WO2015052568A2 - Solid forms of curcumin and derivatives thereof - Google Patents

Solid forms of curcumin and derivatives thereof Download PDF

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Publication number
WO2015052568A2
WO2015052568A2 PCT/IB2014/002034 IB2014002034W WO2015052568A2 WO 2015052568 A2 WO2015052568 A2 WO 2015052568A2 IB 2014002034 W IB2014002034 W IB 2014002034W WO 2015052568 A2 WO2015052568 A2 WO 2015052568A2
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crystal
bdmc
curcumin
suitable solvent
piperazine
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PCT/IB2014/002034
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English (en)
French (fr)
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WO2015052568A3 (en
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Satyanarayana Chava
Seeta Rama Anjaneyulu GORANTLA
Vamsee Krishna Muppidi
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Laurus Labs Private Limited
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Publication of WO2015052568A3 publication Critical patent/WO2015052568A3/en

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    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

Definitions

  • the present invention generally relates to solid forms of curcumin and derivatives thereof, including its polymorphs and co-crystals.
  • the invention also relates to the therapeutic use of solid forms of curcumin and derivatives thereof and pharmaceutical composition containing them.
  • Curcumin and its derivative namely "bisdesmethoxycurcumin” are the curcuminoids found in the popular Indian spice Turmeric.
  • Curcumin and derivatives thereof have been used for centuries as a remedy for many ailments. Extensive scientific research over the past decade has shown the ability of this compound to modulate multiple cellular targets and hence possesses preventive and therapeutic value against a wide variety of diseases. It is well documented in scientific and patent literature that the main limitation of the use of curcumin-based formulation is its poor solubility and fast metabolism. Due to poor systemic bioavailability after oral administration of curcumin, many research groups have focused on ways to improve its bioavailability.
  • Suitable crystalline forms of a drug is a necessary stage for many orally available drugs.
  • Suitable crystalline forms possess the desired properties of a particular drug.
  • Such suitable crystalline forms may be obtained by forming a co-crystal between the drug and a co-former.
  • Co-crystals often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself.
  • a co-crystal may have different dissolution and solubility properties than the drug.
  • co-crystals may be used as a convenient vehicle for drug delivery, and new drug formulations comprising co-crystals of a given drug may have superior properties, such as solubility, dissolution, hygroscopicity and storage stability over existing formulations of the drug.
  • a co-crystal of a drug is a distinct chemical composition between the drug and co-former, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and co-former individually.
  • co-crystals are comprised of neutral species.
  • a salt unlike a salt, one cannot determine the stoichiometry of a co- crystal based on charge balance. Indeed, one can often obtain cocrystals having stoichiometric ratios of drug to co-former of greater than or less than 1 : 1.
  • co-crystals may be thought of as multi- component crystals composed of neutral molecules. These multi-component assemblies are continuing to excite and find usefulness, particularly within the pharmaceutical arena, for their ability to alter physicochemical properties. More specifically, co-crystals have been reported to alter aqueous solubility and/or dissolution rates, increase stability with respect to relative humidity, and improve bioavailability of active pharmaceutical ingredients.
  • co-crystals A necessary consideration when designing co-crystals, if the end goal is a potential marketed drug-product, is incorporating a suitable co-crystal former (co-former) with an acceptable toxicity profile.
  • co-formers are typically selected from the same list of pharmaceutically accepted salt formers, generally regarded as safe (GRAS) and/or everything added to food in the United States (EAFUS) lists, due to previous occurrence of these molecules in FDA approved drug or food products.
  • GRAS pharmaceutically accepted salt formers
  • EAFUS everything added to food in the United States
  • An additional group of molecules to be considered as possible co-formers are the naturally occurring compounds, nutraceuticals.
  • Indian patent publication 3190/CHE/2010 discloses crystalline form II, III and amorphous form of curcumin and co-crystal of curcumin with resorcinol and pyrogallol.
  • Int. Jl. Of Pharmaceuticals, 439 (1 -2), 63-72, 2012 discloses mechano-chemical grinding of curcumin with co-crystal formers in a fixed stoichiometry ratio resulted in binary eutectic compositions of curcumin-coformer with nicotinamide (1 :2), ferulic acid ( 1 : 1 ), hydroquinone ( 1 : 1), p-hydroxybenzoic acid (1 : 1 ) and 1-tartaric acid (1 : 1).
  • the main objective of the present invention is to provide novel solid forms of curcumin and derivative thereof with physiochemical properties.
  • curcumin derivative means bisdesmethoxycurcumin (herein after the same has been referred as BDMC).
  • solid forms herein used in this specification collectively represents a crystalline form, co-crystals or their polymorphic forms.
  • co-crystals of curcumin and derivatives thereof and their novel crystalline forms were prepared to improve the physiochemical properties of curcumin and ' its derivatives.
  • the cocrystals were prepared using co-formers selected from piperazine, 3 ⁇ 4 nicotinamide, isonicotinamide, caffeine, L-proline, naproxen sodium, ibuprofen sodium and piperidine.
  • Co-crystals of curcumin, its derivative and co-former in stoichiometry 1 :4 to 4: 1 were prepared. According to the invention all the novel solid forms of curcumin and derivatives thereof, namely co-crystal and polymorphs showing enhanced dissolution rate and greater bioavailability.
  • Another aspect of the present invention provides co-crystals of curcumin with co-former selected from the group comprising piperazine, nicotinamide, isonicotinamide, caffeine, L- proline, naproxen sodium, ibuprofen sodium and piperidine.
  • co-crystals of curcumin with co-former wherein curcumin and co-former are present in a molar ratio of 1 :4 to 4: 1.
