WO2017009813A1 - Nouveaux co-cristaux de caféine et leur formes polymorphes - Google Patents

Nouveaux co-cristaux de caféine et leur formes polymorphes Download PDF

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Publication number
WO2017009813A1
WO2017009813A1 PCT/IB2016/054252 IB2016054252W WO2017009813A1 WO 2017009813 A1 WO2017009813 A1 WO 2017009813A1 IB 2016054252 W IB2016054252 W IB 2016054252W WO 2017009813 A1 WO2017009813 A1 WO 2017009813A1
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Prior art keywords
caffeine
cocrystal
piceatannol
suspension
ray powder
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PCT/IB2016/054252
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English (en)
Inventor
Satyanarayana Chava
Sreenivasa Rao Damarla
Seeta Rama Anjaneyulu GORANTLA
Vamsee Krishna Muppidi
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Laurus Labs Private Limited
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Publication of WO2017009813A1 publication Critical patent/WO2017009813A1/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation

Definitions

  • the present invention relates to novel caffeine cocrystals and their polymorphic forms. Further the present invention relates to the therapeutic use of novel caffeine cocrystals and their polymorphic forms as well as composition comprising them.
  • Caffeine (l ,3,7-trimethyl-lH-purine-2,6(3H,7H)-dione) is a natural alkaloid, methyl xanthine, found in various plants. It is a bitter white crystalline solid, whose solubility in water is 22 mg/mL at 25 °C. It is most commonly consumed by humans in infusions extracted from the seed of coffee plant and the leaves of tea bush, as well as from various food and drinks containing products derived from the kola nut. Caffeine is present in medications for asthma, apnea in new borns, and also some over-the-counter medications for headaches.
  • caffeine has the ability to reverse ⁇ plaque deposition in the brain (believed to be the primary cause of Alzheimer's pathogenesis) and thus revert memory and improve cognitive impairment. But owing to the fast absorption rate and short half life, a controlled release formulation of caffeine would be clinically beneficial.
  • 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 cocrystal between the drug and a coformer.
  • Cocrystals often possess more favourable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself.
  • a cocrystals may have different dissolution and solubility properties than the drug.
  • cocrystals may be used as a convenient vehicle for drug delivery, and new drug formulations comprising cocrystals of a given drug may have superior properties, such as solubility, dissolution, hygroscopicity and storage stability over existing formulations of the drug.
  • a cocrystal of a drug is a distinct chemical composition between the drug and coformer, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and coformer individually.
  • cocrystals are comprised of neutral species.
  • charge balance unlike a salt, one cannot determine the stoichiometry of a cocrystal based on charge balance. Indeed, one can often obtain cocrystals having stoichiometric ratios of drug to coformer of greater than or less than 1 : 1.
  • the stoichiometric ratio of an API to coformer is a generally unpredictable feature of a cocrystal.
  • cocrystals 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, cocrystals 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-former A necessary consideration when designing cocrystals, if the end goal is a potential marketed drug-product, is incorporating a suitable cocrystal 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 United States
  • An additional group of molecules to be considered as possible coformers are the naturally occurring compounds, nutraceuticals.
  • cocrystals of caffeine with GRAS listed coformers are known in literature. For example, cocrystals of caffeine with dicarboxylic acids are disclosed in Cryst. Eng.
  • composition comprising at least one nutraceutical compound and at least one cocrystal former with or without impurities; wherein the nutraceutical is selected from the group consisting of vitamin B2 (riboflavin), glucosamine HC1, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L- carnitine HC1, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamin Bl (thiamine HC1), baicalein, luteolin, hesperedin, rosmarinic acid, epicatechin gallate, epigallocatechin, vitamin B9 (folic), genistein, methylvanillin, ethylvanillin, silibinin, diadzein, melatonin, rutin hydrate, vitamin A, retinol, vitamin D2 (ergocalciferol), vitamin E (tocopherol), diosmin, menadione (riboflavin), glucosamine
  • ChromaDex® introduces new caffeine ingredient technology, PURENERGY. It's an innovative patent protected caffeine cocrystal ingredient that is a combination of caffeine and pTeroPure pterosilbene. Purenergy demonstrated in animal models a 6-8 times longer half-life as compared to caffeine alone. This suggests that purenergy may provide longer sustained energy and alertness with a more gradual finish, preventing the crash, typically experienced when ingesting caffeinated products. This patented new ingredient technology should allow formulators of caffeinated products the opportunity to reduce the total amount of caffeine without affecting the consumers' product experience.
