WO2024084426A1 - Solid forms of disodium 3,3'-dioxo-[δ2,2'-biindoline]-5,5'-disulfonate and process for its preparation thereof - Google Patents

Solid forms of disodium 3,3'-dioxo-[δ2,2'-biindoline]-5,5'-disulfonate and process for its preparation thereof Download PDF

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WO2024084426A1
WO2024084426A1 PCT/IB2023/060559 IB2023060559W WO2024084426A1 WO 2024084426 A1 WO2024084426 A1 WO 2024084426A1 IB 2023060559 W IB2023060559 W IB 2023060559W WO 2024084426 A1 WO2024084426 A1 WO 2024084426A1
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indigotindisulfonate sodium
sodium
crystalline form
indigotindisulfonate
preparation
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PCT/IB2023/060559
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French (fr)
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Manik Reddy Pullagurla
Jagadeesh Babu Rangisetty
Bhaskar Reddy Pitta
Kiran Kumar Kothakonda
Rajesham Boge
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Biophore India Pharmaceuticals Pvt. Ltd
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Publication of WO2024084426A1 publication Critical patent/WO2024084426A1/en

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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B7/00—Indigoid dyes
    • C09B7/02—Bis-indole indigos
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0025—Crystal modifications; Special X-ray patterns
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
    • C09B67/0084—Dispersions of dyes
    • C09B67/0085—Non common dispersing agents
    • C09B67/0089—Non common dispersing agents non ionic dispersing agent, e.g. EO or PO addition products
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
    • C09B67/0084—Dispersions of dyes
    • C09B67/0085—Non common dispersing agents
    • C09B67/009—Non common dispersing agents polymeric dispersing agent

Definitions

  • the present invention relates to solid forms of Disodium 3, 3 ’-dioxo- [A 2,2 - biindoline]-5,5’-disulfonate and process for its preparation thereof.
  • the present invention also relates to amorphous form and amorphous solid dispersion of Di sodium 3, 3 ’-dioxo- [A 2,2 -biindoline] -5, 5’ -disulfonate having purity more than 99.0% (w/w) by High performance liquid chromatography (HPLC).
  • HPLC High performance liquid chromatography
  • the present invention further relates to a process for the preparation of crystalline form of 3,3'-dioxo-[2,2'-biindolinylidene]-5,5'-disulfonic acid having purity more than 99.0% (w/w) by High performance liquid chromatography (HPLC).
  • HPLC High performance liquid chromatography
  • Indigotindisulfonate sodium (1) is chemically referred to as Disodium 3,3’-dioxo- [A 2,2 -biindoline] -5, 5’ -disulfonate represented by the following structural formula.
  • Indigodisulfonic acid (2) is chemically referred to as 3,3'-dioxo-[2,2'- biindolinylidene]-5,5'-disulfonic acid represented by the following structural formula.
  • German patent DE201108 describes the synthesis of Indigotindisulfonate sodium by converting 3-(2-nitrophenyl)-2-oxopropanoic acid to (E)-[2,2'-biindolinylidene]- 3,3 '-dione followed by reaction with sulphuric acid to provide Indigotindisulfonate sodium (1). There is no information about the purity and yield of the product.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution, and flow properties of each polymorphic form.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry.
  • amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more like liquids where the arrangement of molecules is random.
  • Amorphous solids do not give a definitive x- ray diffraction pattern (XRD).
  • XRD x- ray diffraction pattern
  • amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide rapid bioavailability.
  • amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacturing process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.
  • the present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
  • In another objective of the present invention is to provide an amorphous form of Indigotindisulfonate sodium (1) and method of making amorphous form of Indigotindisulfonate sodium (1).
  • In another objective of the present invention is to provide an amorphous solid dispersion of Indigotindi sulfonate sodium (1) with one or more pharmaceutically acceptable excipients and method of making amorphous solid dispersion of Indigotindisulfonate sodium (1).
  • In another objective of the present invention is to provide crystalline form Bl, B2 & B3 of Indigotindisulfonate sodium (1) and method of making crystalline form B l, B2 & B3 of Indigotindisulfonate sodium (1).
  • In yet another objective of the present invention is to provide a process for the preparation of crystalline form of Indigodisulfonic acid (2).
  • In further objective of the present invention is to provide the solid forms of Indigotindisulfonate sodium (1), which may comprise of crystalline forms, amorphous form and amorphous solid dispersion having purity more than 99.0 %(w/w) by High performance liquid chromatography (HPLC).
  • HPLC High performance liquid chromatography
  • the present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
  • In one embodiment of the present invention provides an amorphous form of Indigotindisulfonate sodium (1).
  • a process for the preparation of amorphous form of Indigotindisulfonate sodium (1) which comprises: a) dissolving Indigotindisulfonate sodium (1) in water, b) heating the obtained solution at a suitable temperature, c) optionally, cooling the obtained solution in step b), and d) isolating the amorphous form of Indigotindisulfonate sodium (1).