  • curcumin includes curcumin: piperazine (2: 1 ) co-crystal, curcumin: piperazine ( 1 : 1 ) co-crystal, curcumin: nicotinamide ( 1 : 1 ) co-crystal, curcumin: isonicotinamide (1 :2) co-crystal, curcumin: naproxen sodium ( 1 : 1) co-crystal, curcumin: piperidine ( 1 : 1 ) co-crystal and curcumin: ibuprofen sodium (1 : 1) co-crystal as well as their polymorphic forms.
  • Another aspect of the present invention provides a process for the preparation of co-crystals of curcumin, which comprise of adding curcumin to co-former dissolved in a suitable solvent, or adding a co-former to curcumin dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • Another aspect of the present invention provides novel crystalline form of curcumin, here in designated as form X.
  • Another aspect of the present invention provides co-crystals of BDMC (bisdesmethoxycurcumin) with co-former selected from the group comprising piperazine, nicotinamide, isonicotinamide, caffeine, L-proline and piperidine.
  • BDMC piperazine (2: 1 ) co-crystal
  • BDMC piperazine (1 : 1 ) co-crystal
  • BDMC caffeine (1 : 1 ) co-crystal
  • BDMC L-proline ( 1 : 1 ) co-crystal
  • BDMC nicotinamide ( 1 :4) co-crystal
  • BDMC nicotinamide (2:3) co-crystal
  • BDMC isonicotinamide (1 :2) co-crystal
  • BDMC piperidine (1 : 1 ) co-ctystal as well as their polymorphic forms.
  • Another aspect of the present invention provides a process for the preparation of co-crystals of BDMC, which comprise of adding BDMC to co-former dissolved in a suitable solvent, or adding a co-former to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • Another aspect of the present invention provides crystalline form I and form II of BDMC.
  • composition comprising solid forms of curcumin and derivatives thereof of the present invention.
  • Figiire-1 Shows the PXRD pattern of Curcumin: piperazine (2: 1) co-crystal
  • Figure-3 Shows the PXRD pattern of Curcumin: piperazine (1 : 1 ) co-crystal (form I)
  • Figure-4 Shows the DSC of Curcumin: piperazine (1 : 1 ) co-crystal (form I)
  • Figure-5 Shows the PXRD pattern of Curcumin: piperazine ( 1 : 1) co-crystal (form II)
  • Figure-6 Shows the DSC of Curcumin: piperazine (1 : 1) co-crystal (form II)
  • Figure-7 Shows the PXRD pattern of Curcumin: nicotinamide (1 : 1) co-crystal
  • Figure-8 Shows the DSC of Curcumin: nicotinamide (1:1) co-crystal
  • Figure-13 Shows the PXRD pattern of Curcumin: piperidine (1:1) co-crystal
  • Figure-15 Shows the PXRD pattern of Curcumin: ibuprofen sodium (1:1) co-crystal
  • Figure-16 Shows the DSC of Curcumin: ibuprofen sodium (1:1) co-crystal
  • Figure-17 Shows the PXRD pattern of crystalline form X of curcumin
  • Figure-18 Shows the DSC of crystalline form X of curcumin
  • Figure-20 Shows the PXRD pattern of BDMC: piperazine (2:1) co-crystal
  • Figure-21 Shows the DSC of BDMC: piperazine (2:1) co-crystal
  • Figure-22 Shows the PXRD pattern of BDMC: piperazine (1:1) co-crystal (form I)
  • Figure-23 Shows the DSC of BDMC: piperazine (1:1) co-crystal (form I)
  • Figure-24 Shows the PXRD pattern of BDMC: piperazine (1:1) co-crystal (form II)
  • Figure-25 Shows the DSC of BDMC: piperazine (1 :1) co-crystal (form II)
  • Figure-26 Shows the PXRD pattern of BDMC: caffeine (1:1) co-crystal
  • Figiire-27 Shows the DSC of BDMC: caffeine (1:1) co-crystal
  • Figure-28 Shows the PXRD pattern of BDMC: L-proline (1:1) co-crystal
  • Figure-29 Shows the DSC of BDMC: L-proline (1:1) co-crystal
  • Figure-30 Shows the PXRD pattern of BDMC: nicotinamide (1:4) co-crystal
  • Figure-31 Shows the DSC of BDMC: nicotinamide (1:4) co-crystal
  • Figure-32 Shows the PXRD pattern of BDMC: nicotinamide (2:3) co-crystal
  • Figure-33 Shows the DSC of BDMC: nicotinamide (2:3) co-crystal
  • Figure-34 Shows the PXRD pattern of BDMC: isonicotinamide (1:2) co-crystal
  • Figure-35 Shows the DSC of BDMC: isonicotinamide (1:2) co-crystal
  • Figure-30 Shows the PXRD pattern of BDMC: piperidine (1:1) co-crystal
  • Figure-37 Shows the DSC of BDMC: piperidine (1:1) co-crystal
  • Figure-40 Shows the PXRD pattern of crystalline form II of BDMC
  • Figure-41 Shows the DSC of crystalline form II of BDMC
  • the present invention provides co-crystals of curcumin with co-former selected from the group comprising piperazine, nicotinamide, isonicotinamide, caffeine, L-proline, naproxen sodium, ibuprofen sodium and piperidine.
  • co-crystals of curcumin with co- former wherein curcumin and co-former are present in a molar ratio of 1 :4 to 4: 1.
  • the present invention provides co-crystals of curcumin, including curcumin: piperazine (2: 1 ) co-crystal, curcumin: piperazine (1 : 1) co-crystal, curcumin: nicotinamdie ( 1 : 1 ) co-crystal, curcumin: isonicotinamide (1 :2) co-crystal, curcumin: naproxen sodium ( 1 : 1) co-crystal, curcumin: piperidine ( 1 : 1) co-crystal and curcumin: ibuprofen sodium (1 : 1 ) co-crystal.
