WO2022224269A1 - Co-crystals, salts and solid forms of niraparib - Google Patents

Co-crystals, salts and solid forms of niraparib Download PDF

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WO2022224269A1
WO2022224269A1 PCT/IN2022/050369 IN2022050369W WO2022224269A1 WO 2022224269 A1 WO2022224269 A1 WO 2022224269A1 IN 2022050369 W IN2022050369 W IN 2022050369W WO 2022224269 A1 WO2022224269 A1 WO 2022224269A1
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Prior art keywords
crystal
proline
niraparib tosylate
niraparib
tosylate
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PCT/IN2022/050369
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French (fr)
Inventor
Srinivas Laxminarayan Pathi
Arijit Das
Ramanaiah CHENNURU
Pullareddy LAKKIREDDY
Ramesh DEVARAPALLI
Ramesh Reddy MUDDA
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Cipla Limited
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Publication of WO2022224269A1 publication Critical patent/WO2022224269A1/en

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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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Niraparib sold under the brand name Zejula, is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
  • PARP poly(ADP-ribose) polymerase
  • Niraparib is chemically known as 2-[4-[(3S)-3-piperidyl]phenyl]- indazole-7- carboxamide. Niraparib, was first described in U.S. Pat. No.8,071,623B2, and has the following chemical structure: Formula I Pharmaceutical active ingredients (APIs) can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, co-crystals and amorphous solids. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability and other performance characteristics of the drugs. Niraparib exhibits stereoisomerism due to the presence of a single chiral center.
  • Niraparib may exist in a number of different polymorphic forms.
  • the anhydrate form has been detected by DSC but is only formed at very high temperatures.
  • the crystallization ensures routine production of the monohydrate form which is conformed routinely by XRPD.
  • Crystalline forms of Niraparib and salts thereof can possess advantageous properties in terms of their solubility and/or stability and/or bioavailability and/or impurity profile and/or filtration characteristics and/or drying characteristics and/or their ability to be handled and/or micronized and/or preparation of solid oral forms.
  • a solid state form of niraparib, (3S)-3- ⁇ 4-[7-(amino-carbonyl)-2H-indazol-2- yl]phenyl ⁇ piperidinium p-toluenesulfonate monohydrate (1:1:1), is disclosed in U.S. Patent No.8,436,185 B2.
  • Formula II WO2018183354 is directed to Form I, Form II and Form III of Niraparib tosylate, each substantially free of the other two forms.
  • WO 2020/072796 is directed to crystalline Form I, Form II ,Form III, Form IV and Form V of Niraparib free base.
  • WO 2020/072860 is directed to crystalline anhydrous Form A of Niraparib tosylate.
  • Niraparib tosylate monohydrate hereinafter referred to as “Niraparib tosylate” is classified as having low solubility based on the experimentally determined solubility over the pH range according to the BCS guidelines (BCS Class II). Due to low solubility, particle size distribution is controlled in the active substance specification. Due to low solubility in water, Niraparib has a low dissolution rate and as a result exhibits poor bioavailability. Hence, it is necessary to find crystal form with high solubility with improve efficiency of the drug.
  • Niraparib aqueous solubility of Niraparib or its pharmaceutically acceptable salt or a stereoisomer or tautomer thereof, especially the solubility in a gastric or intestinal environment may be distinctly enhanced by combining this drug with certain co-formers.
  • An object of the present invention is to provide novel solid state forms of Niraparib such as novel crystalline forms and co-crystals. Another object of the present invention is to provide a process for the preparation of novel solid state forms of Niraparib. Yet another object of the invention is to provide pharmaceutical composition comprising a therapeutically effective amount of novel solid state forms of Niraparib and at least one pharmaceutically acceptable carrier Yet another object of the invention is to provide method of treatment of human or animal body by therapy, wherein novel solid state forms of Niraparib, are useful.
  • the present invention is directed to novel pharmaceutical compounds comprising Niraparib tosylate and a co-former, methods of preparing such pharmaceutical compounds, and methods of treating epithelial ovarian, fallopian tube, or primary peritoneal cancer with such pharmaceutical compounds.
  • the novel solid state forms may be a co-crystal or a polymorph of a co-crystal.
  • a “co-crystal” according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure.
  • a “co-crystal” consists of a fixed ratio of atoms that are held together in a defined spatial arrangement by ionic, covalent, hydrogen bonds, van der Waals forces or ⁇ - ⁇ interactions.
  • the elements of a “co-crystal” comprise Niraparib tosylate and a co- former, water, ions, or solvents.
  • a “co-crystal” according to the present invention represent “a druggable form” of a Niraparib tosylate with a co-former.
  • A” druggable form” as used herein is defined as any form (salt, amorphous, crystal (of a salt), co- crystal, solution, dispersion, mixture, etc.) that Niraparib tosylate with a co- former component might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom.
  • a co-former is selected from an alkaloid and an organic acid.
  • the present invention provides novel synergistic pharmaceutical compounds of Niraparib tosylate with an alkaloid component.
  • the present invention provides novel synergistic pharmaceutical compounds of Niraparib tosylate with group of organic acids.
  • the novel pharmaceutical compounds are relatively stable towards the moisture and humidity, thereby representing an amorphous or a crystalline form of pharmaceutical compound, thus exhibit better solubility, dissolution rate, hence enhanced bioavailability and efficacy of the parent molecule in lower doses.
  • the co-crystals of the present invention could be either in a crystalline or amorphous form.
  • the co-crystals of Niraparib tosylate of the present invention have been characterized by means of Powder X-ray diffraction pattern (PXRD) and differential scanning calorimetry (DSC).
  • PXRD Powder X-ray diffraction pattern
  • DSC differential scanning calorimetry
  • a variety of other solid state spectroscopic techniques can be used including, but not limited to, Raman spectroscopy, FTIR spectroscopy, vibrational spectroscopy, polarized light microscopy (PLM), and solid state NMR, the 13 C NMR and 1 H NMR (in a suitable solvent, e.g., in D 2 O or DMSO-D6 ) to evaluate the chemical structure, Dynamic Gravimetric Vapor Sorption (DVS) to evaluate the hygroscopicity, thermogravimetric analysis (TGA) to evaluate the thermal properties, and/or chromatography (e.g., HPLC) in a suitable solvent to evaluate the purity.
  • DXRD
  • Products as described herein can be further analyzed via Karl Fischer Titration (KF) to determine the water content. Products as described herein can be further analyzed via Polarized light microscopy (PLM), ORTEP diagram and powder dissolution.
  • KF Karl Fischer Titration
  • PLM Polarized light microscopy
  • the co-crystals of the present invention could be used for the preparation of Niraparib tosylate in the free base form or in the form of any other co-crystals of Niraparib tosylate.
  • Figure 1 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C1
  • Figure 2 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - L-Proline co-crystal Form C1.
  • Figure 3 is a Thermogravimetric Analysis curve (“TGA”) of Niraparib tosylate - L-Proline co-crystal Form C1.
  • Figure 4 is an X-ray powder diffractogram of Niraparib tosylate - Oxalic acid co-crystal Form C1
  • Figure 5 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - Oxalic acid co-crystal Form C1.
  • Figure 6 is a Thermogravimetric Analysis curve (“TGA”) of Niraparib tosylate - Oxalic acid co-crystal Form C1.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis curve
  • Figure 7 is an ORTEP representation of Niraparib tosylate - L-Proline co- crystal Form C1
  • Figure 8 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 1.2
  • Figure 9 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 4.5
  • Figure 10 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 6.8
  • Figure 11 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 4.