  • In another embodiment of the present invention provides an amorphous solid dispersion of Indigotindisulfonate sodium (1).
  • crystalline forms Bl, B2 provides crystalline forms Bl, B2
  • a process for the preparation of crystalline forms Bl, B2 & B3 of Indigotindisulfonate sodium (1) which comprises: a) dissolving Indigotindi sulfonate sodium (1) in a suitable solvent or mixture thereof, b) heating the obtained suspension at 50-70°C, c) optionally, cooling the obtained solution in step b) to 25-35°C, and d) isolating the crystalline forms of Indigotindisulfonate sodium (1).
  • According to the embodiment of present invention provides a process for the preparation of crystalline form of Indigodisulfonic acid (2), which comprises: a) dissolving Indigodisulfonic acid (2) in water, b) heating the obtained mixture or suspension below 55°C, c) adding alcoholic solvent to the mixture obtained in step b), d) optionally, cooling the obtained solution in step c) to 0-5°C, and e) isolating the crystalline form of Indigodisulfonic acid (2).
  • Figure 1 Illustrates X-Ray Diffraction (XRD) pattern of amorphous form of Indigotindisulfonate sodium (1)
  • Figure 2 Illustrates X-Ray Diffraction (XRD) pattern of crystalline form Bl of Indigotindisulfonate sodium (1)
  • Figure 3 Illustrates X-Ray Diffraction (XRD) pattern of crystalline form B2 of Indigotindisulfonate sodium (1)
  • Figure 4 Illustrates X-Ray Diffraction (XRD) pattern of crystalline form B3 of Indigotindisulfonate sodium (1)
  • Figure 5 Illustrates X-Ray Diffraction (XRD) pattern of crystalline form of Indigodisulfonic acid (2). DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
  • XRPD X-ray powder diffraction
  • a process for the preparation of amorphous form of Indigotindisulfonate sodium (1) which comprises: a) dissolving Indigotindi sulfonate sodium (1) in water, b) heating the obtained solution at 55-70°C, c) optionally, cooling the obtained solution in step b), and d) isolating the amorphous form of Indigotindisulfonate sodium (1).
  • In another embodiment of the present invention provides an amorphous solid dispersion of Indigotindisulfonate sodium (1).
  • the suitable pharmaceutically acceptable excipient is selected from but not limited to lactose, maltose, sucrose, sorbitol, mannitol, polysorbate, maltodextrin, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), polyethylene glycol (PEG), polyethylene glycol-2000 (PEG-2000), polyethylene glycol-4000 (PEG- 4000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30 (PVP K-30), Copovidone, magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), soluplus , Neusilin , Eu
  • hydroxypropyl beta cyclodextrin HPpCD
  • Eudragit polyvinylpyrrolidone K-30
  • HPMC-E3 hydroxy propyl methyl cellulose-E3
  • Eudragit-EPO hydroxy propyl methyl cellulose -E3
  • HPBCD hydroxypropyl beta cyclodextrin
  • DCP Dicalcium phosphate
  • the ratio of Indigotindisulfonate sodium (1) and the pharmaceutically acceptable excipient may range from 1:1 to 1:5.
  • In another embodiment of the present invention provides a crystalline form B 1 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 2.
  • XRPD X-ray powder diffraction
  • the crystalline form B 1 of Indigotindi sulfonate sodium (1) which is characterized by an X-ray powder diffraction pattern having peaks at 18.64 ⁇ 0.2, 18.88 ⁇ 0.2, 26.47 ⁇ 0.2, 26.65 ⁇ 0.2, and 28.51 ⁇ 0.2 in 20 (2Theta).
  • the crystalline form B l Indigotindisulfonate sodium (1) which is further characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 5.35 ⁇ 0.2, 8.88 ⁇ 0.2, 18.64 ⁇ 0.2, 18.88 ⁇ 0.2, 26.47 ⁇ 0.2, 26.65 ⁇ 0.2, 27.38 ⁇ 0.2, 28.00 ⁇ 0.2, 28.16 ⁇ 0.2, 28.51 ⁇ 0.2, 30.55 ⁇ 0.2, 30.81 ⁇ 0.2, 30.99 ⁇ 0.2, 33.25 ⁇ 0.2, and 33.76 ⁇ 0.2 in 20 (2Theta).
  • XRPD X-ray powder diffraction
  • a crystalline form B2 of Indigotindisulfonate sodium (1) which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 3.
  • XRPD X-ray powder diffraction
  • the crystalline form B2 of Indigotindi sulfonate sodium (1) which is characterized by an X-ray powder diffraction pattern having peaks at 5.2 ⁇ 0.2, 10.23 ⁇ 0.2, 18.40 ⁇ 0.2, 19.55 ⁇ 0.2, and 22.25 ⁇ 0.2 in 29 (2Theta).