  • the present invention provides a curcumin: piperazine co-crystal.
  • the present invention provides a curcumin: piperazine co-crystal, wherein the molar ratio of curcumin: piperazine is 2:1.
  • the present invention provides curcumin: piperazine (2: 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline curcumin: piperazine (2: 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure- 1 .
  • PXRD Powder X-Ray diffraction
  • crystalline curcumin piperazine (2: 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 5.45, 8.36, 9.57, 10.96, 14.59, 16.09, 16.52, 1 7.07, 19.26, 21.50, 23.41 and 29.12 ⁇ 0.2 °20.
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline curcumin: piperazine (2: 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-2.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of co- crystal of curcumin: piperazine (2: 1 ), which comprises, adding curcumin to piperazine dissolved in a suitable solvent, or adding piperazine to curcumin dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent for dissolving piperazine and/or curcumin is selected from the group consisting of nitriles, alcohols, esters, water and the like and mixtures thereof; preferably acetonitrile, propionitrile, benzonitrile, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, ethyl acetate, isopropyl acetate, propylacetate and the like and mixtures thereof; more preferably methanol.
  • Suitable temperature for dissolving piperazine/curcumin in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 30 minutes to about 6 hours; preferably about 2 hours to about 4 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a curcumin: piperazine co-crystal, wherein the molar ratio of curcumin: piperazine is 1 : 1.
  • the present invention provides curcumin: piperazine (1 : 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline form I of curcumin: piperazine ( 1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-3.
  • crystalline form I of curcumin piperazine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 4.05, 8.32, 12.54, 15.64, 16.03, 16.69, 17.57, 20.45, 23.43, 24.91 and 25.59 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline form I of curcumin: piperazine (1 : 1) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-4.
  • the present invention provides a process for the preparation of crystalline form I of curcumin: piperazine (1 : 1 ) co-crystal, which comprises, adding curcumin to piperazine dissolved in a suitable solvent, or adding piperazine to curcumin dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for crystalline form I of curcumin: piperazine (1 : 1 ) co-crystal is selected from the group consisting of alcohols, esters, nitriles and the like; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, methyl acetate, ethyl acetate, isopropyl acetate, propylacetate, acetonitrile, propionitrile, benzonitrile, and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving piperazine/curcumin in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 30 minutes to about 8 hours; preferably about 4 hours to about 6 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides crystalline form II of curcumin: piperazine ( 1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-5.
  • PXRD Powder X-Ray diffraction
  • crystalline form II of curcumin piperazine (1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 20 peaks at about 9.74, 10.88, 1 1.70, 12.82, 14.01 , 15.72, 16.47, 17.97, 20.30, 22.44 and 24.01 ⁇ 0.2 °20.
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline form II of curcumin: piperazine ( 1 : 1) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-6.
  • the present invention provides a process for the preparation of crystalline form II of curcumin: piperazine (1 : 1) co-crystal, which comprises, adding curcumin to piperazine dissolved in a suitable solvent, or adding piperazine to curcumin dissolved in a suitable solvent, optionally seeding, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for crystalline form II of curcumin: piperazine ( 1 : 1 ) co-crystal is selected from the group consisting of alcohols, nitriles and the like; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, acetonitrile, propionitrile, benzonitrile, and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving piperazine/curcumin in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be caixied out for a sufficient period of time of about 2 hours to about 36 hours; preferably about 12 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a curcumin: nicotinamide co-crystal.
  • the present invention provides curcumin: nicotinamide co-crystal, wherein the molar ratio of curcumin: nicotinamide is 1 : 1
  • the present invention provides curcumin: nicotinamide (1 : 1 ) co- crystal in crystalline form.
  • the present invention provides crystalline curcumin: nicotinamide (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-7.
  • the present invention provides crystalline curcumin: nicotinamide (1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-8.
  • the present invention provides a process for the preparation of curcumin: nicotinamide ( 1 : 1 ) co-crystal, which comprises;
  • the suitable solvent used herein for curcumin nicotinamide (1 : 1 ) cocrystals is selected from the group consisting of alcohols, esters, ketones, nitriles and the like; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, metylacetate, ethylacetate, propylacetate, isopropylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, benzonitrile, and the like and mixtures thereof; more preferably propyl acetate.
  • Suitable temperature for dissolving nicotinamide/curcumin in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to about 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation; the co-crystal obtained can be isolated by techniques known in the art.
  • the present invention provides a curcumin: isonicotinamide co- crystal.
  • the present invention provides curcumin: isonicotinamide co- crystal, wherein the molar ratio of curcumin: isonicotinamide is 1 :2. In another embodiment, the present invention provides curcumin: isonicotinamide (1 :2) co- crystal in crystalline form.
  • the present invention provides crystalline curcumin: isonicotinamide ( 1 :2) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-9.
  • the present invention provides crystalline curcumin: isonicotinamide (1 :2) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure- 10.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of curcumin: isonicotinamide (1 :2) co-crystal, which comprises;
  • the suitable solvent used herein for curcumin isonicotinamide ( 1 :2) co-crystal is selected from the group consisting of ester, alcohol, ketone and the like; preferably methyl acetate, ethyl acetate, isopropyl acetate, propylacetate, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof; more preferably ethyl acetate.
  • Suitable temperature for dissolving isonicotinamide /curcumin in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to about 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation; the co-crystal obtained can be isolated by techniques known in the art.
  • the present invention provides a curcumin: naproxen sodium co- crystal.
  • the present invention provides a curcumin: naproxen sodium co- crystal, wherein the molar ratio of curcumin: naproxen sodium is 1 : 1.
  • the present invention provides curcumin: naproxen sodium (1 : 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline curcumin: naproxen sodium ( 1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-1 1.