  • Figure 12 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 5.
  • Figure 13 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 5.
  • DSC Differential Scanning Calorimetry
  • Pharmaceutical co-crystals can be defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature. By co-crystallizing the Niraparib tosylate with a co-former, a new solid form is created having different properties from the Niraparib tosylate or the conformer.
  • a co-crystal may have a different melting point, dissolution, solubility, hygroscopicity, bioavailability, toxicity, crystal morphology, density, loading volume, compressibility, physical stability, chemical stability, shelf life, taste, production costs, and/or manufacturing method than the drug.
  • co-former refers to a compound other than Niraparib tosylate that is also a component of the co-crystal. Thus, the co-former is part of the co- crystalline lattice.
  • the co-former is typically a GRAS (generally regarded as safe) compound and need not exhibit any therapeutic or pharmacological activity of its own.
  • co-former is selected from one or more pharmaceutically acceptable alkaloids.
  • An alkaloid is selected from but not limited to L-proline, nicotinamide and caffeine.
  • Preferably alkaloid is L-proline.
  • co-former is selected from one or more pharmaceutically acceptable organic acids.
  • pharmaceutically acceptable organic acids see Handbook of Pharmaceutical Salts - Properties, Selection, and Use, P. Heinrich Stahl, CamiUe G. Wermuth (Eds.) VHCA (Verlag Helvetica Chemica Acta -Ziirich), Wiley-VCH (New York) 2002, which is incorporated herein by reference.
  • Organic acids are preferably selected from but not limited to oxalic acid, fumaric acid and 3,5-dihydroxy benzoic acid.
  • the present invention provides a novel co-crystal of Niraparib tosylate with L-proline.
  • the co-crystal may be in the form of a derivative thereof.
  • the derivative may be a pharmaceutically acceptable solvate, hydrate, tautomer, anhydrate, complex, polymorph or combination thereof.
  • the co-crystals comprise Niraparib tosylate and L-proline within the same crystalline phase in a molar ratio ranging from 2 :1 to 1:2. More preferably the molar ratio is 1 :1. Accordingly, the co-crystal of Niraparib tosylate with L-proline is characterized by having the chemical structure as depicted in Formula (III).
  • a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C1”.
  • Form C1 a percentage of the co-crystal is in crystalline form.
  • at least about 50% of the co-crystal is in crystalline form.
  • at least about 80 or at least about 90% of the co-crystal is in crystalline form.
  • the co-crystal of Niraparib tosylate with L-proline can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom.
  • co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 7.63, 8.96, 14.07, 16.69 and 25.96 ⁇ 0.2 ⁇ 2 ⁇ .
  • the XRPD diffractogram may comprise further peaks at 14.79, 18.00, 18.77, 23.83 and 27.56 ⁇ 0.2 ⁇ 2 ⁇ .
  • the co-crystal of Niraparib tosylate with L-proline is characterized by having an XRD pattern as shown in Figure 1.
  • the crystalline Form C1 of the co-crystal of Niraparib tosylate with L-proline is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 215.19 ⁇ 5°C; a peak maximum at around 216.74 ⁇ 5°C and an enthalpy 81.98 j/g.
  • crystalline Form C1 of Niraparib tosylate with L-proline may be characterized by having a DSC spectrum as shown in Figure 2.
  • crystalline Form C1 of the co-crystal of Niraparib tosylate with L-proline may also be characterized by having a thermogravimetric analysis as shown in Figure 3.
  • TGA data indicated a weight loss of 0.09% at temperatures up to 120°C.
  • the TGA analysis indicates the crystalline Form C1 of Niraparib tosylate with L- proline is the anhydrous form.
  • the crystalline Form C1 of Niraparib tosylate with L-proline may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about 7.63, 8.96, 14.07, 16.69 and 25.96 ⁇ 0.2 °2 ⁇ ; an X-ray powder diffraction pattern having peaks at about 14.79, 18.00, 18.77, 23.83 and 27.56 ⁇ 0.2 °2 ⁇ ; a XRPD diffractogram as depicted in Figure 1; a DSC thermogram having a first endothermic peak in the range of about 215.19 ⁇ 5°C °C, a peak maximum at around 216.74 ⁇ 5°C and an enthalpy 81.98 j/g; a D
  • the molecule observed in the asymmetric unit of the single crystal structure is consistent with the Formula III molecular structure.
  • the asymmetric unit shown in Figure 7 contains co-crystal of Niraparib tosylate - L-Proline in the 1 : 1 molar ratio. Indicative Stability
  • Niraparib tosylate L-Proline co-crystal (Form-C1) prepared as per the present disclosure was studied by storing the samples at 2-8°C, 25°C/ 60% RH; and 40°C/ 75% RH storage conditions upto 6 months. The samples were analysed for PXRD, HPLC purity and water content at predetermined time intervals of 1M, 2M, 3M and 6M. The stability data collected after 6 months of storage are tabulated below in Table 2.
  • a process for preparing co-crystal of Niraparib tosylate with L-proline comprising, a. dissolving Niraparib tosylate and L-proline in a first organic solvent selected from the group comprising of C 1 -C 5 alcohol or a mixture of C 1 - C 5 alcohols thereof; b. removing the solvent under reduced pressure to obtain a residue; c. stirring the residue for sufficient time in a second organic solvent selected from polar aprotic solvent, ketone, nitriles, ethers, esters, hydrocarbons and the like; d. isolating the co-crystal of Niraparib tosylate with L-proline; and e. drying.
  • Niraparib tosylate used for the above process, as well as for the following processes, may be in any polymorphic form or in a mixture of any polymorphic forms such as hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.
  • the Niraparib tosylate used in the processes of the present invention can be obtained by any method known in the art, such as the one described in the US 8,436,185 B2.
  • the first organic solvent C 1 -C 5 alcohol is preferably selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, amyl alcohol and the like.
  • first organic solvent is methanol.
  • the second organic solvent is preferably selected from the group comprising of polar aprotic solvent such as N,N- dimethylacetamide (DMAC), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4- dioxane and the like; ether solvent such as methyl t-butyl ether, diisoproyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; halogenated solvent such as dichloromethane, dichloroethane, chloro
  • organic solvent is selected from but not limited to nitrile solvent.
  • dissolution step is done at about 40°C to about 80°C, more preferably at about 50°C to about 70°C to obtain a solution.
  • the evaporation is done under reduced pressure.
  • the process further comprises a stirring step.
  • the stirring is for about 1 hour to about 24 hours, more preferably for about 2 hours to about 20 hours.
  • the stirring is done at about 50°C to about 80°C.
  • the obtained solid form is isolated.
  • the isolation is done by centrifugation.
  • the drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 50°C, for about 1 hour to about 10 hours, more preferably for about 2 hours to about 8 hours.
  • the co-crystal of Niraparib tosylate with L-proline (Form-C1), obtained as per the present invention is substantially free from other forms of Niraparib tosylate.
  • "Substantially free" from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities.
  • a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C2”.
  • Form C2 a percentage of the co-crystal is in crystalline form.
  • at least about 50% of the co-crystal is in crystalline form.
  • at least about 80 or at least about 90% of the co-crystal is in crystalline form.
  • the co-crystal of Niraparib tosylate with L-proline can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom.
  • co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 9.08, 14.20, 16.90, 18.17 and 20.1 ⁇ 0.2 ⁇ 2 ⁇ .
  • the co-crystal of Niraparib tosylate with L-proline is characterized by having an XRD pattern as shown in Figure 11 and Figure 12.