  • the crystalline form B2 Indigotindisulfonate sodium (1) which is further characterized by an X-ray powder diffraction pattern having peaks at 5.2 ⁇ 0.2, 10.23 ⁇ 0.2, 18.40 ⁇ 0.2, 19.55 ⁇ 0.2, 22.25 ⁇ 0.2, 26.07 ⁇ 0.2, 26.66 ⁇ 0.2, 30.01 ⁇ 0.2, 30.62 ⁇ 0.2, and 36.67 ⁇ 0.2 in 29 (2Theta).
  • In another embodiment of the present invention provides a crystalline form B3 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 4.
  • XRPD X-ray powder diffraction
  • the embodiment of the present invention provides the crystalline form B3 of Indigotindi sulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 18.56 ⁇ 0.2, 18.71 ⁇ 0.2, 17.90 ⁇ 0.2, 33.90 ⁇ 0.2, 31.02 ⁇ 0.2 and 23.35 ⁇ 0.2 in 29 (2Theta).
  • the crystalline form B3 Indigotindisulfonate sodium (1) which is further characterized by an X-ray powder diffraction pattern having peaks at 9.96 ⁇ 0.2, 15.6 + 0.2, 16.18 + 0.2, 16.93 + 0.2, 17.90 + 0.2, 18.56 + 0.2, 18.71 + 0.2, 20.10 + 0.2, 23.35 + 0.2, 24.64 + 0.2, 25.07 + 0.2, 27.31 + 0.2, 27.96 + 0.2, 28.43 + 0.2, 29.87 + 0.2, 30.37 + 0.2, 31.02 + 0.2, 33.90 + 0.2, 36.13 + 0.2, 37.92 + 0.2, 39.02 + 0.2, 41.26 + 0.2, 45.44 + 0.2 and 47.05 ⁇ 0.2 in 20 (2Theta).
  • a process for the preparation of crystalline forms Bl, B2 & B3 of Indigotindisulfonate sodium (1) which comprises: a) dissolving Indigotindi sulfonate sodium (1) in a suitable solvent or mixture thereof, b) heating the reaction mass to a suitable temperature, c) cooling the reaction mass to a suitable temperature, and d) isolating the crystalline forms of Indigotindisulfonate sodium (1).
  • the solvent used in step (a) is selected from “alcoholic solvents” such as methanol, ethanol, n propanol, isopropanol, n butanol, isobutanol, t butanol and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N methyl pyrrolidone (NMP) and the like; “polar solvents” such as water and or mixtures thereof.
  • alcoholic solvents such as methanol, ethanol, n propanol, isopropanol, n butanol, isobutanol, t butanol and the like
  • ester solvents such
  • isolating of solid forms of Indigotindisulfonate sodium (1) involves removal of solvent is carried out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), sprayfreeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or by any other suitable techniques known in the art.
  • suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization),
  • drying of solid forms of Indigotindisulfonate sodium (1) is conducted in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be conducted at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • Solid forms of Indigotindisulfonate sodium (1) prepared according to the present invention is micronized or milled in conventional techniques 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 are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronisation may be performed before drying, or after the completion of drying of the product.
  • a pharmaceutical composition comprising Indigotindisulfonate sodium (1) of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Indigotindisulfonate sodium (1) is prepared by the process described in PCT (Patent cooperation treaty) publication number WO2018116325 Al or by any other process.
  • a crystalline form of Indigodisulfonic acid (2) which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 5.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction spectrum
  • According to the embodiment of present invention provides a process for the preparation of crystalline form of Indigodisulfonic acid (2), which comprises: a) dissolving Indigodisulfonic acid (2) in water, b) heating the obtained mixture or suspension at 50-55°C, c) adding alcoholic solvent to the solution obtained in step b), d) optionally, cooling the obtained solution in step c) to 0-5°C, and e) isolating the crystalline form of Indigodisulfonic acid (2).
  • the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or its mixture thereof.
  • the starting material Indigodisulfonic acid (2) is prepared by the process described in PCT (Patent cooperation treaty) publication number WO2018116325 Al or by any other process.
  • in further embodiment of the present invention provides the solid forms of Indigotindisulfonate sodium (1), which may comprise of crystalline forms, amorphous form and amorphous solid dispersion is having purity greater than 99.0 %(w/w) by High performance liquid chromatography (HPLC).
  • HPLC High performance liquid chromatography
  • Example- 1 Preparation of amorphous form of Indigotindisulfonate sodium
  • Example-3 Preparation of solid dispersion of Indigotindisulfonate sodium (1) with hydroxy propyl methyl cellulose-E3 (HPMC-E3)
  • Indigotindisulfonate sodium (1) 250 mg
  • Co-povidone 500 mg
  • the reaction mass was transferred to a petri dish and freeze dried for lyophilization. The solid was further dried at below 45 °C to get title compound.
