To this 20 ml of methylene dichloride and 2.5 g of (Hydroxypropyl)methyl cellulose E3 (HPMC-E3) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with (Hydroxypropyl)methyl cellulose E3 (HPMC-E3). Yield: 56%.
Example-14: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Hydroxypropyl cellulose (HPC)
2.5 g of Mitapivat sulfate (1) was dissolved in 60 ml of methanol at room temperature and stirred for 15 to 30 minutes. To this 20 ml of methylene dichloride and 2.5 g of Hydroxypropyl cellulose (HPC) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Hydroxypropyl cellulose (HPC). Yield: 58%.
Example- 15: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Polyvinylpyrrolidone (PVP)-K-30 (PVP-K-30).
5.0 g of Mitapivat sulfate (1) was dissolved in 200 ml of methanol at room temperature. To this 15.0 g of Polyvinylpyrrolidone (PVP)-K-30 (PVP-K-30) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Polyvinylpyrrolidone (PVP)-K-30 (PVP-K-30). Yield: 65%.
Example-16: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Copovidone
5.0 g of Mitapivat sulfate (1) was dissolved in 100 ml of methanol at room temperature. To this 5.0 g of copovidone was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings: Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with copovidone. Yield: 62%.
Example- 17: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with HPMC-E3
5.0 g of Mitapivat sulfate (1) was dissolved in a mixture of 250 ml of methanol and methylene dichloride at room temperature. To this 15.0 g of (Hydroxypropyl)methyl cellulose E3 (HPMC-E3) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with (Hydroxypropyl)methyl cellulose E3 (HPMC-E3). Yield: 64%.
Example- 18: Preparation of amorphous solid dispersion of Mitapivat sulfate
(1) with Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS)
5.0 g of Mitapivat sulfate (1) was dissolved in a mixture of 250 ml of methanol and methylene dichloride at room temperature. To this 15.0 g of Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS). Yield: 64%.
Example-19: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with Polyethylene Glycol 6000 (PEG-6000)
5.0 g of Mitapivat sulfate (1) was dissolved in 150 ml of methanol at room temperature. To this 15.0 g of Polyethylene Glycol 6000 (PEG-6000) was added at room temperature and stirred for 15 to 30 minutes. The obtained clear solution was filtered. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 50°C
Outlet Temperature : 30°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried in Vacuum air tray dryer (VTD) to yield amorphous solid dispersion Mitapivat sulfate (1) with Polyethylene Glycol 6000 (PEG-6000). Yield: 66%.
Example-20: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with hydroxypropyl beta cyclodextrin (HPpCD).
250 mg of Mitapivat sulfate and 250 mg of hydroxypropyl beta cyclodextrin (HPpCD) were taken at room temperature. To this mixture of 5 ml of dimethyl sulfoxide (DMSO) and 2.5 ml of water were added and stirred for 15 to 30 minutes. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.
Example-21: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with maltose.
250 mg of Mitapivat sulfate (1) and 250 mg of maltose were taken at room temperature. To this mixture of 10 ml of dimethyl sulfoxide (DMSO) and 10 ml of water were added and stirred for 10 to 15 minutes at room temperature. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.
Example-22: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with maltodextrin.
250 mg of Mitapivat sulfate (1) and 250 mg of maltodextrin were taken at room temperature. To this mixture of 10 ml of dimethyl sulfoxide (DMSO) and 10 ml of water were added and stirred for 10 to 15 minutes at room temperature. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.
Example-23: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with mannitol.
250 mg of Mitapivat sulfate (1) and 250 mg of mannitol were taken at room temperature. To this mixture of 10 ml of dimethyl sulfoxide (DMSO) and 10 ml of water were added and stirred for 10 to 15 minutes at room temperature. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.
Example-24: Preparation of amorphous solid dispersion of Mitapivat sulfate (1) with isomalt.
250 mg of Mitapivat sulfate (1) and 250 mg of isomalt were taken at room temperature. To this mixture of 10 ml of dimethyl sulfoxide (DMSO) and 10 ml of water were added and stirred for 10 to 15 minutes at room temperature. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield solid dispersion of Mitapivat sulfate (1). Yield: 90%.

Claims

We Claim:
1. An amorphous solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
2. The amorphous solid dispersion of Mitapivat sulfate as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from hydroxypropyl beta cyclodextrin (HPpCD), polyvinylpyrrolidone-K-30 (PVP- K-30), Soluplus, Eudragit, sulfobutylether-P-cyclodextrin (SBCED), (Hydroxypropyl)methyl cellulose E3 (HPMC-E3), Hydroxypropyl cellulose (HPC), Copovidone, Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS), Polyethylene Glycol 6000 (PEG-6000), maltose, maltodextrin, mannitol, isomalt and/or its mixture thereof.
3. The amorphous solid dispersion of Mitapivat sulfate as claimed in claim 1, wherein the ratio of Mitapivat sulfate and pharmaceutically acceptable carrier is about 1:0.05 to about 1:5.
4. A process for preparation of solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients, the process comprising: a) preparing a solution of Mitapivat sulfate of formula (1) together with one or more pharmaceutically acceptable excipients in one or more solvents; and b) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
5. A process for the preparation of solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients, the process comprising: a) providing a solution of Mitapivat sulfate of formula (1) in one or more solvents, b) adding one or more pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Mitapivat sulfate of formula (1) with one or more pharmaceutically acceptable excipients.
6. The process for preparing solid dispersion of Mitapivat sulfate of formula (1) as claimed in claim 4 and 5, wherein the solvent is selected from chloro solvents, alcohol solvents, polar-aprotic solvents, polar solvents and/or mixture thereof.
7. A pharmaceutical composition comprising solid dispersion of Mitapivat sulfate of formula (1) of with one or more pharmaceutically acceptable excipients.
8. A process for the preparation of amorphous form of Mitapivat sulfate (1), which comprising of: a) dissolving Mitapivat sulfate (1) in one or more solvents, b) optionally, adding one or more anti-solvent(s) to the solution obtained from step a), and c) isolating the amorphous form of Mitapivat sulfate (1).
9. The process as claimed in claim 8, wherein in step-a) the solvent is selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2-butanol, t-butanol, and the like; "polar- aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; anti-solvent is selected from ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4- dioxane and the like.
10. The amorphous solid dispersion of Mitapivat sulfate (1) as claimed in claim 1, having an X-ray powder diffraction pattern substantially as shown in figure-
Figure imgf000025_0001
PCT/IB2024/054240 2023-05-02 2024-05-02 Solid forms of 8-quinoline sulfonamide, n-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl] phenyl]-sulfate and its process for preparation thereof Pending WO2024228131A1 (en)

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Citations (2)

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US11254652B2 (en) * 2017-11-22 2022-02-22 Agios Pharmaceuticals, Inc. Crystalline forms of N-(4-(4-(cyclopropymethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
US20230098234A1 (en) * 2020-01-28 2023-03-30 Teva Pharmaceuticals International Gmbh Solid state forms of mitapivat and process for preparation thereof

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US11254652B2 (en) * 2017-11-22 2022-02-22 Agios Pharmaceuticals, Inc. Crystalline forms of N-(4-(4-(cyclopropymethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
US20230098234A1 (en) * 2020-01-28 2023-03-30 Teva Pharmaceuticals International Gmbh Solid state forms of mitapivat and process for preparation thereof

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Title
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