  • the crystalline Form C2 of the co-crystal of Niraparib tosylate with L-proline is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 215.41 ⁇ 5°C; a peak maximum at around 217.40 ⁇ 5°C and an enthalpy 95.737 j/g.
  • crystalline Form C2 of Niraparib tosylate with L-proline may be characterized by having a DSC spectrum as shown in Figure 13.
  • the crystalline Form C2 of Niraparib tosylate with L-proline may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about : 9.08, 14.20, 16.90, 18.17 and 20.1 ⁇ 0.2 °2 ⁇ ; a XRPD diffractogram as depicted in Figure 11; a XRPD diffractogram as depicted in Figure 12; a DSC thermogram having a first endothermic peak in the range of about 215.41 ⁇ 5°C; a peak maximum at around 217.40 ⁇ 5°C and an enthalpy 95.737 j/g; a DSC pattern as depicted in Figure 13; and combinations thereof.
  • a process for preparing co-crystal of Niraparib tosylate with L-proline comprising, a. stirring L-proline in a first organic solvent selected from the group comprising of C 1 -C 5 alcohol or a mixture of C 1 -C 5 alcohols thereof; b. mixing Niraparib tosylate; c. heating the mixture for sufficient time; d. isolating the co-crystal of Niraparib tosylate with L-proline; and e. drying.
  • the first organic solvent C 1 -C 5 alcohol is preferably selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, amyl alcohol and the like.
  • first organic solvent is isopropanol.
  • L-Proline is stirred in alcohol at about 25°C to about 70°C, more preferably at about 40°C to about 60°C.
  • the process further comprises a heating step.
  • the heating is done at about 50°C to about 90°C, more preferably at about 60°C to about 85°C, for about 1 hour to about 20 hours, more preferably for about 2 hours to about 10 hours.
  • the process further comprises a cooling step.
  • the cooling is done at about 20°C to about 30°C, for about 30 minutes to about 5 hours, more preferably for about 1 hour to about 3 hours.
  • the obtained solid form is isolated.
  • the isolation is done by centrifugation.
  • Niraparib tosylate L-Proline co-crystal (Form-C2) may be obtained by the process comprising, a. stirring Niraparib tosylate and L-proline in a polar aprotic solvent or mixture thereof; b. heating the mixture for sufficient time; c. isolating the co-crystal of Niraparib tosylate with L-proline; and d. drying.
  • polar aprotic solvent is selected from the group comprising of N,N- dimethylacetamide (DMAC), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; nitrile solvent such as acetonitrile, propionitrile, butyronitrile and the like.
  • polar aprotic solvent is acetonitrile.
  • after mixing heating is done for about 1 hour to about 20 hours, more preferably for about 2 hours to about 10 hours.
  • the heating is done at about 50°C to about 90°C, more preferably at about 60°C to about 80°C.
  • the process further comprises a cooling step.
  • the cooling is done at about 30°C to about 40°C.
  • the obtained solid form is isolated.
  • the isolation is done by centrifugation.
  • the drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 50°C, for about 2 hour to about 10 hours, more preferably for about 3 hours to about 6 hours.
  • the co-crystal of Niraparib tosylate with L-proline (Form-C2), obtained as per the present invention is substantially free from other forms of Niraparib tosylate.
  • "Substantially free” from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities.
  • the present invention provides a novel co-crystal of Niraparib tosylate with oxalic acid.
  • the co-crystal may be in the form of a derivative thereof.
  • co-crystal is mono oxalic acid co-crystal.
  • the mono oxalic acid co-crystal can, in certain embodiments, be in hydrated or solvated form.
  • co-crystal is di oxalic acid co-crystal.
  • the di oxalic acid co-crystal can, in certain embodiments, be in hydrated or solvated form.
  • the co-crystals comprises Niraparib tosylate and oxalic acid within the same crystalline phase in a molar ratio ranging from 2 :1 to 1:2.
  • the co-crystal of Niraparib tosylate with oxalic acid is characterized by having the chemical structure as depicted in Formula (IV).
  • a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C1”.
  • Form C1 a given percentage of the co-crystal is in crystalline form.
  • at least about 50% of the co-crystal is in crystalline form.
  • at least about 80 or at least about 90% of the co-crystal is in crystalline form.
  • the co-crystal of Niraparib tosylate with oxalic acid can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom.
  • co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.94, 8.20, 11.78 and 16.78 ⁇ 0.2 ⁇ 2 ⁇ .
  • the XRPD diffractogram may comprise further peaks at 12.77, 15.63, 17.77, 20.74 and 22.20 ⁇ 0.2 ⁇ 2 ⁇ .
  • the co-crystal of Niraparib tosylate with oxalic acid is characterized by having an XRD pattern as shown in Figure 4.
  • the crystalline Form C1 of the co-crystal of Niraparib tosylate with oxalic acid is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 184.96 ⁇ 5°C; a peak maximum at around 186.93 ⁇ 5°C and an enthalpy 67.67 j/g.
  • crystalline Form C1 of Niraparib tosylate with oxalic acid may be characterized by having a DSC spectrum as shown in Figure 5.
  • crystalline Form C1 of the co-crystal of Niraparib tosylate with oxalic acid may also be characterized by having a thermogravimetric analysis as shown in Figure 6.
  • TGA data indicated a weight loss of 0.11% at temperatures up to 120°C.
  • the TGA analysis indicates the crystalline Form C1 of Niraparib tosylate with oxalic acid is the anhydrous form.
  • the crystalline Form C1 of Niraparib tosylate with oxalic acid may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about 5.94, 8.20, 11.78 and 16.78 ⁇ 0.2 °2 ⁇ ; an X-ray powder diffraction pattern having peaks at about 12.77, 15.63, 17.77, 20.74 and 22.20 ⁇ 0.2 °2 ⁇ ; a XRPD diffractogram as depicted in Figure 4; a DSC thermogram having a first endothermic peak in the range of about 184.96 ⁇ 5°C °C, a peak maximum at around 186.93 ⁇ 5°C and an enthalpy 67.67 j/g; a
  • a process for preparing co-crystal of Niraparib tosylate with oxalic acid comprising, a. Mixing Niraparib tosylate and oxalic acid in a suitable organic solvent selected from the group comprising of polar aprotic solvent, ketone, nitriles, ethers, esters, hydrocarbons and the like thereof; b. stirring for sufficient time; c. isolating the co-crystal of Niraparib tosylate with oxalic acid; and d. drying.
  • a suitable organic solvent selected from the group comprising of polar aprotic solvent, ketone, nitriles, ethers, esters, hydrocarbons and the like thereof.
  • the organic solvent is preferably selected from the group comprising of polar aprotic solvent such as N,N- dimethylacetamide (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; ether solvent such as methyl /-butyl ether, diisopropyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; halogenated solvent such as dichloromethane, dichloroethane, chloroform and the like; C6-C10 substituted
  • organic solvent is selected from but not limited to nitrile such as acetonitrile, propionitrile and the like.
  • mixing is done at about 20°C to about 30°C.
  • the process further comprises a stirring step.
  • the stirring is for about 1 hour to about 10 hours, more preferably for about 2 hours to about 5 hours.
  • the stirring is done at about 30°C to about 90°C; more preferably at about 50°C to about 80°C.
  • the process further comprises a cooling step.
  • cooling is done at about 25°C to about 30°C.
  • the obtained solid form is isolated.
  • the isolation is done by centrifugation.