  • PXRD Powder X-Ray diffraction
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline curcumin: naproxen sodium (1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure- 12.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of curcumin: naproxen sodium (1 : 1) co-crystal, which comprises; adding curcumin to naproxen sodium in a suitable solvent, or adding naproxen sodium to curcumin in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • Suitable temperature for dissolving curcumin/naproxen sodium in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 6 hours to about 36 hours; preferably about 24 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • Sonication of curcumin and naproxen sodium mixture in a suitable solvent can be carried out by methods known in the art.
  • the present invention provides a process for the preparation of curcumin naproxen sodium ( 1 : 1 ) co-crystal, which comprises grinding a mixture of curcumin and naproxen sodium in a suitable solvent. Grinding the mixture of curcumin and naproxen sodium in a suitable solvent can be carried out by physical grinding process known in the art.
  • the suitable solvent used for the preparation of curcumin naproxen sodium ( 1 : 1) co-crystal is selected from the group consisting of alcohol, ketone, ester and the like; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, propylacetate and the like and mixtures thereof; more preferably acetone.
  • the present invention provides a curcumin: piperidine co-crystal.
  • the present invention provides a curcumin: piperidine co-crystal, wherein the molar ratio of curcumin: piperidine is 1 : 1.
  • the present invention provides curcumin: piperidine (1 : 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline curcumin: piperidine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure- 13.
  • PXRD Powder X-Ray diffraction
  • crystalline curcumin piperidine ( 1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 9.65, 10.64, 10.94, 1 1.97, 12.33, 13.06, 14.16, 15.86, 16.74, 17.90, 18.05, 18.32, 18.82, 22.82, 24.82, 24.24, 26.44, 27.51 , 28.83, 31.35, 32.31 , 34.41 and 38.12 ⁇ 0.2° 2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline curcumin: piperidine (1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure- 14.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of curcumin: piperidine (1 : 1 ) co-crystal, which comprises, adding curcumin to piperidine dissolved in a suitable solvent, or adding piperidine to curcumin dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for curcumin: piperidine (1 : 1) co- crystal is selected from the group consisting of nitriles, alcohols, esters and mixtures thereof; preferably acetonitrile, propionitrile, benzonitrile, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, ethyl acetate, isopropyl acetate, propylacetate and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving curcumin/piperidine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 30 minutes to about 24 hours; preferably about 15 hours to about 17 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a curcumin: ibuprofen sodium co- crystal.
  • the present invention provides a curcumin: ibuprofen sodium co- crystal, wherein the molar ratio of curcumin: ibuprofen sodium is 1 : 1.
  • the present invention provides curcumin: ibuprofen sodium ( 1 : 1) co-crystal in crystalline form.
  • the present invention provides crystalline curcumin: ibuprofen sodium (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure- 15.
  • PXRD Powder X-Ray diffraction
  • crystalline curcumin ibuprofen sodium ( 1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 5.02, 5.53, 8.90, 10.10, 1 1.08, 13.86, 15.29, 16.77, 18.17, 19.37, 20.33, 22.37, 23.24, 24.99, 28.46, 29.54 and 32.83 ⁇ 0.2° 20.
  • the present invention provides crystalline curcumin: ibuprofen sodium (1 : 1) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-16.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of curcumin: ibuprofen sodium (1 : 1 ) co-crystal, which comprises,
  • the suitable solvent used herein for curcumin: ibuprofen sodium (1 : 1 ) co-crystal is selected from the group consisting of alcohols, esters, ketones, nitriles and the like and mixtures thereof; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, metylacetate, ethylacetate, propylacetate, isopropylacetate, acetone, methyl ethyl . ketone, methyl isobutyl ketone, acetonitrile, propionitrile, benzonitrile, and the like and mixtures thereof more preferably acetone.
  • Suitable temperature for dissolving ciircumin/ibuprofen sodium in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the reaction mass of step a) can be diluted with a suitable solvent and then the reaction mass subjected to sonication for 15-30 mins to obtain the product.
  • the isolation of curcumin ibuprofen sodium (1 : 1) cocrystai can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides crystalline form X of curcumin.
  • the present invention provides crystalline form X of curcumin and wherein the crystalline form X is monohydrate.
  • the present invention provides crystalline form X of curcumin characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-17.
  • crystalline form X of curcumin characterized by Powder X-Ray diffraction (PXRD) partem comprising 2 ⁇ peaks at about 6.80, 7.33, 10.44, 13.00, 13.72, 14.81 , 16.74, 19.51 , 20.85, 23.52, 26.03, 26.39, 27.27, 28.39 and 30.26 ⁇ 0.2 °20.
  • the present invention provides crystalline form X of curcumin characterized by Differential Scanning Calorimetry (DSC) as shown in figure- 18.
  • DSC Differential Scanning Calorimetry
  • the present invention provides crystalline form X of curcumin characterized by TGA shown in figure- 19.
  • the present invention provides a process for the preparation of crystalline form X of curcumin, which comprises,
  • step b) adding step a) solution in to water,
  • the suitable solvent used herein for crystalline form X of curcumin is selected from the group consisting of alcohols, ketone, nitrile or water and mixtures thereof; preferably methanol, isopropanol, propanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, water and the like and mixtures thereof more preferably acetone.
  • the dissolution of curcumin in a suitable solvent can be carried out at a suitable temperature of about 25°C to reflux temperature, preferably at about 50°C to about 60°C.
  • the resultant solution of step a) can be added in to water followed by kept aside at a temperature of about -20°C to 5°C; preferably at about 5°C for a period of about 12 hours to 80 hours; preferably about 70 to about 72 hrs.
  • the precipitated crystals can be isolated by any process known in the art, for example filtration/decantation and followed by optional step of drying.