  • Example-5 Preparation of solid dispersions of Indigotindisulfonate sodium (1) with Hydroxypropyl beta-Cyclodextrin (HPpCD)
  • Indigotindisulfonate sodium (1) 250 mg
  • HPpCD Hydroxypropyl beta-Cyclodextrin
  • Example-6 Preparation of Crystalline form Bl of Indigotindisulfonate sodium (1)
  • Example-7 Preparation of Crystalline form B2 of Indigotindisulfonate sodium (1)
  • Example-8 Preparation of Crystalline form B3 of Indigotindisulfonate sodium (1)

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Abstract

The present invention relates to solid forms of Disodium 3,3'-dioxo-[Δ2,2'-biindoline]- 5,5'-disulfonate and process for its preparation thereof. The present invention also relates to amorphous form and amorphous solid dispersion of Disodium 3,3'-dioxo- [Δ2,2'-biindoline]-5,5'-disulfonate is having purity greater than 99.0% (w/w) by HPLC. The present invention further relates to process for the preparation of crystalline form of 3,3'-dioxo-[2,2'-biindolinylidene]-5,5'-disulfonic acid is having purity greater than 99.0% (w/w) by HPLC.

Description

"SOLID FORMS OF DISODIUM 3,3’-DIOXO-[A2’2 -BIINDOLINE]-5,5’- DISULFONATE AND PROCESS FOR ITS PREPARATION THEREOF"
FIELD OF THE INVENTION
The present invention relates to solid forms of Disodium 3, 3 ’-dioxo- [A2,2 - biindoline]-5,5’-disulfonate and process for its preparation thereof.
The present invention also relates to amorphous form and amorphous solid dispersion of Di sodium 3, 3 ’-dioxo- [A2,2 -biindoline] -5, 5’ -disulfonate having purity more than 99.0% (w/w) by High performance liquid chromatography (HPLC).
The present invention further relates to a process for the preparation of crystalline form of 3,3'-dioxo-[2,2'-biindolinylidene]-5,5'-disulfonic acid having purity more than 99.0% (w/w) by High performance liquid chromatography (HPLC).
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.
Indigotindisulfonate sodium (1) is chemically referred to as Disodium 3,3’-dioxo- [A2,2 -biindoline] -5, 5’ -disulfonate represented by the following structural formula.
Figure imgf000003_0001
Indigodisulfonic acid (2) is chemically referred to as 3,3'-dioxo-[2,2'- biindolinylidene]-5,5'-disulfonic acid represented by the following structural formula.
Figure imgf000004_0001
German patent DE201108, describes the synthesis of Indigotindisulfonate sodium by converting 3-(2-nitrophenyl)-2-oxopropanoic acid to (E)-[2,2'-biindolinylidene]- 3,3 '-dione followed by reaction with sulphuric acid to provide Indigotindisulfonate sodium (1). There is no information about the purity and yield of the product.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution, and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry.
Furthermore, amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more like liquids where the arrangement of molecules is random. Amorphous solids do not give a definitive x- ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide rapid bioavailability. Furthermore, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacturing process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.
OBJECTIVE OF THE INVENTION
The present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
In another objective of the present invention is to provide an amorphous form of Indigotindisulfonate sodium (1) and method of making amorphous form of Indigotindisulfonate sodium (1).
In another objective of the present invention is to provide an amorphous solid dispersion of Indigotindi sulfonate sodium (1) with one or more pharmaceutically acceptable excipients and method of making amorphous solid dispersion of Indigotindisulfonate sodium (1).
In another objective of the present invention is to provide crystalline form Bl, B2 & B3 of Indigotindisulfonate sodium (1) and method of making crystalline form B l, B2 & B3 of Indigotindisulfonate sodium (1).
In yet another objective of the present invention is to provide a process for the preparation of crystalline form of Indigodisulfonic acid (2).
In further objective of the present invention is to provide the solid forms of Indigotindisulfonate sodium (1), which may comprise of crystalline forms, amorphous form and amorphous solid dispersion having purity more than 99.0 %(w/w) by High performance liquid chromatography (HPLC). SUMMARY OF THE INVENTION
The present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
In one embodiment of the present invention provides an amorphous form of Indigotindisulfonate sodium (1).
According to the embodiment of present invention provides a process for the preparation of amorphous form of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindisulfonate sodium (1) in water, b) heating the obtained solution at a suitable temperature, c) optionally, cooling the obtained solution in step b), and d) isolating the amorphous form of Indigotindisulfonate sodium (1).
In another embodiment of the present invention provides an amorphous solid dispersion of Indigotindisulfonate sodium (1).