  • the main objective of the present invention is to provide cocrystals of caffeine with improved physiochemical properties.
  • the present invention encompasses novel cocrystals of caffeine with coformer selected from the group comprising sinapic acid, piceatannol, luteolin, naringenin, resveratrol and catechin, as well as their polymorphic forms having improved physiochemical properties over known caffeine crystals.
  • coformer selected from the group comprising sinapic acid, piceatannol, luteolin, naringenin, resveratrol and catechin, as well as their polymorphic forms having improved physiochemical properties over known caffeine crystals.
  • the present invention encompasses cocrystals of caffeine with coformer, wherein the caffeine and coformer are present in a molar ratio of 1:4 to 4: 1.
  • novel cocrystals of caffeine of the present invention as well as their polymorphic forms are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, Differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA) and Nuclear magnetic resonance (NMR).
  • XRPD X-ray powder diffraction
  • DSC Differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • NMR Nuclear magnetic resonance
  • the present invention encompasses a process for the preparation of cocrystals of caffeine, which comprises dissolving or suspending a coformer in a suitable solvent; mixing caffeine with the obtained solution or suspension; or vice versa; stirring the suspension or solution for sufficient period of time and isolating the cocrystals of caffeine; wherein the suitable solvent is selected from the group comprising C 1-4 alcohols, esters, water and mixtures thereof.
  • the present invention encompasses cocrystals of caffeine with sinapic acid.
  • the present invention encompasses cocrystals of caffeine with sinapic acid, wherein the caffeine and sinapic acid are present in a molar ratio of 1 : 1.
  • the present invention encompasses crystalline form of caffeine: sinapic acid (1 : 1) cocrystal, designated herein as caffeine: sinapic acid (1: 1) cocrystal Form I, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 7.77, 10.41, 11.62, 11.92, 15.64, 18.25, 21.76, 25.51, 26.42 and 27.47 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 1 ; a differential scanning calorimetry substantially as depicted in Figure 2; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 3 ; or a combination thereof.
  • an x-ray powder diffraction pattern having one or more peaks at about 7.77, 10.41, 11.62, 11.92, 15.64, 18.25, 21.76, 25.51, 26.42 and 27.47 ⁇ 0.2° 2 ⁇
  • the present invention encompasses crystalline form of caffeine: sinapic acid (1: 1) cocrystal, designated herein as caffeine: sinapic acid (1: 1) cocrystal Form II, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 7.65, 10.48, 11.19, 12.37, 15.38, 16.03, 17.42, 19.41, 23.15, 23.96, 24.92, 26.21, 26.77 and 27.09 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 4; a differential scanning calorimetry (DSC) substantially as depicted in Figure 5; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 6; or a combination thereof.
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention encompasses cocrystals of caffeine with piceatannol.
  • the present invention encompasses cocrystals of caffeine with piceatannol, wherein the caffeine and piceatannol are present in a molar ratio of 3:2.
  • the present invention encompasses crystalline form of caffeine: piceatannol (3:2) cocrystal, designated herein as caffeine: piceatannol (3:2) cocrystal Form I, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.33, 8.84, 12.1 1, 12.32, 12.76, 14.23, 14.84, 16.12, 17.82, 19.75, 20.95, 21.70, 24.71 and 26.34 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 7; a differential scanning calorimetry substantially as depicted in Figure 8; a thermo gravimetric analysis substantially as depicted in Figure 9; or a combination thereof.
  • the present invention encompasses crystalline caffeine: piceatannol (3:2) cocrystal; designated herein as caffeine: piceatannol (3:2) cocrystal Form II, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 11.27, 12.46, 14.98, 15.61, 17.48, 17.97, 20.90, 22.03, 24.97 and 26.36 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 10; a differential scanning calorimetry (DSC) substantially as depicted in Figure 11 ; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 12; or a combination thereof.
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention encompasses crystalline caffeine: piceatannol (3:2) cocrystal; designated herein as caffeine: piceatannol (3:2) cocrystal Form III, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 8.49, 11.05, 11.93, 12.58, 13.85, 14.91, 15.84, 17.12, 21.56, 23.25, 25.89, 26.87, 27.65 and 29.41 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 13; a differential scanning calorimetry substantially as depicted in Figure 14; a thermo gravimetric analysis substantially as depicted in Figure 15; or a combination thereof.