  • the drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 40°C, for about 1 hour to about 10 hours, more preferably for about 2 hours to about 5 hours.
  • the co-crystal of Niraparib tosylate with oxalic acid, obtained per the present invention is substantially free from other forms of Niraparib tosylate. "Substantially free" from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities.
  • the present invention provides a pharmaceutical composition comprising therapeutically effective amount of co crystals of Niraparib tosylate prepared by the processes of the present invention.
  • the pharmaceutical composition comprising a therapeutically effective amount of Niraparib tosylate with any one of the co-crystal former as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients.
  • the pharmaceutical composition of the invention may be any pharmaceutical form which contains the co-crystals of the invention.
  • the pharmaceutical composition may be solid form such as tablets, powders, capsule, liquid suspension or an injectable composition along with any suitable carrier well known in the prior art.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms.
  • the invention relates to administering 'an effective amount' of the 'composition of invention' to the subject suffering from cancer. Accordingly, Niraparib tosylate co-crystals and the pharmaceutical composition containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for the treatment of cancer.
  • the invention further discloses use of the "composition of the invention" in preparing the medicament intended to treat cancer.
  • Example 1 Process to prepare Niraparib tosylate : L-Proline co-crystal (Form-C1): Niraparib tosylate (3.0 g) and L-proline (0.693 g) were dissolved in 27 volumes of methanol at 55-60°C. The solution was concentrated in a rotavapor at 55-60°C to get the residue. Charged 10 volumes of acetonitrile into the above residue and stirred for 2-3 hours at 70-75°C. The solids were isolated by filtration and dried at 45-50°C for 3-4 hours to yield the title compound. H-NMR reveals a molar ratio of Niraparib tosylate to L-proline of about 1:1.
  • Niraparib tosylate Oxalic acid co-crystal (Form-C1): Niraparib tosylate (3 g) and oxalic acid (1.48 g) were mixed with 15 volumes of acetonitrile. The contents were stirred at 70-75°C for 2-3 hours. The solids were cooled to RT and isolated by filtration and dried under vacuum to yield the title compound. The crystallinity was confirmed by XRD, DSC and TGA and identified as Form C1 as depicted in Figures 4 to 6.
  • Example 3 Determination of the solubility of Niraparib tosylate : L-Proline co- crystal (Form-C1) in comparison to Niraparib tosylate monohydrate (Form I ) in buffered solutions (Solubility as a Function of pH)
  • the aqueous solubility of Niraparib tosylate : L-Proline co-crystal (Form-C1) was compared with Niraparib tosylate monohydrate (Form I).
  • the solubility of Form C1 of the invention was determined at pH 1.2 (Gastric Buffer), pH 4.5 (Acetate Buffer) and pH 6.8 (Intestinal Buffer), by suspending 0.3 g of Form- C1 and Form I in 30 mL of corresponding aqueous solution.
  • the samples were allowed to equilibrate at ambient temperature for at least 24 hours for pH 1.2, 4.5 and 6.8 Buffers.
  • the supernatant was filtered and used for the solubility determination by UV-VIS spectroscopy.
  • the solid residue was analyzed by XRPD.
  • the solubility data obtained are shown in Tables 3 to 5. The data and Figures 8-10 indicated that the solubility is pH and temperature dependent. Table 3 pH solubility data at pH 1.2
  • Niraparib tosylate L-Proline co-crystal (Form-C1) is having comparable solubility with Niraparib tosylate monohydrate (Form I ) in all the above studied pH buffers.
  • Example 4 Process to prepare Niraparib tosylate L-Proline co-crystal (Form-C2): Niraparib tosylate (5.0 g) and L-proline (1.137 g) were stirred in 30 volumes of acetonitrile at reflux temperature for 4-5 hours. The solids were isolated by filtration and dried at 50-60°C for 3-4 hours to yield the title compound.
  • Niraparib tosylate L-Proline co-crystal (Form-C2): Niraparib tosylate (5.0 g) was added in a mixture of L-proline (1.4 g) and IPA (100 ml) at 50°C. The contents were heated to 70-75°C for 6 hours. The contents were cooled to 25-30°C and stirred further at 25-30°C for 1 hour. The solids were isolated by filtration and dried at 45-50°C for 3-4 hours to yield the title compound.

Abstract

The present disclosure relates to co-crystals, salts and crystalline forms of Niraparib of Formula (I). More particularly, the present invention relates to novel polymorphic forms and synergistic pharmaceutical co-crystals comprising Niraparib and to processes of preparation thereof. The invention further relates to pharmaceutical compositions comprising novel polymorphic forms and synergistic co-crystals and at least one pharmaceutically acceptable excipient. The invention further provides novel crystalline forms of the novel pharmaceutical co-crystals.

Description

CO-CRYSTALS, SALTS AND SOLID FORMS OF NIRAPARIB Technical field of invention: The present disclosure provides co-crystals, salts and crystalline forms of Niraparib and methods for the preparation, use, isolation of such forms and pharmaceutical compositions comprising said forms. Background of the invention: Niraparib, sold under the brand name Zejula, is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Niraparib, is chemically known as 2-[4-[(3S)-3-piperidyl]phenyl]- indazole-7- carboxamide. Niraparib, was first described in U.S. Pat. No.8,071,623B2, and has the following chemical structure:
Figure imgf000002_0001
Formula I Pharmaceutical active ingredients (APIs) can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, co-crystals and amorphous solids. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability and other performance characteristics of the drugs. Niraparib exhibits stereoisomerism due to the presence of a single chiral center. The stereochemistry originates and is controlled in the synthesis. The prior art suggest that Niraparib may exist in a number of different polymorphic forms. The anhydrate form has been detected by DSC but is only formed at very high temperatures. The crystallization ensures routine production of the monohydrate form which is conformed routinely by XRPD. Crystalline forms of Niraparib and salts thereof can possess advantageous properties in terms of their solubility and/or stability and/or bioavailability and/or impurity profile and/or filtration characteristics and/or drying characteristics and/or their ability to be handled and/or micronized and/or preparation of solid oral forms. A solid state form of niraparib, (3S)-3-{4-[7-(amino-carbonyl)-2H-indazol-2- yl]phenyl} piperidinium p-toluenesulfonate monohydrate (1:1:1), is disclosed in U.S. Patent No.8,436,185 B2.