According to the embodiment of present invention provides a process for the preparation of amorphous solid dispersion containing Indigotindisulfonate sodium (1) with one or more pharmaceutically acceptable excipient(s), which comprises: a) dissolving Indigotindisulfonate sodium (1) and at least one pharmaceutically acceptable excipient in water, b) isolating amorphous solid dispersion of Indigotindisulfonate sodium (1) with one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention provides crystalline forms Bl, B2
Figure imgf000006_0001
According to the embodiment of present invention provides a process for the preparation of crystalline forms Bl, B2 & B3 of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindi sulfonate sodium (1) in a suitable solvent or mixture thereof, b) heating the obtained suspension at 50-70°C, c) optionally, cooling the obtained solution in step b) to 25-35°C, and d) isolating the crystalline forms of Indigotindisulfonate sodium (1).
In yet another embodiment of the present invention provides crystalline form of Indigodisulfonic acid (2)
According to the embodiment of present invention provides a process for the preparation of crystalline form of Indigodisulfonic acid (2), which comprises: a) dissolving Indigodisulfonic acid (2) in water, b) heating the obtained mixture or suspension below 55°C, c) adding alcoholic solvent to the mixture obtained in step b), d) optionally, cooling the obtained solution in step c) to 0-5°C, and e) isolating the crystalline form of Indigodisulfonic acid (2).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Illustrates X-Ray Diffraction (XRD) pattern of amorphous form of Indigotindisulfonate sodium (1)
Figure 2: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form Bl of Indigotindisulfonate sodium (1)
Figure 3: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form B2 of Indigotindisulfonate sodium (1)
Figure 4: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form B3 of Indigotindisulfonate sodium (1)
Figure 5: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form of Indigodisulfonic acid (2). DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to solid forms of Indigotindisulfonate sodium (1) and method of making solid forms of Indigotindisulfonate sodium (1).
In one embodiment of the present invention provides an amorphous form of Indigotindisulfonate sodium (1), which is characterized by X-ray powder diffraction (XRPD) pattern as depicted in Figure 1.
According to the embodiment of present invention provides a process for the preparation of amorphous form of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindi sulfonate sodium (1) in water, b) heating the obtained solution at 55-70°C, c) optionally, cooling the obtained solution in step b), and d) isolating the amorphous form of Indigotindisulfonate sodium (1).
In another embodiment of the present invention provides an amorphous solid dispersion of Indigotindisulfonate sodium (1).
According to the embodiment of present invention provides a process for the preparation of amorphous solid dispersion containing Indigotindisulfonate sodium (1) with one or more pharmaceutically acceptable excipient(s), which comprises: a) dissolving Indigotindisulfonate sodium (1) and at least one pharmaceutically acceptable excipient in water, and b) isolating amorphous solid dispersion of Indigotindisulfonate sodium (1) with one or more pharmaceutically acceptable excipients.
According to the embodiment of present invention, the suitable pharmaceutically acceptable excipient is selected from but not limited to lactose, maltose, sucrose, sorbitol, mannitol, polysorbate, maltodextrin, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), polyethylene glycol (PEG), polyethylene glycol-2000 (PEG-2000), polyethylene glycol-4000 (PEG- 4000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30 (PVP K-30), Copovidone, magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), soluplus , Neusilin , Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP), croscarmellose, sodium croscarmellose, a- cyclodextrin, P-Cyclodextrin, y-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-P-cyclodextrin (SBCED) or the like. Preferably hydroxypropyl beta cyclodextrin (HPpCD), Eudragit, polyvinylpyrrolidone K-30 (PVP K-30), hydroxy propyl methyl cellulose-E3 (HPMC-E3), Eudragit-EPO, hydroxy propyl methyl cellulose -E3 (HPMC-E3), hydroxypropyl beta cyclodextrin (HPBCD), Neusilin, Dicalcium phosphate (DCP), were used in the present invention, preferably using polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG), more preferably using polyvinylpyrrolidone (PVP).
According to the embodiment of present invention, wherein the ratio of Indigotindisulfonate sodium (1) and the pharmaceutically acceptable excipient may range from 1:1 to 1:5.
In another embodiment of the present invention provides a crystalline form B 1 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 2.
According to the embodiment of the present invention provides the crystalline form B 1 of Indigotindi sulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 18.64 ± 0.2, 18.88 ± 0.2, 26.47 ± 0.2, 26.65 ± 0.2, and 28.51 ± 0.2 in 20 (2Theta). According to the embodiment of the present invention provides the crystalline form B l Indigotindisulfonate sodium (1), which is further characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 5.35 ± 0.2, 8.88 ± 0.2, 18.64 ± 0.2, 18.88 ± 0.2, 26.47 ± 0.2, 26.65 ± 0.2, 27.38 ± 0.2, 28.00 ± 0.2, 28.16 ± 0.2, 28.51 ± 0.2, 30.55 ± 0.2, 30.81 ± 0.2, 30.99 ± 0.2, 33.25 ± 0.2, and 33.76 ± 0.2 in 20 (2Theta).