  • the present invention provides co-crystals of BDMC (bisdesmethoxycurcumin) with co-former selected from the group comprising piperazine, nicotinamide, isonicotinamide, caffeine, L-proline and piperidine.
  • co-crystals of BDMC with co- former, wherein BDMC and coformer are present in a molar ratio of 1 :4 to 4: 1.
  • the present invention provides cocrystals of BDMC including BDMC: piperazine (2: 1) co-crystal, BDMC: piperazine (1 : 1 ) co-crystal, BDMC: caffeine (1 : 1 ) co-crystal, BDMC: L-proline ( 1 : 1 ) co-crystal, BDMC: nicotinamide (1 :4) co-crystal, BDMC: nicotinamide (2:3) co-crystal, BDMC: isonicotinamide ( 1 :2) co-crystal and BDMC: piperidine ( 1 : 1 ) co-crystal.
  • the present invention provides a BDMC: piperazine co-crystal.
  • the present invention provides a BDMC: piperazine co-crystal, wherein the molar ratio of BDMC: piperazine is 2: 1.
  • the present invention provides BDMC: piperazine (2: 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline BDMC: piperazine (2: 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-20.
  • PXRD Powder X-Ray diffraction
  • crystalline BDMC piperazine (2: 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 7.75, 15.56, 17.90, 18.86, 21.42, 23.45, 24.82 and 25.78 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline BDMC: piperazine (2: 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-21.
  • the present invention provides a process for the preparation of BDMC: piperazine (2: 1) co-crystal, which comprises; adding BDMC to piperazine dissolved in a suitable solvent, or adding piperazine to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for BDMC piperazine (2: 1) co- crystal is selected from the group consisting of alcohols, ketone, nitrile and mixtures thereof; preferably methanol, isopropanol, propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and the like; more preferably methanol.
  • Suitable temperature for dissolving BDMC/piperazine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 30 minutes to about 6 hours; preferably about 2 hours to about 4 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a BDMC: piperazine co-crystal, wherein the molar ratio of BDMC: piperazine is 1 : 1 .
  • the present invention provides BDMC: piperazine (1 : 1) co-crystal in crystalline form-I.
  • the present invention provides crystalline form-I of BDMC: piperazine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-22.
  • crystalline form-I of BDMC piperazine ( 1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 6.48, 1 1.26, 1 1.41 , 13.14, 16.03, 16.46, 16.55, 17.76, 18.38, 18.94, 19.68, 20.94, 22.35, 23.52, 24.89, 25.47, 26.97, 27.57 and 28.98 ⁇ 0.2 °2 ⁇ .
  • the present invention provides crystalline form-I of BDMC: piperazine ( 1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-23.
  • the present invention provides a process for the preparation of crystalline form I of BDMC: piperazine (1 : 1 ) co-crystal, which comprises; adding BDMC to piperazine dissolved in a suitable solvent, or adding piperazine to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for crystalline form-I of BDMC: piperazine (1 : 1) co-crystal is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving BDMC/piperazine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 6 hours to 36 hours; preferably about 22 hours to about 32 hours.
  • the isolation of the product can be carried out by any process Icnown in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a BDMC: piperazine ( 1 : 1 ) co-crystal in crystalline form-II.
  • the present invention provides crystalline form-II of BDMC: piperazine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-24.
  • PXRD Powder X-Ray diffraction
  • crystalline form-II of BDMC piperazine ( 1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 6.46, 1 1 .40, 13.10, 14.37, 16.62, 17.69, 19.04, 19.65, 20.12, 22.33, 24.77, 25.95, 26.92, 27.55, 29.53 and 32.23 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline form-II of BDMC: piperazine (1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-25.
  • the present invention provides a process for the preparation of crystalline form II of BDMC: piperazine (1 : 1 ) co-crystal, which comprises; adding BDMC to piperazine dissolved in a suitable solvent, or adding piperazine to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for crystalline form II of BDMC piperazine (1 : 1 ) co-crystal is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving BDMC/piperazine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 30 minutes to 10 hours; preferably about 6 hours to about 8 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a BDMC: caffeine co-crystal. In another embodiment, the present invention provides a BDMC: caffeine co-crystal, wherein the molar ratio of BDMC: caffeine is 1 : 1.
  • the present invention provides BDMC: caffeine ( 1 : 1) co-crystal in crystalline form.
  • the present invention provides crystalline BDMC: caffeine (1 : 1 ) co- crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-26.
  • PXRD Powder X-Ray diffraction
  • crystalline BDMC caffeine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 20 peaks at about 9.20, 10.66, 12.33, 13.99, 17.33, 18.34, 19.91 , 20.98, 22.80, 26.40 and 35.42 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline BDMC: caffeine ( 1 : 1 ) co- crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-27.
  • the present invention provides a process for the preparation of BDMC: caffeine (1 : 1 ) co-crystal, which comprises; adding BDMC to caffeine dissolved in a suitable solvent, or adding caffeine to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for BDMC caffeine (1 : 1 ) co- crystal is selected from the group consisting of nitrile such as acetonitrile, propionitrile and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohol such as methanol, ethanol, isopropanol and the like; ether such as diethyl ether, tetrahydrofuran, methyl tert. butyl ether and the like and mixtures thereof; more preferably methanol.
  • nitrile such as acetonitrile, propionitrile and the like
  • ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • alcohol such as methanol, ethanol, isopropanol and the like
  • ether such as diethyl ether, tetrahydrofuran, methyl tert
  • Suitable temperature for dissolving BDMC/caffine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 6 hours to 30 hours; preferably about 8 hours to about 16 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides another process for the preparation of BDMC: caffeine (1 : 1 ) co-crystal, which comprises grinding the mixture of BDMC and caffeine in a suitable solvent. Grinding the mixture of BDMC and caffeine in a suitable solvent can be carried out by physical grinding process known in the art.