  • the present invention encompasses cocrystals of caffeine with piceatannol, wherein the caffeine and piceatannol are present in a molar ratio of 2: 1.
  • the present invention encompasses crystalline form of caffeine: piceatannol (2: 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.01, 9.55, 10.67, 11.99, 14.52, 15.07, 19.27, 21.54, 24.15, 26.01, 26.83 and 29.16 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 16; a differential scanning calorimetry substantially as depicted in Figure 17; a thermo gravimetric analysis substantially as depicted in Figure 18; or a combination thereof.
  • the present invention encompasses crystalline form of caffeine: piceatannol (2: 1) cocrystal is a hydrate, characterized by a weight loss of about 15% by thermo gravimetric analysis.
  • the present invention encompasses cocrystals of caffeine with naringenin.
  • the present invention encompasses cocrystals of caffeine with naringenin, wherein the caffeine and naringenin are present in a molar ratio of 1 : 1.25.
  • the present invention encompasses crystalline form of caffeine: naringenin (1 : 1.25) cocrystal, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.77, 7.48, 9.51, 12.18, 13.37, 14.89, 15.99, 17.72, 19.89, 21.70, 22.61 and 26.73 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 19; a differential scanning calorimetry substantially as depicted in Figure 20; a thermo gravimetric analysis substantially as depicted in Figure 21 ; or a combination thereof.
  • the present invention encompasses cocrystals of caffeine with luteolin.
  • the present invention encompasses cocrystals of caffeine with luteolin, wherein the caffeine and luteolin are present in a molar ratio of 1 : 1.
  • the present invention encompasses crystalline form of caffeine: luteolin ( 1 : 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 10.92, 1 1.42, 11.72, 12.54, 14.81, 23.54, 26.31 and 31.90 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 22; a differential scanning calorimetry substantially as depicted in Figure 23; a thermo gravimetric analysis substantially as depicted in Figure 24; or a combination thereof.
  • the present invention encompasses cocrystals of caffeine with resveratrol. In another embodiment, the present invention encompasses cocrystals of caffeine with resveratrol, wherein the caffeine and resveratrol are present in a molar ratio of 1 : 1.
  • the present invention encompasses crystalline form of caffeine: resveratrol ( 1 : 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 4.44, 8.87, 1 1.91, 12.34, 13.11, 13.30, 13.99, 15.48, 17.16, 17.44, 18.01, 18.82, 19.90, 22.30, 23.88, 24.80, 25.54, 26.03, 26.38, 26.89, 27.25 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 25; a differential scanning calorimetry substantially as depicted in Figure 26; a thermo gravimetric analysis substantially as depicted in Figure 27; or a combination thereof.
  • the present invention encompasses crystalline form of caffeine: catechin (1 : 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 8.57, 10.21 , 11.66, 12.04, 12.87, 13.99, 14.42, 14.94, 15.87, 16.39, 17.63, 18.51 , 20.63, 21.03, 23.58, 24.23, 25.64, 26.66, 27.07, 29.75 and 30.42 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 28; a differential scanning calorimetry substantially as depicted in Figure 29; a thermo gravimetric analysis substantially as depicted in Figure 30; or a combination thereof.
  • the present invention encompasses composition comprising cocrystals of caffeine and their polymorphic forms described above.
  • Figure 1 illustrates a characteristic x-ray powder diffractogram of caffeine: sinapic acid (1 : 1) cocrystal Form I.
  • Figure 2 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: sinapic acid (1 : 1) cocrystal Form I.
  • Figure 3 illustrates a characteristic thermo gravimetric analysis of caffeine: sinapic acid (1: 1) cocrystal Form I.
  • Figure 4 illustrates a characteristic x-ray powder diffractogram of caffeine: sinapic acid (1: 1) cocrystal Form II.
  • Figure 5 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: sinapic acid (1: 1) cocrystal Form II.
  • Figure 6 illustrates a characteristic thermo gravimetric analysis of caffeine: sinapic acid (1: 1) cocrystal Form II.
  • Figure 7 illustrates a characteristic x-ray powder diffractogram of caffeine: piceatannol (3:2) cocrystal Form I.
  • Figure 8 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: piceatannol (3:2) cocrystal Form I.
  • Figure 9 illustrates a characteristic thermo gravimetric analysis of caffeine: piceatannol (3:2) cocrystal Form I.