In another embodiment of the present invention provides a crystalline form B2 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 3.
According to the embodiment of the present invention provides the crystalline form B2 of Indigotindi sulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 5.2 ± 0.2, 10.23 ± 0.2, 18.40 ± 0.2, 19.55 ± 0.2, and 22.25 ± 0.2 in 29 (2Theta).
According to the embodiment of the present invention provides the crystalline form B2 Indigotindisulfonate sodium (1), which is further characterized by an X-ray powder diffraction pattern having peaks at 5.2 ± 0.2, 10.23 ± 0.2, 18.40 ± 0.2, 19.55 ± 0.2, 22.25 ± 0.2, 26.07 ± 0.2, 26.66 ± 0.2, 30.01 ± 0.2, 30.62 ± 0.2, and 36.67 ± 0.2 in 29 (2Theta).
In another embodiment of the present invention provides a crystalline form B3 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 4.
According to the embodiment of the present invention provides the crystalline form B3 of Indigotindi sulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 18.56 ± 0.2, 18.71 ± 0.2, 17.90 ± 0.2, 33.90 ± 0.2, 31.02 ± 0.2 and 23.35 ± 0.2 in 29 (2Theta). According to the embodiment of the present invention provides the crystalline form B3 Indigotindisulfonate sodium (1), which is further characterized by an X-ray powder diffraction pattern having peaks at 9.96 ± 0.2, 15.6 + 0.2, 16.18 + 0.2, 16.93 + 0.2, 17.90 + 0.2, 18.56 + 0.2, 18.71 + 0.2, 20.10 + 0.2, 23.35 + 0.2, 24.64 + 0.2, 25.07 + 0.2, 27.31 + 0.2, 27.96 + 0.2, 28.43 + 0.2, 29.87 + 0.2, 30.37 + 0.2, 31.02 + 0.2, 33.90 + 0.2, 36.13 + 0.2, 37.92 + 0.2, 39.02 + 0.2, 41.26 + 0.2, 45.44 + 0.2 and 47.05 ± 0.2 in 20 (2Theta).
According to the embodiment of present invention provides a process for the preparation of crystalline forms Bl, B2 & B3 of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindi sulfonate sodium (1) in a suitable solvent or mixture thereof, b) heating the reaction mass to a suitable temperature, c) cooling the reaction mass to a suitable temperature, and d) isolating the crystalline forms of Indigotindisulfonate sodium (1).
According to the embodiment of present invention, the solvent used in step (a) is selected from “alcoholic solvents” such as methanol, ethanol, n propanol, isopropanol, n butanol, isobutanol, t butanol and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N methyl pyrrolidone (NMP) and the like; “polar solvents” such as water and or mixtures thereof.
According to the embodiment of present invention, isolating of solid forms of Indigotindisulfonate sodium (1) involves removal of solvent is carried out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), sprayfreeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or by any other suitable techniques known in the art.
According to the embodiment of present invention, drying of solid forms of Indigotindisulfonate sodium (1) is conducted in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be conducted at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
Solid forms of Indigotindisulfonate sodium (1) prepared according to the present invention is micronized or milled in conventional techniques 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 are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronisation may be performed before drying, or after the completion of drying of the product.
According to the embodiment of present invention a pharmaceutical composition comprising Indigotindisulfonate sodium (1) of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
According to the embodiment of present invention provides the starting material Indigotindisulfonate sodium (1) is prepared by the process described in PCT (Patent cooperation treaty) publication number WO2018116325 Al or by any other process. In yet another embodiment of the present invention provides a crystalline form of Indigodisulfonic acid (2), which is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 5. According to the embodiment of the present invention provides the characteristic
X-ray powder diffraction spectrum (XRPD) peaks of crystalline form of
Indigodisulfonic acid (2) are provided in Table 1:
Table 1:
Figure imgf000013_0001
Table 2:
Figure imgf000013_0002
Figure imgf000014_0001
According to the embodiment of present invention provides a process for the preparation of crystalline form of Indigodisulfonic acid (2), which comprises: a) dissolving Indigodisulfonic acid (2) in water, b) heating the obtained mixture or suspension at 50-55°C, c) adding alcoholic solvent to the solution obtained in step b), d) optionally, cooling the obtained solution in step c) to 0-5°C, and e) isolating the crystalline form of Indigodisulfonic acid (2). According to the embodiment of the present invention provides, the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or its mixture thereof. According to the embodiment of present invention provides the starting material Indigodisulfonic acid (2) is prepared by the process described in PCT (Patent cooperation treaty) publication number WO2018116325 Al or by any other process.
In further embodiment of the present invention provides the solid forms of Indigotindisulfonate sodium (1), which may comprise of crystalline forms, amorphous form and amorphous solid dispersion is having purity greater than 99.0 %(w/w) by High performance liquid chromatography (HPLC).