Figure imgf000003_0001
Formula II WO2018183354 is directed to Form I, Form II and Form III of Niraparib tosylate, each substantially free of the other two forms. WO 2020/072796 is directed to crystalline Form I, Form II ,Form III, Form IV and Form V of Niraparib free base. WO 2020/072860 is directed to crystalline anhydrous Form A of Niraparib tosylate. Niraparib tosylate monohydrate hereinafter referred to as “Niraparib tosylate” is classified as having low solubility based on the experimentally determined solubility over the pH range according to the BCS guidelines (BCS Class II). Due to low solubility, particle size distribution is controlled in the active substance specification. Due to low solubility in water, Niraparib has a low dissolution rate and as a result exhibits poor bioavailability. Hence, it is necessary to find crystal form with high solubility with improve efficiency of the drug. It has now been found that the aqueous solubility of Niraparib or its pharmaceutically acceptable salt or a stereoisomer or tautomer thereof, especially the solubility in a gastric or intestinal environment may be distinctly enhanced by combining this drug with certain co-formers. In view of the foregoing, it would be desirable to provide new forms of Niraparib. Further, it would be desirable to have reliable processes for producing these forms of Niraparib. Additionally, the various forms of Niraparib could be used to prepare improved pharmaceutical compositions. It has further been found that certain salts and certain co-crystals, of Niraparib show advantageous properties for use as medical application forms of Niraparib. Preferred ones among these solid forms are those comprising Niraparib tosylate and co-former within the same crystalline phase. OBJECTIVES OF THE INVENTION An object of the present invention is to provide novel solid state forms of Niraparib such as novel crystalline forms and co-crystals. Another object of the present invention is to provide a process for the preparation of novel solid state forms of Niraparib. Yet another object of the invention is to provide pharmaceutical composition comprising a therapeutically effective amount of novel solid state forms of Niraparib and at least one pharmaceutically acceptable carrier Yet another object of the invention is to provide method of treatment of human or animal body by therapy, wherein novel solid state forms of Niraparib, are useful. SUMMARY The present invention is directed to novel pharmaceutical compounds comprising Niraparib tosylate and a co-former, methods of preparing such pharmaceutical compounds, and methods of treating epithelial ovarian, fallopian tube, or primary peritoneal cancer with such pharmaceutical compounds. The novel solid state forms may be a co-crystal or a polymorph of a co-crystal. A “co-crystal” according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. A “co-crystal” consists of a fixed ratio of atoms that are held together in a defined spatial arrangement by ionic, covalent, hydrogen bonds, van der Waals forces or π- π interactions. According to the present invention the elements of a “co-crystal” comprise Niraparib tosylate and a co- former, water, ions, or solvents. In addition, a “co-crystal” according to the present invention represent “a druggable form” of a Niraparib tosylate with a co-former. A” druggable form” as used herein is defined as any form (salt, amorphous, crystal (of a salt), co- crystal, solution, dispersion, mixture, etc.) that Niraparib tosylate with a co- former component might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom. A co-former is selected from an alkaloid and an organic acid. In a first aspect, the present invention provides novel synergistic pharmaceutical compounds of Niraparib tosylate with an alkaloid component. In a second aspect, the present invention provides novel synergistic pharmaceutical compounds of Niraparib tosylate with group of organic acids. The novel pharmaceutical compounds are relatively stable towards the moisture and humidity, thereby representing an amorphous or a crystalline form of pharmaceutical compound, thus exhibit better solubility, dissolution rate, hence enhanced bioavailability and efficacy of the parent molecule in lower doses. The co-crystals of the present invention could be either in a crystalline or amorphous form. The co-crystals of Niraparib tosylate of the present invention have been characterized by means of Powder X-ray diffraction pattern (PXRD) and differential scanning calorimetry (DSC). A variety of other solid state spectroscopic techniques can be used including, but not limited to, Raman spectroscopy, FTIR spectroscopy, vibrational spectroscopy, polarized light microscopy (PLM), and solid state NMR, the 13C NMR and 1H NMR (in a suitable solvent, e.g., in D2O or DMSO-D6 ) to evaluate the chemical structure, Dynamic Gravimetric Vapor Sorption (DVS) to evaluate the hygroscopicity, thermogravimetric analysis (TGA) to evaluate the thermal properties, and/or chromatography (e.g., HPLC) in a suitable solvent to evaluate the purity. Products as described herein can be further analyzed via Karl Fischer Titration (KF) to determine the water content. Products as described herein can be further analyzed via Polarized light microscopy (PLM), ORTEP diagram and powder dissolution. The co-crystals of the present invention could be used for the preparation of Niraparib tosylate in the free base form or in the form of any other co-crystals of Niraparib tosylate. These and other features, aspects, and advantages of the disclosure will be apparent from a reading of the following detailed description together with the accompanying drawings, which are briefly described below. The invention includes any combination of the above-noted embodiments as well as combinations of any features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined in a specific embodiment description herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C1 Figure 2 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - L-Proline co-crystal Form C1. Figure 3 is a Thermogravimetric Analysis curve (“TGA”) of Niraparib tosylate - L-Proline co-crystal Form C1. Figure 4 is an X-ray powder diffractogram of Niraparib tosylate - Oxalic acid co-crystal Form C1 Figure 5 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - Oxalic acid co-crystal Form C1. Figure 6 is a Thermogravimetric Analysis curve (“TGA”) of Niraparib tosylate - Oxalic acid co-crystal Form C1. Figure 7 is an ORTEP representation of Niraparib tosylate - L-Proline co- crystal Form C1 Figure 8 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 1.2 Figure 9 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 4.5 Figure 10 shows the pH - dependent solubility of Niraparib tosylate - L-Proline co-crystal Form C1 with Niraparib tosylate monohydrate, Form I in buffer solutions at pH 6.8 Figure 11 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 4. Figure 12 is an X-ray powder diffractogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 5. Figure 13 is a Differential Scanning Calorimetry (“DSC”) thermogram of Niraparib tosylate - L-Proline co-crystal Form C2 prepared according to Example 5. Detailed Description of Invention Pharmaceutical co-crystals can be defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature. By co-crystallizing the Niraparib tosylate with a co-former, a new solid form is created having different properties from the Niraparib tosylate or the conformer. For example, a co-crystal may have a different melting point, dissolution, solubility, hygroscopicity, bioavailability, toxicity, crystal morphology, density, loading volume, compressibility, physical stability, chemical stability, shelf life, taste, production costs, and/or manufacturing method than the drug. The term "co-former" refers to a compound other than Niraparib tosylate that is also a component of the co-crystal. Thus, the co-former is part of the co- crystalline lattice. The co-former is typically a GRAS (generally regarded as safe) compound and need not exhibit any therapeutic or pharmacological activity of its own. In one embodiment “co-former” is selected from one or more pharmaceutically acceptable alkaloids. An alkaloid is selected from but not limited to L-proline, nicotinamide and caffeine. Preferably alkaloid is L-proline. In a second embodiment “co-former” is selected from one or more pharmaceutically acceptable organic acids. For a list of pharmaceutically acceptable organic acids, see Handbook of Pharmaceutical Salts - Properties, Selection, and Use, P. Heinrich Stahl, CamiUe G. Wermuth (Eds.) VHCA (Verlag Helvetica Chemica Acta -Ziirich), Wiley-VCH (New York) 2002, which is incorporated herein by reference. Organic acids are preferably selected from but not limited to oxalic acid, fumaric acid and 3,5-dihydroxy benzoic acid. In the first aspect, the present invention provides a novel co-crystal of Niraparib tosylate with L-proline. The co-crystal may be in the form of a derivative thereof. The derivative may be a pharmaceutically acceptable solvate, hydrate, tautomer, anhydrate, complex, polymorph or combination thereof. Preferably, the co-crystals comprise Niraparib tosylate and L-proline within the same crystalline phase in a molar ratio ranging from 2 :1 to 1:2. More preferably the molar ratio is 1 :1. Accordingly, the co-crystal of Niraparib tosylate with L-proline is characterized by having the chemical structure as depicted in Formula (III).