  • Figure 10 illustrates a characteristic x-ray powder diffractogram of caffeine: piceatannol (3:2) cocrystal Form II.
  • Figure 11 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: piceatannol cocrystal Form II.
  • Figure 12 illustrates a characteristic thermo gravimetric analysis of caffeine: piceatannol (3:2) cocrystal Form II.
  • Figure 13 illustrates a characteristic x-ray powder diffractogram of caffeine: piceatannol (3:2) cocrystal Form III.
  • Figure 14 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: piceatannol (3:2) cocrystal Form III.
  • Figure 15 illustrates a characteristic thermo gravimetric analysis of caffeine: piceatannol (3:2) cocrystal Form III.
  • Figure 16 illustrates a characteristic x-ray powder diffractogram of caffeine: piceatannol (2: 1) cocrystal.
  • Figure 17 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: piceatannol (2: 1) cocrystal.
  • Figure 18 illustrates a characteristic thermo gravimetric analysis of caffeine: piceatannol (2: 1) cocrystal.
  • Figure 19 illustrates a characteristic x-ray powder diffractogram of caffeine: naringenin (1: 1.25) cocrystal.
  • Figure 20 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: naringenin (1.1.25) cocrystal.
  • Figure 21 illustrates a characteristic thermo gravimetric analysis of caffeine: naringenin (1.1.25) cocrystal.
  • Figure 22 illustrates a characteristic x-ray powder diffractogram of caffeine: luteolin (1: 1) cocrystal.
  • Figure 23 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: luteolin (1: 1) cocrystal.
  • Figure 24 illustrates a characteristic thermo gravimetric analysis of caffeine: luteolin (1: 1) cocrystal.
  • Figure 25 illustrates a characteristic x-ray powder diffractogram of caffeine: resveratrol (1: 1) cocrystal.
  • Figure 26 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: resveratrol (1 : 1) cocrystal.
  • Figure 27 illustrates a characteristic thermo gravimetric analysis of caffeine: resveratrol (1: 1) cocrystal.
  • Figure 28 illustrates a characteristic x-ray powder diffractogram of caffeine: catechin (11) cocrystal.
  • Figure 29 illustrates a characteristic differential scanning calorimetric thermogram of caffeine: catechin (1: 1) cocrystal.
  • Figure 30 illustrates a characteristic thermo gravimetric analysis of caffeine: catechin (1: 1) cocrystal.
  • Figure 31 illustrates the comparison data of intrinsic dissolution data of caffeine anhydrous and caffeine cocrystals of the present invention.
  • Figure 32 illustrates the comparison data of powder dissolution data of caffeine anhydrous and caffeine cocrystals of the present invention.
  • the present invention encompasses cocrystals of caffeine with coformer selected from the group comprising sinapic acid, piceatannol, naringenin, luteolin, resveratrol and catechin.
  • the present invention encompasses cocrystals of caffeine with coformer, wherein the caffeine and coformer are present in a molar ratio of 1 :4 to 4: 1.
  • the present invention encompasses novel cocrystals of caffeine, including caffeine: sinapic acid, caffeine: piceatannol, caffeine: naringenin, caffeine: luteolin, caffeine: resveratrol and caffeine: catechin.
  • the present invention encompasses cocrystals of caffeine with sinapic acid.
  • the present invention encompasses cocrystals of caffeine with sinapic acid, wherein the caffeine and sinapic acid present in a molar ratio of 1 : 1.
  • the present invention encompasses caffeine: sinapic acid ( 1 : 1) cocrystal in crystalline form.
  • the present invention encompasses a process for the preparation of caffeine: sinapic acid (1 : 1) cocrystal, which comprises dissolving or suspending sinapic acid in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: sinapic acid (1 : 1) cocrystal, wherein the suitable solvent is selected from the group comprising C 1-4 alcohols, esters and the like and mixtures thereof.
  • the present invention encompasses crystalline form of caffeine: sinapic acid cocrystal, designated herein as caffeine: sinapic acid cocrystal Form I, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 7.77, 10.41 , 11.62, 11.92, 15.64, 18.25, 21.76, 25.51, 26.42 and 27.47 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 1 ; a differential scanning calorimetry substantially as depicted in Figure 2; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 3; or a combination thereof.