  • the suitable solvent used herein the grinding step is selected from the group consisting of nitrile such as acetonitrile, propionitrile and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohol such as methanol, ethanol, isopropanol and the like; ether such as diethyl ether, tetrahydrofuran, methyl tert. butyl ether and the like and mixtures thereof; more preferably methanol.
  • nitrile such as acetonitrile, propionitrile and the like
  • ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • alcohol such as methanol, ethanol, isopropanol and the like
  • ether such as diethyl ether, tetrahydrofuran, methyl tert. butyl ether and the like and mixture
  • the present invention provides a BDMC: L-proline co-crystal.
  • the present invention provides BDMC: L-proline co-crystal, wherein the molar ratio of BDMC: L-proline is 1 : 1.
  • the present invention provides BDMC: L-proline (1 : 1 ) co-crystal in crystalline form.
  • the present invention provides crystalline BDMC: L-proline (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PX D) pattern shown in figure-28.
  • crystalline BDMC L-proline (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 9.09, 9180, 12.45, 14.25, 16.12, 17.96, 18.68, 19.08, 19.36, 20.65, 24.04, 24.47, 26.54, 26.92, 27.74 and 27.91 ⁇ 0.2 °2 ⁇ .
  • the present invention provides crystalline BDMC: L-proline (1 : 1) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-29.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of BDMC: L-proline (1 : 1 ) co-crystal, which comprises; adding BDMC to L-proline dissolved in a suitable solvent, or adding L-proline to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for BDMC L-proline (1 : 1 ) cocrystals is selected from the group consisting of alcohol such as methanol, ethanol, isopropanol and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof; more preferably methanol.
  • Suitable temperature for dissolving BDMC/L-proline in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 6 hours to 30 hours; preferably about 8 hours to about 16 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides a process for the preparation of BDMC: L-proline (1 : 1 ) co-crystal, comprising grinding a mixture of BDMC and caffeine, optionally in presence of suitable solvent.
  • the suitable solvent used herein for grinding is selected from the group consisting of alcohol such as methanol, ethanol, isopropanol and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof; more preferably methanol.
  • the present invention provides a BDMC: nicotinamide co-crystal.
  • the present invention provides a BDMC: nicotinamide co-crystal, wherein the molar ratio of BDMC with nicotinamide is 1 :4.
  • the present invention provides BDMC: nicotinamide (1 :4) co- crystals in crystalline form.
  • the present invention provides crystalline BDMC: nicotinamide (1 :4) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-30.
  • PXRD Powder X-Ray diffraction
  • crystalline BDMC nicotinamide ( 1 :4) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 4.94, 5.27, 9.41 , 9.84, 10.76, 13.83, 14.76, 16.22, 17.23, 18.76, 19.64, 20.51 , 21.10, 21.54, 22.13, 22.78, 24.28, 24.59, 26.23, 26.76, 27.82 and 30.89 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline BDMC: nicotinamide (1 :4) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figiire-31.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of BDMC: nicotinamide (1 :4) co-crystal, which comprises;
  • the suitable solvent used herein for BDMC nicotinamide (1 :4) co- crystal is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; alcohol such as methanol, ethanol, isopropanol, isobutanol and the like and mixtures thereof; more preferably propyl acetate.
  • Suitable temperature for dissolving BDMC and nicotinamide in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation, the cocrystal obtained can be isolated by techniques known in the art, for example filtration or decantation.
  • the present invention provides a process for the preparation of BDMC: nicotinamide (1 :4) co-crystal, comprising slurrying the mixture of BDMC and nicotinamide in a ratio of 1 :4 in a suitable solvent for a sufficient period of time.
  • the suitable solvent used herein for BDMC nicotinamide (1 :4) co- crystal is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; alcohol such as methanol, ethanol, isopropanol, isobutanol and the like and mixtures thereof; more preferably propyl acetate.
  • the present invention provides BDMC: nicotinamide co-crystal, wherein the molar ratio of BDMC: nicotinamide is 2:3.
  • the present invention provides BDMC: nicotinamide (2:3) co- crystal in crystalline form.
  • the present invention provides crystalline BDMC: nicotinamide (2:3) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-32.
  • PXRD Powder X-Ray diffraction
  • crystalline BDMC nicotinamide (2:3) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 5.80, 6.40, 9.59, 1 1.25, 12.29, 13.71 , 15.24, 15.65, 16.17, 16.77, 18.10, 19.21 , 20.20, 20.72, 21.39, 22.70, 23.14, 23.87, 26.57, 28.65 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline BDMC: nicotinamide (2:3) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-33.
  • the present invention provides a process for the preparation of BDMC: nicotinamide (2:3) co-crystal, which comprises;
  • the suitable solvent used herein for BDMC nicotinamide (2:3) co- crystal is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; alcohol such as methanol, ethanol, isopropanol, isobutanol and the like and mixtures thereof; more preferably propyl acetate.
  • Suitable temperature for dissolving BDMC and nicotinamide in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation, the cocrystal obtained can be isolated by techniques known in the art, for example filtration or decantation.
  • the present invention provides a process for the preparation of BDMC: nicotinamide (2:3) co-crystal, which comprises of slurrying mixture of BDMC and nicotinamide in a ratio of 2:3 in a suitable solvent and isolating the solid.
  • the suitable solvent used herein for slurring BDMC and nicotinamide is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; alcohol such as methanol, ethanol, isopropanol, isobutanol and the like and mixtures thereof; more preferably propyl acetate.
  • the slurring process of a mixture of BDMC and nicotinamide can be carried out in a suitable solvent as mentioned above for sufficient period of time of about 6 hours to 15 hours, preferably about 12- 14 hours at 25°C to 35°C.