Figure imgf000011_0001
Advantageously, in a second aspect, a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C1”. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form. In an embodiment, the co-crystal of Niraparib tosylate with L-proline can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 7.63, 8.96, 14.07, 16.69 and 25.96 ±0.2˚2θ. The XRPD diffractogram may comprise further peaks at 14.79, 18.00, 18.77, 23.83 and 27.56 ±0.2˚2θ. In another embodiment, the co-crystal of Niraparib tosylate with L-proline is characterized by having an XRD pattern as shown in Figure 1. The crystalline Form C1 of the co-crystal of Niraparib tosylate with L-proline is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 215.19±5°C; a peak maximum at around 216.74 ±5°C and an enthalpy 81.98 j/g. In an embodiment, crystalline Form C1 of Niraparib tosylate with L-proline may be characterized by having a DSC spectrum as shown in Figure 2. In an embodiment, crystalline Form C1 of the co-crystal of Niraparib tosylate with L-proline may also be characterized by having a thermogravimetric analysis as shown in Figure 3. TGA data indicated a weight loss of 0.09% at temperatures up to 120°C. The TGA analysis indicates the crystalline Form C1 of Niraparib tosylate with L- proline is the anhydrous form. The crystalline Form C1 of Niraparib tosylate with L-proline may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about 7.63, 8.96, 14.07, 16.69 and 25.96 ± 0.2 °2θ; an X-ray powder diffraction pattern having peaks at about 14.79, 18.00, 18.77, 23.83 and 27.56 ± 0.2 °2θ; a XRPD diffractogram as depicted in Figure 1; a DSC thermogram having a first endothermic peak in the range of about 215.19±5°C °C, a peak maximum at around 216.74 ±5°C and an enthalpy 81.98 j/g; a DSC pattern as depicted in Figure 2; a TGA pattern as depicted in Figure 3; and combinations thereof. In an embodiment, Oak Ridge Thermal Ellipsoid Plot (ORTEP) of the co- crystal of Niraparib tosylate - L-Proline was drawn with Mercury. The ellipsoids are at 50% probability. In an embodiment, an ORTEP drawing of co-crystal of Niraparib tosylate - L- Proline is shown in Figure 7. A summary of the crystal data and crystallographic data collection parameters are provided in Table 1 below. Table 1
Figure imgf000013_0001
The molecule observed in the asymmetric unit of the single crystal structure is consistent with the Formula III molecular structure. The asymmetric unit shown in Figure 7 contains co-crystal of Niraparib tosylate - L-Proline in the 1 : 1 molar ratio. Indicative Stability
The stability of Niraparib tosylate : L-Proline co-crystal (Form-C1) prepared as per the present disclosure was studied by storing the samples at 2-8°C, 25°C/ 60% RH; and 40°C/ 75% RH storage conditions upto 6 months. The samples were analysed for PXRD, HPLC purity and water content at predetermined time intervals of 1M, 2M, 3M and 6M. The stability data collected after 6 months of storage are tabulated below in Table 2.
Table 2. Indicative Stability of Niraparib tosylate : L-Proline co-crystal (Form-C1)
Figure imgf000014_0001
Figure imgf000015_0001
* Samples were exposed to atmosphere and odd water content result observed, hence water content was not analysed.
The data indicates that there is no significant change with respect to PXRD, HPLC purity and water content in all the storage conditions up to 6 months.
According to a third aspect of the present invention, there is provided a process for preparing co-crystal of Niraparib tosylate with L-proline, the process comprising, a. dissolving Niraparib tosylate and L-proline in a first organic solvent selected from the group comprising of C1-C5 alcohol or a mixture of C1- C5 alcohols thereof; b. removing the solvent under reduced pressure to obtain a residue; c. stirring the residue for sufficient time in a second organic solvent selected from polar aprotic solvent, ketone, nitriles, ethers, esters, hydrocarbons and the like; d. isolating the co-crystal of Niraparib tosylate with L-proline; and e. drying.
Niraparib tosylate used for the above process, as well as for the following processes, may be in any polymorphic form or in a mixture of any polymorphic forms such as hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof. The Niraparib tosylate used in the processes of the present invention can be obtained by any method known in the art, such as the one described in the US 8,436,185 B2. The first organic solvent C1-C5 alcohol, is preferably selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, amyl alcohol and the like. Preferably, first organic solvent is methanol. The second organic solvent is preferably selected from the group comprising of polar aprotic solvent such as N,N- dimethylacetamide (DMAC), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4- dioxane and the like; ether solvent such as methyl t-butyl ether, diisoproyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; halogenated solvent such as dichloromethane, dichloroethane, chloroform and the like; C6-C10 substituted aromatic hydrocarbons, and C1-C5 halogenated hydrocarbons; water and mixtures thereof. Preferably, organic solvent is selected from but not limited to nitrile solvent. Preferably, dissolution step is done at about 40°C to about 80°C, more preferably at about 50°C to about 70°C to obtain a solution. Typically, following the heating step, the evaporation is done under reduced pressure. Preferably, after addition of a second organic solvent, the process further comprises a stirring step. Preferably, the stirring is for about 1 hour to about 24 hours, more preferably for about 2 hours to about 20 hours. Preferably, the stirring is done at about 50°C to about 80°C. Preferably, the obtained solid form is isolated. Preferably, the isolation is done by centrifugation. The drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 50°C, for about 1 hour to about 10 hours, more preferably for about 2 hours to about 8 hours. The co-crystal of Niraparib tosylate with L-proline (Form-C1), obtained as per the present invention is substantially free from other forms of Niraparib tosylate. "Substantially free" from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities. Advantageously, in a fourth aspect, a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C2”. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form. In an embodiment, the co-crystal of Niraparib tosylate with L-proline can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 9.08, 14.20, 16.90, 18.17 and 20.1 ±0.2˚2θ. In another embodiment, the co-crystal of Niraparib tosylate with L-proline is characterized by having an XRD pattern as shown in Figure 11 and Figure 12. The crystalline Form C2 of the co-crystal of Niraparib tosylate with L-proline is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 215.41±5°C; a peak maximum at around 217.40 ±5°C and an enthalpy 95.737 j/g. In an embodiment, crystalline Form C2 of Niraparib tosylate with L-proline may be characterized by having a DSC spectrum as shown in Figure 13. The crystalline Form C2 of Niraparib tosylate with L-proline may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about : 9.08, 14.20, 16.90, 18.17 and 20.1 ± 0.2 °2θ; a XRPD diffractogram as depicted in Figure 11; a XRPD diffractogram as depicted in Figure 12; a DSC thermogram having a first endothermic peak in the range of about 215.41±5°C; a peak maximum at around 217.40 ±5°C and an enthalpy 95.737 j/g; a DSC pattern as depicted in Figure 13; and combinations thereof. According to a fifth aspect of the present invention, there is provided a process for preparing co-crystal of Niraparib tosylate with L-proline, the process comprising, a. stirring L-proline in a first organic solvent selected from the group comprising of C1-C5 alcohol or a mixture of C1-C5 alcohols thereof; b. mixing Niraparib tosylate; c. heating the mixture for sufficient time; d. isolating the co-crystal of Niraparib tosylate with L-proline; and e. drying. The first organic solvent C1-C5 alcohol, is preferably selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, amyl alcohol and the like. Preferably, first organic solvent is isopropanol. Preferably, L-Proline is stirred in alcohol at about 25°C to about 70°C, more preferably at about 40°C to about 60°C. Preferably, after mixing Niraparib tosylate, the process further comprises a heating step. Preferably, the heating is done at about 50°C to about 90°C, more preferably at about 60°C to about 85°C, for about 1 hour to about 20 hours, more preferably for about 2 hours to about 10 hours. Typically, following the heating step, the process further comprises a cooling step. Preferably, the cooling is done at about 20°C to about 30°C, for about 30 minutes to about 5 hours, more preferably for about 1 hour to about 3 hours. Preferably, the obtained solid form is isolated. Preferably, the isolation is done by centrifugation. The drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 50°C, for about 1 hour to about 10 hours, more preferably for about 2 hours to about 8 hours. Alternatively, Niraparib tosylate : L-Proline co-crystal (Form-C2) may be obtained by the process comprising, a. stirring Niraparib tosylate and L-proline in a polar aprotic solvent or mixture thereof; b. heating the mixture for sufficient time; c. isolating the co-crystal of Niraparib tosylate with L-proline; and d. drying. Preferably polar aprotic solvent is selected from the group comprising of N,N- dimethylacetamide (DMAC), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; nitrile solvent such as acetonitrile, propionitrile, butyronitrile and the like. Preferably, polar aprotic solvent is acetonitrile. Preferably, after mixing heating is done for about 1 hour to about 20 hours, more preferably for about 2 hours to about 10 hours. Preferably, the heating is done at about 50°C to about 90°C, more preferably at about 60°C to about 80°C. Typically, following the heating step, the process further comprises a cooling step. Preferably, the cooling is done at about 30°C to about 40°C. Preferably, the obtained solid form is isolated. Preferably, the isolation is done by centrifugation. The drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 50°C, for about 2 hour to about 10 hours, more preferably for about 3 hours to about 6 hours. The co-crystal of Niraparib tosylate with L-proline (Form-C2), obtained as per the present invention is substantially free from other forms of Niraparib tosylate. "Substantially free" from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities. In a sixth aspect, the present invention provides a novel co-crystal of Niraparib tosylate with oxalic acid. The co-crystal may be in the form of a derivative thereof. The derivative may be a pharmaceutically acceptable solvate, hydrate, tautomer, anhydrate, complex, polymorph or combination thereof. In one embodiment, co-crystal is mono oxalic acid co-crystal. The mono oxalic acid co-crystal can, in certain embodiments, be in hydrated or solvated form. In another embodiment, co-crystal is di oxalic acid co-crystal. The di oxalic acid co-crystal can, in certain embodiments, be in hydrated or solvated form. Preferably, the co-crystals comprises Niraparib tosylate and oxalic acid within the same crystalline phase in a molar ratio ranging from 2 :1 to 1:2. More preferably the molar ratio is 1 :1. Accordingly, the co-crystal of Niraparib tosylate with oxalic acid is characterized by having the chemical structure as depicted in Formula (IV).