  • an x-ray powder diffraction pattern having one or more peaks at about 7.77, 10.41 , 11.62, 11.92, 15.64, 18.25, 21.76, 25.51, 26.42 and 27.47 ⁇ 0.2° 2 ⁇
  • an x-ray powder diffraction pattern substantially as depicte
  • the present invention encompasses a process for the preparation of caffeine: sinapic acid (1: 1) cocrystal Form I, which comprises dissolving or suspending sinapic acid in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: sinapic acid (1: 1) cocrystal Form I; wherein the suitable solvent is C 1-4 alcohol.
  • the caffeine is added to a solution of sinapic acid in a suitable C 1-4 alcohol solvent such as methanol, ethanol, isopropanol and the like and mixtures thereof, more preferably methanol, to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: sinapic acid (1: 1) cocrystal Form I is obtained.
  • the stirring is done for about 2 hrs to 8 hrs, more preferably for about 3 hrs.
  • the Form I solid may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses crystalline form of caffeine: sinapic acid (1 : 1) cocrystal, designated herein as caffeine: sinapic acid cocrystal Form II, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 7.65, 10.48, 11.19, 12.37, 15.38, 16.03, 17.42, 19.41, 23.15, 23.96, 24.92, 26.21, 26.77 and 27.09 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 4; a differential scanning calorimetry (DSC) substantially as depicted in Figure 5; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 6; or a combination thereof.
  • an x-ray powder diffraction pattern having one or more peaks at about 7.65, 10.48, 11.19, 12.37, 15.38, 16.03, 17.42, 19.41, 23.15, 23.96, 24.92, 26.
  • the present invention encompasses a process for the preparation of caffeine: sinapic acid (1 : 1) cocrystal Form II, which comprises dissolving or suspending sinapic acid in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: sinapic acid (1: 1) cocrystal Form II; wherein the suitable solvent is an ester solvent.
  • the sinapic acid is added to a solution of caffeine in a suitable ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and the like; and mixtures thereof, more preferably ethylacetate, to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: sinapic acid (1: 1) cocrystal Form II is obtained.
  • the stirring is done for about 2 hrs to 8 hrs, more preferably for about 3.5 hrs.
  • the Form II solid may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses cocrystals of caffeine with piceatannol.
  • the present invention encompasses cocrystals of caffeine with piceatannol, wherein the caffeine and piceatannol present in the molar ratio of 3:2.
  • the present invention encompasses a process for the preparation of caffeine: piceatannol (3:2) cocrystal which comprises dissolving or suspending piceatannol in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: piceatannol (3:2) cocrystals, wherein the suitable solvent is selected from the group comprising Ci_ 4 alcohols, esters and the like and mixtures thereof.
  • the present invention encompasses caffeine: piceatannol (3:2) cocrystal in crystalline form.
  • the present invention encompasses crystalline form of caffeine: piceatannol (3:2) cocrystal, designated herein as caffeine: piceatannol (3:2) cocrystal Form I, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.33, 8.84, 12.11, 12.32, 12.76, 14.23, 14.84, 16.12, 17.82, 19.75, 20.95, 21.70, 24.71 and 26.34 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 7; a differential scanning calorimetry substantially as depicted in Figure 8; a thermo gravimetric analysis substantially as depicted in Figure 9; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: piceatannol (3:2) cocrystal Form I, which comprises dissolving or suspending piceatannol in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the solution or suspension and isolating the caffeine: piceatannol (3:2) cocrystal Form I; wherein the suitable solvent is a Ci_ 4 alcohol.
  • the caffeine is added to a solution of piceatannol in a suitable Ci_ 4 alcohol solvent such as methanol, ethanol, isopropanol and the like; and mixtures thereof, more preferably ethanol to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25 °C to about 35°C until caffeine: piceatannol (1 : 1) cocrystal Form I is obtained.
  • the stirring is done for about 2 hrs to 12 hrs, more preferably for about 5 hrs.
  • the Form I solid may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses crystalline form of caffeine: piceatannol (3:2) cocrystal; herein designated as caffeine: piceatannol (3:2) cocrystal Form II, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 11.27, 12.46, 14.98, 15.61, 17.48, 17.97, 20.90, 22.03, 24.97 and 26.36 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 10; a differential scanning calorimetry (DSC) substantially as depicted in Figure 11 ; a thermo gravimetric analysis (TGA) substantially as depicted in Figure 12; or a combination thereof.