  • the present invention provides a BDMC: isonicotinamide co- crystal.
  • the present invention provides a BDMC: isonicotinamide co- crystal, wherein the molar ratio of BDMC: isonicotinamide is 1 :2. In another embodiment, the present invention provides BDMC: isonicotinamide (1 :2) co- crystal in crystalline form.
  • the present invention provides crystalline BDMC: isonicotinamide (1 :2) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-34.
  • PXRD Powder X-Ray diffraction
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline BDMC: isonicotinamide (1 :2) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-35.
  • the present invention provides a process for the preparation of BDMC: isonicotinamide (1 :2) co-crystal, which comprises,
  • the suitable solvent used herein for BDMC: isonicotinamide ( 1 :2) co-crystal is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; alcohol such as methanol, ethanol, isopropanol, isob tanol and the like and mixtures thereof; more preferably ethyl acetate.
  • Suitable temperature for dissolving BDMC and isonicotinamide in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation, the cocrystal obtained can be isolated by techniques known in the art, for example filtration or decantation.
  • the present invention provides a BDMC: piperidine co-crystal.
  • the present invention provides a BDMC: piperidine co-crystal, wherein the molar ratio of BDMC: piperidine is 1 : 1.
  • the present invention provides BDMC: piperidine (1 : 1) co-crystal in crystalline form.
  • the present invention provides crystalline BDMC: piperidine (1 : 1 ) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-36.
  • crystalline BDMC piperidine ( 1 : 1) co-crystal characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 9.82, 1 1.97, 13.57, 14.19, 14.99, 15.33, 17.21 , 17.68, 18.74, 21 .18, 22.69, 23.66, 25.06, 27.64 and 30.69 ⁇ 0.2 °2 ⁇ .
  • the present invention provides crystalline BDMC: piperidine (1 : 1 ) co-crystal characterized by Differential Scanning Calorimetry (DSC) as shown in figure-37.
  • the present invention provides a process for the preparation of BDMC: piperidine (1 : 1 ) co-crystal, which comprises, adding BDMC to piperidine dissolved in a suitable solvent, or adding piperidine to BDMC dissolved in a suitable solvent, and stirring the mixture for sufficient period of time and isolating the solid.
  • the suitable solvent used herein for BDMC: piperidine (1 : 1) co- crystal is selected from the group consisting of alcohols, nitriles and the like; preferably methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tertiary butanol, acetonitrile, propionitrile, benzonitrile, and the like and mixtures thereof; more preferably acetonitrile.
  • Suitable temperature for dissolving BDMC/piperidine in a suitable solvent at about 25°C to reflux temperature; preferably at about 25°C to 45°C.
  • the stirring can be carried out for a sufficient period of time of about 6 hours to 30 hours; preferably about 8 hours to about 16 hours.
  • the isolation of the product can be carried out by any process known in the art, for example filtration and followed by optional step of drying.
  • the present invention provides BDMC in crystalline form.
  • the present invention provides crystalline form I and form II of BDMC.
  • the present invention provides crystalline form-I of BDMC characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-38.
  • crystalline form-I of BDMC characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 7.65, 9.16, 10.51 , 12.73, 13.36, 14.33, 18.57, 19.25, 20.06, 21.07, 21 .26, 21.83, 23.97, 24.42, 25.31 , 25.99, 27.16, 29.04, 30.37 and 31.42 ⁇ 0.2 °20.
  • the present invention provides crystalline form-I of BDMC characterized by Differential Scanning Calorimetry (DSC) as shown in figure-39.
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of crystalline form-I of BDMC which comprises,
  • the suitable solvent used herein for crystalline form-I of BDMC is selected from the group consisting of ester such as ethyl acetate, isopropyl acetate, propylacetate and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile such as acetonitrile, propionitrile and the like; alcohol such as methanol, ethanol, isopropanol and the like and mixtures thereof; more preferably ethyl acetate.
  • ester such as ethyl acetate, isopropyl acetate, propylacetate and the like
  • ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • nitrile such as acetonitrile, propionitrile and the like
  • alcohol such as methanol, ethanol, isopropanol and the like
  • Suitable temperature for dissolving BDMC in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation, the obtained crystalline form-I of BDMC can be isolated by techniques known in the art, for example filtration or decantation.
  • the present invention provides crystalline form-II of BDMC characterized by Powder X-Ray diffraction (PXRD) pattern shown in figure-40.
  • PXRD Powder X-Ray diffraction
  • crystalline form-II of BDMC characterized by Powder X-Ray diffraction (PXRD) pattern comprising 2 ⁇ peaks at about 5.66, 1 1.40, 1 1.78, 12.77, 13.75, 14.29, 16.17, 17.29, 18.34, 19.30, 20.80, 21.61 , 22.56, 23.19, 23.77, 24.59, 25.86, 26.57, 27.13 and 27.93 ⁇ 0.2 °2 ⁇ .
  • PXRD Powder X-Ray diffraction
  • the present invention provides crystalline form-II of BDMC characterized by Differential Scanning Calorimetry (DSC) as shown in figure-41 .
  • DSC Differential Scanning Calorimetry
  • the present invention provides a process for the preparation of crystalline form-II of BDMC which comprises,
  • the suitable solvent used herein for crystalline form-II of BDMC is selected from the group consisting of ester such as methylacetate, ethyl acetate, isopropyl acetate, propylacetate, n-butylacetate and the like; nitrile such as acetonitrile, propionitrile and the like; alcohol such as methanol, ethanol, propanol, isopropanol, isobutanol, n-butanol and the like; halogenated solvents such as chloroform, methylene chloride, ethylene chloride and the like; more preferably acetonitrile.