Figure imgf000021_0001
Advantageously, in a seventh aspect , a given percentage of the co-crystal is in crystalline form, which is herein and in the claims designated as “Form C1”. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form. In an embodiment, the co-crystal of Niraparib tosylate with oxalic acid can be characterized as having peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.94, 8.20, 11.78 and 16.78 ±0.2˚2θ. The XRPD diffractogram may comprise further peaks at 12.77, 15.63, 17.77, 20.74 and 22.20 ±0.2˚2θ. In another embodiment, the co-crystal of Niraparib tosylate with oxalic acid is characterized by having an XRD pattern as shown in Figure 4. The crystalline Form C1 of the co-crystal of Niraparib tosylate with oxalic acid is characterized as having a DSC spectrum exhibiting an endothermic peak with onset at around 184.96 ±5°C; a peak maximum at around 186.93 ±5°C and an enthalpy 67.67 j/g. In an embodiment, crystalline Form C1 of Niraparib tosylate with oxalic acid may be characterized by having a DSC spectrum as shown in Figure 5. In an embodiment, crystalline Form C1 of the co-crystal of Niraparib tosylate with oxalic acid may also be characterized by having a thermogravimetric analysis as shown in Figure 6. TGA data indicated a weight loss of 0.11% at temperatures up to 120°C. The TGA analysis indicates the crystalline Form C1 of Niraparib tosylate with oxalic acid is the anhydrous form. The crystalline Form C1 of Niraparib tosylate with oxalic acid may be further characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about 5.94, 8.20, 11.78 and 16.78 ± 0.2 °2θ; an X-ray powder diffraction pattern having peaks at about 12.77, 15.63, 17.77, 20.74 and 22.20 ± 0.2 °2θ; a XRPD diffractogram as depicted in Figure 4; a DSC thermogram having a first endothermic peak in the range of about 184.96±5°C °C, a peak maximum at around 186.93 ±5°C and an enthalpy 67.67 j/g; a DSC pattern as depicted in Figure 5; a TGA pattern as depicted in Figure 6; and combinations thereof. According to eighth aspect of the present invention, there is provided a process for preparing co-crystal of Niraparib tosylate with oxalic acid, the process comprising, a. Mixing Niraparib tosylate and oxalic acid in a suitable organic solvent selected from the group comprising of polar aprotic solvent, ketone, nitriles, ethers, esters, hydrocarbons and the like thereof; b. stirring for sufficient time; c. isolating the co-crystal of Niraparib tosylate with oxalic acid; and d. drying. The organic solvent is preferably selected from the group comprising of polar aprotic solvent such as N,N- dimethylacetamide (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; ether solvent such as methyl /-butyl ether, diisopropyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; halogenated solvent such as dichloromethane, dichloroethane, chloroform and the like; C6-C10 substituted aromatic hydrocarbons, and C1-C5 halogenated hydrocarbons; water and mixtures thereof. Preferably, organic solvent is selected from but not limited to nitrile such as acetonitrile, propionitrile and the like. Preferably, mixing is done at about 20°C to about 30°C. Preferably, the process further comprises a stirring step. Preferably, the stirring is for about 1 hour to about 10 hours, more preferably for about 2 hours to about 5 hours. Preferably, the stirring is done at about 30°C to about 90°C; more preferably at about 50°C to about 80°C. Preferably, the process further comprises a cooling step. Preferably, cooling is done at about 25°C to about 30°C. Preferably, the obtained solid form is isolated. Preferably, the isolation is done by centrifugation. The drying may be done in a vacuum oven at a temperature of about 25°C to about 60°C, more preferably at about 30°C to about 40°C, for about 1 hour to about 10 hours, more preferably for about 2 hours to about 5 hours. The co-crystal of Niraparib tosylate with oxalic acid, obtained per the present invention is substantially free from other forms of Niraparib tosylate. "Substantially free" from other forms of Niraparib tosylate shall be understood to mean that the co-crystals of Niraparib tosylate contain less than 10%, preferably less than 5%, of any other forms of Niraparib tosylate and less than 1% of other impurities. The present invention provides a pharmaceutical composition comprising therapeutically effective amount of co crystals of Niraparib tosylate prepared by the processes of the present invention. The pharmaceutical composition comprising a therapeutically effective amount of Niraparib tosylate with any one of the co-crystal former as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients. Further, the pharmaceutical composition of the invention may be any pharmaceutical form which contains the co-crystals of the invention. The pharmaceutical composition may be solid form such as tablets, powders, capsule, liquid suspension or an injectable composition along with any suitable carrier well known in the prior art. The dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. The invention relates to administering 'an effective amount' of the 'composition of invention' to the subject suffering from cancer. Accordingly, Niraparib tosylate co-crystals and the pharmaceutical composition containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for the treatment of cancer. The invention further discloses use of the "composition of the invention" in preparing the medicament intended to treat cancer. The invention will now be further described by the following examples, which are illustrative rather than limiting. Examples Example 1 Process to prepare Niraparib tosylate : L-Proline co-crystal (Form-C1): Niraparib tosylate (3.0 g) and L-proline (0.693 g) were dissolved in 27 volumes of methanol at 55-60°C. The solution was concentrated in a rotavapor at 55-60°C to get the residue. Charged 10 volumes of acetonitrile into the above residue and stirred for 2-3 hours at 70-75°C. The solids were isolated by filtration and dried at 45-50°C for 3-4 hours to yield the title compound. H-NMR reveals a molar ratio of Niraparib tosylate to L-proline of about 1:1. The crystallinity was confirmed by XRD, DSC and TGA and identified as Form C1 as depicted in Figures 1 to 3. Example 2 Process to prepare Niraparib tosylate : Oxalic acid co-crystal (Form-C1): Niraparib tosylate (3 g) and oxalic acid (1.48 g) were mixed with 15 volumes of acetonitrile. The contents were stirred at 70-75°C for 2-3 hours. The solids were cooled to RT and isolated by filtration and dried under vacuum to yield the title compound. The crystallinity was confirmed by XRD, DSC and TGA and identified as Form C1 as depicted in Figures 4 to 6. Example 3 Determination of the solubility of Niraparib tosylate : L-Proline co- crystal (Form-C1) in comparison to Niraparib tosylate monohydrate (Form I ) in buffered solutions (Solubility as a Function of pH) The aqueous solubility of Niraparib tosylate : L-Proline co-crystal (Form-C1) was compared with Niraparib tosylate monohydrate (Form I). The solubility of Form C1 of the invention was determined at pH 1.2 (Gastric Buffer), pH 4.5 (Acetate Buffer) and pH 6.8 (Intestinal Buffer), by suspending 0.3 g of Form- C1 and Form I in 30 mL of corresponding aqueous solution. The samples were allowed to equilibrate at ambient temperature for at least 24 hours for pH 1.2, 4.5 and 6.8 Buffers. The supernatant was filtered and used for the solubility determination by UV-VIS spectroscopy. The solid residue was analyzed by XRPD. The solubility data obtained are shown in Tables 3 to 5. The data and Figures 8-10 indicated that the solubility is pH and temperature dependent. Table 3 pH solubility data at pH 1.2