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention encompasses a process for the preparation of caffeine: piceatannol (3:2) cocrystal Form II, which comprises dissolving or suspending piceatannol in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: piceatannol (3:2) cocrystal Form II; wherein the suitable solvent is an ester solvent.
  • the caffeine is added to a solution of piceatannol in a suitable ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like and mixtures thereof, more preferably ethyl acetate, to form a suspension; further the stirring is carried out for sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: piceatannol (1: 1) cocrystal Form II is obtained.
  • the stirring is done for about 2 hrs to 12 hrs, more preferably for about 5 hrs.
  • the Form II solid may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses crystalline caffeine: piceatannol (3:2) cocrystal; herein designated as caffeine: piceatannol (3:2) cocrystal Form III, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 8.49, 11.05, 11.93, 12.58, 13.85, 14.91, 15.84, 17.12, 21.56, 23.25, 25.89, 26.87, 27.65 and 29.41 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 13; a differential scanning calorimetry substantially as depicted in Figure 14; a thermo gravimetric analysis substantially as depicted in Figure 15; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: piceatannol (3:2) cocrystal Form III, which comprises dissolving or suspending piceatannol in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: piceatannol (3:2) cocrystal Form III; wherein the suitable solvent is C 1-4 alcohol solvent.
  • the caffeine is added to a solution of piceatannol in a suitable C 1-4 alcohol solvent such as methanol, ethanol, isopropanol and the like; and mixtures thereof, more preferably methanol to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: piceatannol (1 : 1) cocrystal Form III is obtained.
  • the stirring is done for about 2 hrs to 30 hrs, more preferably for about 21 hrs.
  • the Form III solid may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses cocrystals of caffeine with piceatannol, wherein caffeine and piceatannol present in a molar ratio of 2: 1.
  • the present invention encompasses caffeine: piceatannol (2: 1) cocrystals in crystalline form.
  • the present invention encompasses crystalline form of caffeine: piceatannol (2: 1) cocrystal is a hydrate, characterized by a weight loss of about 15% by thermo gravimetric analysis.
  • the present invention encompasses crystalline form of caffeine: piceatannol (2: 1) cocrystals characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.01 , 9.55, 10.67, 11.99, 14.52, 15.07, 19.27, 21.54, 24.15, 26.01, 26.83 and 29.16 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 16; a differential scanning calorimetry substantially as depicted in Figure 17; a thermo gravimetric analysis substantially as depicted in Figure 18; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: piceatannol (2: 1) cocrystal by slurrying caffeine: piceatannol cocrystal Form I in water for a sufficient period of time to obtain caffeine: piceatannol (2: 1) cocrystal.
  • the slurrying is carried out for sufficient period of time at room temperature until caffeine: piceatannol (2: 1) cocrystal is obtained. More preferably, the slurrying is done for about 2 hrs to 12 hrs, most preferably for about 4.5 hrs.
  • the caffeine: piceatannol (2: 1) cocrystal may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses cocrystals of caffeine with naringenin. In another embodiment, the present invention encompasses cocrystals of caffeine with naringenin, wherein the caffeine and naringenin present in a molar ratio of 1 : 1.25.
  • the present invention encompasses crystalline form of caffeine: naringenin (1 : 1.25) cocrystal, characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 6.77, 7.48, 9.51, 12.18, 13.37, 14.89, 15.99, 17.72, 19.89, 21.70, 22.61 and 26.73 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 19; a differential scanning calorimetry substantially as depicted in Figure 20; a thermo gravimetric analysis substantially as depicted in Figure 21 ; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: naringenin (1: 1.25) cocrystal, which comprises dissolving or suspending naringenin or salts thereof in a suitable solvent; mixing caffeine with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: naringenin (1: 1.25) cocrystal; wherein the suitable solvent is Q_ 4 alcohol.
  • the aqueous solution of caffeine was added to a solution of naringenin or its salts thereof such as sodium or potassium, obtained by dissolving naringenin in a suitable C 1-4 alcohol solvent such as methanol, ethanol, isopropanol and the like; and mixtures thereof, more preferably methanol, at a suitable temperature of about 25°C to about 65°C; preferably at about 55-65°C; to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: naringenin (1: 1.25) cocrystal is obtained.
  • the stirring is done for about 1 hrs to 9 hrs, more preferably for about 2 hrs.
  • the caffeine: naringenin (1 : 1.25) cocrystal may be further isolated by the methods known in the art, for example filtration.