  • ester such as methylacetate, ethyl acetate, isopropyl acetate, propylacetate, n-butylacetate and the like
  • nitrile such as acetonitrile, propionitrile and the like
  • alcohol such as methanol, ethanol, propanol, isopropanol
  • Suitable temperature for dissolving BDMC in a suitable solvent at about 25°C to reflux temperature; preferably at about 50°C to 80°C.
  • the solvent from the obtained solution can be evaporated slowly by keeping it open under atmospheric conditions and after the solvent evaporation, the obtained crystalline form-Il of BDMC can be isolated by techniques known in the art, for example filtration or decantation.
  • solid forms of curcumin and derivatives thereof described above are stable under ambient conditions; further solid forms of curcumin and derivatives thereof described above having higher dissolution rate compared to the known solid forms of curcumin and its derivatives.
  • compositions comprising one or more solid forms of curcumin or BDMC or its co-crystals, such as pharmaceutical or nutraceutical dosage forms.
  • Such pharmaceutical dosage forms may include one or more excipients, including, without limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other conventional excipients and additives.
  • compositions of the invention can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art.
  • additional formulation additives and agents will often be biologically inactive and can be administered to humans without causing deleterious side effects or interactions.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
  • Solid forms of curcumin and BDMC were characterized by one or more of techniques such as PXRD, FT-IR, NMR, Thermo gravimetric analysis (TGA) and DSC techniques.
  • Curcumin 500 mg
  • nicotinamide 331.52 mg
  • Curcumin ( 1 g) and isonicotinamide (1.326 g) was dissolved in ethyl acetate (95 ml) at 60°C and the solution was filtered then kept for slow evaporation. After one day crystal was observed and was analyzed.
  • Curcumin (4 g) was dissolved in acetone (88 ml) at room temperature. To this clear solution, naproxen sodium (1.833 g) was added and the slurry continued for 24 hours. The material was filtered and analyzed.
  • Example-8 Preparation of curcumin: ibuprofen sodium (1 :1) co-crystal
  • Curcumin (3 g) and ibuprofen sodium (1.875 g) was dissolved in acetone ( 10 ml) at 60°C and precipitate immediately observed. To this precipitate, acetone (20 ml) was added at 60°C. The reaction mass was sonic slurried for 15 mins. The material was filtered, suck dried and analyzed.
  • Curcumin 1. 104 g was dissolved in acetone (18 ml) at 60°C and the obtained clear solution immediately added to water (6 ml). The resulting clear solution filtered and kept aside at 5°C. After one day crystalline orange color powder observed. After three days decanted the solution and crystalline powder was separated.
  • Example-13 Preparation of BDMC: caffeine (1 : 1) co-crystal
  • Example-15 Preparation of BDMC: nicotinamide (1:4) co-crystal
  • Method-1 BDMC (500 mg) and nicotinamide (797.3 mg) was dissolved in propylacetate (75 ml) at 60°C and the solution was filtered, then kept for slow evaporation. After 20 days the crystal observed was analyzed.
  • Example-16 Preparation of BDMC: nicotinamide (2:3) co-crystal
  • Method-1 BDMC (2 g) and nicotinamide ( 1.196 g) was suspended in propylacetate (28 ml) and the slurry continued for overnight. Propylacetate (5 ml) was added to this suspension and slurry continued for an hour. Filtered the solid and analyzed.
  • Method-2 BDMC (500 mg) and nicotinamide (331.2 mg) was dissolved in propylacetate (30 ml) at 70°C and the solution was filtered then kept for slow solvent evaporation. After 9 days three type of crystals observed and yellow crystals were manually separated and analyzed.
  • Example-17 Preparation of BDMC: isonicotinamide (1 :2) co-crystal
  • BDMC 500 mg
  • isonicotinamide 331.5 mg
  • ethyl acetate 90 ml
  • the solution was filtered then kept for slow evaporation. After one day crystal was observed was analyzed.
  • BDMC (l g) was dissolved in ethyl acetate (40 ml) at 60°C and the solution obtained was kept aside for solvent evaporation. After 4 days, formed red crystals were separated manually and analyzed.
  • the PXRD pattern of obtained crystalline fonn-I of BDMC was shown in figure-38.
  • BDMC ( l g) was dissolved in acetonitrile (60 ml) at 60°C and the solution obtained was kept aside for solvent evaporation. After one day small crystals are harvested and these crystals after 4 days converted to form-II.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019197366A1 (en) 2018-04-11 2019-10-17 Letavis Ab Co-crystals
WO2021202872A1 (en) * 2020-04-01 2021-10-07 Natural Extraction Systems, LLC Compositions and methods related to isomers of curcumin
WO2022013565A1 (en) 2020-07-17 2022-01-20 University Of Lincoln New curcumin co-crystals and uses
ES2913376R1 (es) * 2019-09-06 2022-06-15 Alparis Sa De Cv Compuestos de curcumina y aminoacidos basicos

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WO2012138907A2 (en) * 2011-04-05 2012-10-11 Translational Genomics Research Institute Solid forms of curcumin

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019197366A1 (en) 2018-04-11 2019-10-17 Letavis Ab Co-crystals
CN112041308A (zh) * 2018-04-11 2020-12-04 拉塔维斯公司 共晶体
EP4079728A1 (en) 2018-04-11 2022-10-26 Letavis AB Co-crystals
US11560358B2 (en) 2018-04-11 2023-01-24 Letavis Ab Resveratrol-piperazine co-crystals
ES2913376R1 (es) * 2019-09-06 2022-06-15 Alparis Sa De Cv Compuestos de curcumina y aminoacidos basicos
WO2021202872A1 (en) * 2020-04-01 2021-10-07 Natural Extraction Systems, LLC Compositions and methods related to isomers of curcumin
WO2022013565A1 (en) 2020-07-17 2022-01-20 University Of Lincoln New curcumin co-crystals and uses

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