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 amorphous form of Indigotindisulfonate sodium
(1)
Water (120 ml) was added to Indigotindisulfonate sodium (1) (2 gm) and heated to 60-65 °C to get the clear solution. The resulting solution was cooled to room temperature and lyophilized to get title compound. The PXRD pattern of the obtained compound is shown in figure 1.
Example-2: Preparation of Amorphous form of Indigotindisulfonate sodium
(1)
Water (120 ml) was added to Indigotindisulfonate sodium (1) (2 gm) and heated to 60-65 °C to get the clear solution. The solvent was evaporated in rotavapor under reduced pressure to get title compound.
Example-3: Preparation of solid dispersion of Indigotindisulfonate sodium (1) with hydroxy propyl methyl cellulose-E3 (HPMC-E3)
Indigotindisulfonate sodium (1) (250 mg) and hydroxy propyl methyl cellulose-E3 (HPMC-E3) (500 mg) were added to water (20 mL) at 25-30 °C and stirred for 10- 15 minutes. The reaction mass was transferred to a petri dish and freeze dried for lyophilization. The solid was further dried at below 45°C to get title compound. Example-4: Preparation of solid dispersions of Indigotindisulfonate sodium (1) with Co-povidone
Indigotindisulfonate sodium (1) (250 mg) and Co-povidone (500 mg) were added to water (20 mL) at 25-30 °C and stirred for 10-15 minutes. The reaction mass was transferred to a petri dish and freeze dried for lyophilization. The solid was further dried at below 45 °C to get title compound.
Example-5: Preparation of solid dispersions of Indigotindisulfonate sodium (1) with Hydroxypropyl beta-Cyclodextrin (HPpCD)
Indigotindisulfonate sodium (1) (250 mg) and Hydroxypropyl beta-Cyclodextrin (HPpCD) (500mg) were added to water (50 mL) at 25-30 °C and stirred for 10-15 mins. The reaction mass was transferred to a petri dish and freeze dried for lyophilization. The solid was further dried at below 45°C to get title compound.
Example-6: Preparation of Crystalline form Bl of Indigotindisulfonate sodium (1)
Water (120 ml) was added to Indigotindisulfonate sodium (1) (2 gm) and heated to 60-65°C to get the clear solution. The resulting solution was cooled to room temperature and Spray dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure 2.
Example-7: Preparation of Crystalline form B2 of Indigotindisulfonate sodium (1)
A Mixture of dimethyl sulfoxide and ethyl acetate (1:3) was added to Indigotindisulfonate sodium (1) (1 gm). The reaction mass was heated to 60-65 °C and stirred for 2-3 hours. Cooled the reaction mass to room temperature. Filtered the resulting solid, washed with ethyl acetate and dried to get the title compound. Yield: 90%. The PXRD pattern of the obtained compound is shown in figure 3.
Example-8: Preparation of Crystalline form B3 of Indigotindisulfonate sodium (1)
Methanol (30 ml) was added to Indigotindisulfonate sodium (1) (1 gm) to get the slurry. The reaction mass was heated to 55-65 °C and stirred for 20-24 hours. Cooled the reaction mass to room temperature. Filtered the resulting solid, washed with methanol and dried to get the title compound. Yield: 90%. The PXRD pattern of the obtained compound is shown in figure 4.
Example-9: Preparation of crystalline form of Indigodisulfonic acid (2)
Indigodisulfonic acid (2) was dissolved in water (90 ml) at room temperature. The reaction temperature was raised to 50-55°C and stirred for 10 minutes. Methanol (200 ml) was then slowly added. Cooled the reaction mass to 0-5°C and stirred for 30-60 minutes. Filtered the resulting solid and dried to get the title compound. Yield: 26.5 g. The PXRD pattern of the obtained compound is shown in figure 5.

Claims

We claim:
1. An amorphous form of Indigotindisulfonate sodium (1).
Figure imgf000018_0001
2. A process for the preparation of amorphous form of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindisulfonate sodium (1) in water; b) heating the mixture below 70°C; c) optionally, cooling the mixture in step b); and d) isolating the amorphous form of Indigotindisulfonate sodium (1).
3. An Amorphous solid dispersion of Indigotindisulfonate sodium (1) with atleast one pharmaceutically acceptable excipient.
4. A process for the preparation of an Amorphous solid dispersion of Indigotindisulfonate sodium (1), which comprises: a) dissolving Indigotindisulfonate sodium (1) and atleast one pharmaceutically acceptable excipient in water, and b) isolating to get amorphous solid dispersion of Indigotindisulfonate sodium (1).