  • the present invention encompasses cocrystals of caffeine with luteolin.
  • the present invention provides cocrystals of caffeine with luteolin, wherein the caffeine and luteolin present in a molar ratio of 1: 1.
  • the present invention encompasses crystalline form of caffeine: luteolin (1: 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 10.92, 11.42, 11.72, 12.54, 14.81, 23.54, 26.31 and 31.90 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 22; a differential scanning calorimetry substantially as depicted in Figure 23; a thermo gravimetric analysis substantially as depicted in Figure 24; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: luteolin (1 : 1) cocrystal, which comprises dissolving or suspending caffeine in a suitable solvent; mixing luteolin with the obtained solution or suspension; stirring the solution or suspension and isolating the caffeine: luteolin (1: 1) cocrystal, wherein the suitable solvent is C 1-4 alcohol.
  • the luteolin was added to a solution of caffeine in a suitable C 1-4 alcohol solvent such as methanol, ethanol, isopropanol and the like and mixtures thereof, more preferably methanol to form a suspension; further the stirring is carried out for a sufficient period of time at a suitable temperature of about 25°C to about 35°C until caffeine: luteolin (1: 1) cocrystal is obtained.
  • the stirring is done for about 15 hrs to 30 hrs; more preferably for about 24 hrs.
  • the caffeine: luteolin (1 : 1) cocrystal may be further isolated by the methods known in the art, for example filtration.
  • the present invention provides cocrystals of caffeine with resveratrol.
  • the present invention provides cocrystals of caffeine with resveratrol, wherein the caffeine and resveratrol present in a molar ratio of 1 : 1.
  • the present invention encompasses crystalline form of caffeine: resveratrol (1: 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 4.44, 8.87, 11.91, 12.34, 13.11, 13.30, 13.99, 15.48, 17.16, 17.44, 18.01, 18.82, 19.90, 22.30, 23.88, 24.80, 25.54, 26.03, 26.38, 26.89 and 27.25 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 25; a differential scanning calorimetry substantially as depicted in Figure 26; a thermo gravimetric analysis substantially as depicted in Figure 27; or a combination thereof.
  • the present invention provides a process for the preparation of caffeine: resveratrol cocrystal by dissolving or suspending caffeine and resveratrol in a suitable ester solvent and evaporating the solvent to obtain caffeine: resveratrol (1: 1) cocrystal.
  • the dissolution of caffeine and resveratrol is carried out in a suitable ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like and mixtures thereof; more preferably in ethyl acetate, at a suitable temperature of about 25°C to about 70°C, more preferably at about 55-65°C; and the obtained solution may be optionally filtered.
  • the obtained filtrate is kept for slow solvent evaporation to obtain caffeine: resveratrol cocrystal.
  • the present invention encompasses crystalline form of caffeine: catechin (1 : 1) cocrystal characterized by data selected from the group consisting of; an x-ray powder diffraction pattern having one or more peaks at about 8.57, 10.21, 11.66, 12.04, 12.87, 13.99, 14.42, 14.94, 15.87, 16.39, 17.63, 18.51, 20.63, 21.03, 23.58, 24.23, 25.64, 26.66, 27.07, 29.75 and 30.42 ⁇ 0.2° 2 ⁇ ; an x-ray powder diffraction pattern substantially as depicted in Figure 28; a differential scanning calorimetry substantially as depicted in Figure 29; a thermo gravimetric analysis substantially as depicted in Figure 30; or a combination thereof.
  • the present invention encompasses a process for the preparation of caffeine: catechin (1 : 1) cocrystal, which comprises dissolving or suspending caffeine in a suitable solvent; mixing catechin with the obtained solution or suspension; stirring the suspension or solution and isolating the caffeine: catechin (1: 1) cocrystal.
  • the catechin is added to a solution of caffeine in a suitable solvent such as water; further the stirring is carried out for sufficient period of time at a suitable temperature of about 25 °C to about 35°C until caffeine: catechin (1 : 1) cocrystal is obtained.
  • the stirring is done for about 2 hrs to 8 hrs, more preferably for about 3.5 hrs.
  • the caffeine: catechin (1: 1) cocrystal may be further isolated by the methods known in the art, for example filtration.
  • the starting nutraceutical caffeine as well as the co-formers such as sinapic acid, piceatannol, luteolin, naringenin, catechin and resveratrol utilized in the present invention is well known in the art and also commercially available.