Figure imgf000027_0001
Table 4 pH solubility data at pH 4.5
Figure imgf000027_0002
Table 5 pH solubility data at pH 6.8
Figure imgf000027_0003
On the other side Niraparib tosylate : L-Proline co-crystal (Form-C1) is having comparable solubility with Niraparib tosylate monohydrate (Form I ) in all the above studied pH buffers. Example 4 Process to prepare Niraparib tosylate : L-Proline co-crystal (Form-C2): Niraparib tosylate (5.0 g) and L-proline (1.137 g) were stirred in 30 volumes of acetonitrile at reflux temperature for 4-5 hours. The solids were isolated by filtration and dried at 50-60°C for 3-4 hours to yield the title compound. H-NMR reveals a molar ratio of Niraparib tosylate to L-proline of about 1:1. The crystallinity was confirmed by XRD, and identified as Form C2 as depicted in Figure 11. Example 5 Process to prepare Niraparib tosylate : L-Proline co-crystal (Form-C2): Niraparib tosylate (5.0 g) was added in a mixture of L-proline (1.4 g) and IPA (100 ml) at 50°C. The contents were heated to 70-75°C for 6 hours. The contents were cooled to 25-30°C and stirred further at 25-30°C for 1 hour. The solids were isolated by filtration and dried at 45-50°C for 3-4 hours to yield the title compound. Water content :0.3% H-NMR reveals a molar ratio of Niraparib tosylate to L-proline of about 1:1. The crystallinity was confirmed by XRD, DSC and identified as Form C2 as depicted in Figures 12 and 13.

Claims

We claim, 1. A co-crystal of niraparib tosylate and L-proline. 2. The co-crystal of claim 1, wherein the molar ratio of niraparib tosylate to L-proline is between 2:1 to 1:2. 3. The co-crystal of claim 1, wherein the molar ratio of niraparib tosylate to L-proline is 1:1. 4. The co-crystal of claim 1, wherein at least about 50% of the co-crystal is in the crystalline form. 5. The co-crystal of claim 4, characterized by XRPD diffractogram with characteristics peaks at 9.08, 14.20, 16.90, 18.17 and 20.1 ± 0.2˚2θ. 6. The co-crystal of claim 4, further characterized by XRPD diffractogram as depicted in Figure 11 and Figure 12. 7. The co-crystal of claim 4, characterized by a DSC thermogram having an endothermic peak with onset at around 215.41±5°C; and a peak maximum at around 217.40 ±5°C. 8. The co-crystal of claim 4, further characterized by having a DSC thermogram as shown in Figure 13. 9. The co-crystal of claim 4, further characterized by data selected from the group consisting of: the group consisting of: an X-ray powder diffraction pattern having peaks at about : 9.08, 14.20, 16.90, 18.17 and 20.1 ± 0.2 °2θ; a XRPD diffractogram as depicted in Figure 11; a XRPD diffractogram as depicted in Figure 12; a DSC thermogram having a first endothermic peak in the range of about 215.41±5°C; a peak maximum at around 217.40 ±5°C; a DSC pattern as depicted in Figure 13; and combinations thereof. 10. A process for preparing co-crystal of niraparib tosylate and L-proline of claim 4, the process comprising, f. stirring L-proline in a first organic solvent selected from the group comprising of C1-C5 alcohol or a mixture of C1-C5 alcohols thereof; g. mixing Niraparib tosylate; h. heating the mixture for sufficient time; i. isolating the co-crystal of Niraparib tosylate with L-proline; and j. drying. 11. The process of claim 10, wherein the first organic solvent C1-C5 alcohol, is preferably selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, amyl alcohol and the like. 12. A process for preparing co-crystal of niraparib tosylate and L-proline of claim 4, the process comprising, a. stirring Niraparib tosylate and L-proline in a polar aprotic solvent or mixture thereof; b. heating the mixture for sufficient time; c. isolating the co-crystal of Niraparib tosylate with L-proline; and d. drying. 13. The process of claim 12, wherein the polar aprotic solvent is selected from the group comprising of N, N- dimethylacetamide (DMAC), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; nitrile solvent such as acetonitrile, propionitrile, butyronitrile and the like. 14. A pharmaceutical composition in the form of a tablets, powders, capsule, liquid suspension or an injectable and the like, comprising the co-crystal of Niraparib tosylate with L-proline of claim 1 and a pharmaceutically acceptable excipient. 15. A pharmaceutical composition of claim 14, wherein the co-crystal of Niraparib tosylate with L-proline is formulated into tablets, film-coated tablets, sugar coated tablets, pills, dragees, capsules, soft gelatin capsules, hard gelatin capsules, troches, aqueous suspensions or solutions, dispersions, injectables and other pharmaceutical forms. 16. A method of prevention and/or treatment of treating epithelial ovarian, fallopian tube, or primary peritoneal cancer and combinations thereof comprising administering to a patient in need thereof a therapeutically effective amount of the co-crystal of Niraparib tosylate with L-proline of claim 1. 17. Use of co-crystal of Niraparib tosylate with L-proline of claim 1, in the manufacture of a medicament for prevention and/or treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer and combinations thereof. 18. Use of co-crystal of Niraparib tosylate with L-proline of claim 1, in the prevention and/or treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer and combinations thereof.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210017151A1 (en) * 2019-07-16 2021-01-21 Apotex Inc. Crystalline Forms of Niraparib Tosylate
WO2021046303A1 (en) * 2019-09-06 2021-03-11 Ebers Tech Inc. Cannabigerol proline cocrystals

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210017151A1 (en) * 2019-07-16 2021-01-21 Apotex Inc. Crystalline Forms of Niraparib Tosylate
WO2021046303A1 (en) * 2019-09-06 2021-03-11 Ebers Tech Inc. Cannabigerol proline cocrystals

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