5. The process as claimed in claim 3 and 4, wherein said pharmaceutical acceptable excipient is selected from the group comprising of lactose, maltose, sucrose, sorbitol, mannitol, polysorbate, maltodextrin, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), polyethylene glycol (PEG), polyethylene glycol-4000 (PEG-4000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), Co-povidone, povidone, magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), soluplus , Neusilin , Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP) , croscarmellose, sodium croscarmellose, a- cyclodextrin, P-Cyclodextrin, y-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-P-cyclodextrin (SBCED) or the like. Preferably hydroxypropyl beta cyclodextrin (HPBCD), Eudragit, polyvinylpyrrolidone K- 30 (PVP K-30), hydroxy propyl methyl cellulose-E3 (HPMC-E3), Eudragit- EPO, hydroxy propyl methyl cellulose -E3 (HPMC-E3), hydroxypropyl beta cyclodextrin (HPBCD), Neusilin, Dicalcium phosphate (DCP) or its mixture thereof.
6. The process as claimed in claim 4, wherein the ratio of Indigotindisulfonate sodium (1) and the pharmaceutically acceptable excipient may range from 1 : 1 to 1:5.
7. A crystalline form Bl of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 18.64 ± 0.2, 18.88 ± 0.2, 26.47 ± 0.2, 26.65 ± 0.2, and 28.51 ± 0.2 in 29 (2Theta) and X-ray powder diffraction (XRPD) pattern as depicted in Figure 2.
8. A process for the preparation of crystalline form B l of Indigotindisulfonate sodium (1) of claim 7, which comprises: a) dissolving Indigotindisulfonate sodium (1) in water, b) heating the mixture below 65 °C, c) optionally, cooling the step b mixture to 25-35°C, and d) isolating the crystalline form B l of Indigotindisulfonate sodium (1).
9. A crystalline form B2 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 5.2 ± 0.2, 10.23 ± 0.2, 18.40 ± 0.2, 19.55 ± 0.2, and 22.25 ± 0.2 in 29 (2Theta) and X-ray powder diffraction (XRPD) pattern as depicted in Figure 3.
10. A process for the preparation of crystalline form B2 of Indigotindisulfonate sodium (1) of claim 9, which comprises: a) dissolving Indigotindisulfonate sodium (1) in a mixture of dimethyl sulfoxide and ethyl acetate, b) heating the mixture below 65°C, c) optionally, cooling the step b) mixture to 25-35°C, and d) isolating the crystalline form B2 of Indigotindisulfonate sodium (1). A crystalline form B3 of Indigotindisulfonate sodium (1), which is characterized by an X-ray powder diffraction pattern having peaks at 18.56 ± 0.2, 18.71 ± 0.2, 17.90 ± 0.2, 33.90 ± 0.2, 31.02 ± 0.2 and 23.35 ± 0.2 in 20 (2Theta) and X-ray powder diffraction (XRPD) pattern as depicted in Figure 4. A process for the preparation of crystalline form B3 of Indigotindisulfonate sodium (1) of claim 11, comprising the steps of: a) dissolving Indigotindisulfonate sodium (1) in methanol, b) heating the mixture below 65°C, c) optionally, cooling the step b mixture to 25-35°C, and d) isolating the crystalline form B3 of Indigotindisulfonate sodium (1). A crystalline form of Indigodisulfonic acid (2), which is characterized by an X-ray powder diffraction pattern having peaks at 4.57 ± 0.2, 18.62 ± 0.2, 23.35 ± 0.2, 26.83 ± 0.2, and 30.96 ± 0.2 in 29 (2Theta) and X-ray powder diffraction (XRPD) pattern as depicted in Figure 5. A process for the preparation of crystalline form of Indigodisulfonic acid (2) of claim 13, which comprises: a) dissolving Indigodisulfonic acid (2) in water, b) heating the obtained suspension at 50-55°C, c) adding alcoholic solvent to the solution obtained in step b), d) optionally, cooling the obtained solution in step c) to 0-5°C, and e) isolating the crystalline form of Indigodisulfonic acid (2). The process as claimed in claim 14, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol or its mixture thereof.
PCT/IB2023/060559 2022-10-19 2023-10-19 Solid forms of disodium 3,3'-dioxo-[δ2,2'-biindoline]-5,5'-disulfonate and process for its preparation thereof WO2024084426A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093866A2 (en) * 2015-12-01 2017-06-08 Dishman Pharmaceuticals And Chemicals Limited An improved process for the preparation of indigo carmine
WO2018116325A1 (en) * 2016-12-23 2018-06-28 Biophore India Pharmaceuticals Pvt. Ltd. Novel process for the preparation of indigotindisulfonate sodium (indigo carmine)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093866A2 (en) * 2015-12-01 2017-06-08 Dishman Pharmaceuticals And Chemicals Limited An improved process for the preparation of indigo carmine
WO2018116325A1 (en) * 2016-12-23 2018-06-28 Biophore India Pharmaceuticals Pvt. Ltd. Novel process for the preparation of indigotindisulfonate sodium (indigo carmine)

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