  • the caffeine and coformers either prepared by the methods known in the art or procured from commercial sources.
  • the present invention encompasses composition comprising one or more co-crystals of caffeine as described above.
  • Such compositions may be used in the preparation of pharmaceuticals, nutraceuticals, nutritional supplements, food composition and the like or itself as pharmaceutical or nutraceutical dosage form.
  • Intrinsic dissolution rate (IDR) data (in 1% SLS aqueous solution) suggest that the caffeine cocrystals and their polymorphic forms of the present invention exhibits less solubility and slow release rate of caffeine when compared with known caffeine anhydrous.
  • Figure-31 shows the comparison of intrinsic dissolution rate data of caffeine cocrystals of the present invention and the known anhydrous caffeine.
  • Further powder dissolution data suggest that the caffeine cocrystals and their polymorphic forms of the present invention exhibits less solubility and slow release rate of caffeine when compared with known caffeine anhydrous.
  • Figure-32 shows the comparison of powder dissolution data of caffeine cocrystals of the present invention and the known anhydrous caffeine.
  • Intrinsic dissolution rate (IDR) and Powder dissolution rate (PDR) of caffeine and cocrystals thereof discussed above can be carried out under the following conditions;
  • Milli-Q water Acetonitrile; Potassium dihydrogen phosphate; Ortho phosphoric acid and Sodium lauryl sulphate.
  • the content of individual drug can be measured by the known methods such as HPLC, UV and the like;
  • Example-2 Preparation of caffeine: sinapic acid (1: 1) cocrystal Form II:
  • HPLC Caffeine: 49.28% & sinapic acid: 50.68%
  • the XRPD is set forth in 4;
  • the DSC is set forth in Figure 5;
  • the TGA is set forth in Figure 6.
  • Piceatannol (3.77 g) was dissolved in ethanol (36 ml) at 25-35°C. To this solution, caffeine (3 g) was added and slurried for 5 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: piceatannol (3:2) cocrystal Form I.
  • the XRPD is set forth in 7;
  • the DSC is set forth in Figure 8;
  • the TGA is set forth in Figure 9.
  • Piceatannol (3.14 g) was dissolved in ethyl acetate (50 ml) at 25-35°C. To this solution, caffeine (2.5 g) was added and slurried for 5 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: piceatannol (3:2) cocrystal Form II.
  • the XRPD is set forth in 10;
  • the DSC is set forth in Figure 11;
  • the TGA is set forth in Figure 12.
  • Piceatannol (1.50 g) was dissolved in methanol (24 ml) at 25-35°C. To this solution, caffeine (1.2 g) was added and slurried for 21 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: piceatannol (3:2) cocrystal Form III.
  • the XRPD is set forth in 13;
  • the DSC is set forth in Figure 14;
  • the TGA is set forth in Figure 15.
  • the crystalline Form I of caffeine piceatannol cocrystal (900 mg) was slurried in water (90 ml) for 4.5 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: piceatannol (2: 1) cocrystal.
  • Example-7 Preparation of caffeine: naringenin (1: 1.25) cocrystal: Naringenin (4.737 g) was dissolved in methanol (72 ml) at 60°C. To this solution, aqueous solution of caffeine (3g of caffeine dissolved in 66 ml of water) was added. Then the reaction mass was slurried for 2 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: naringenin cocrystal (1 : 1.25).
  • the XRPD is set forth in 19;
  • the DSC is set forth in Figure 20;
  • the TGA is set forth in Figure 21.
  • Example-8 Preparation of caffeine: naringenin (1 : 1.25) cocrystal:
  • Potassium naringenin (1.55 g) was a dissolved in methanol (40 ml) at 25-35°C and 12N hydrochloric acid (0.5 ml) was added to it. To this, aqueous solution of caffeine (970 mg dissolved in 40 ml of water) was added at 25-35°C and slurried for 6 hrs. The solid obtained was filtered and suck dried to get caffeine: naringenin (1: 1.25) cocrystal.
  • Example-10 Preparation of caffeine: resveratrol (1: 1) cocrystal:
  • Caffeine (100 mg) and resveratrol (173.92 mg) was dissolved in ethyl acetate (10 ml) at 60 °C. The obtained solution was filtered and the filtrate was kept for slow solvent evaporation at 25-35°C.
  • Caffeine: resveratrol (1: 1) cocrystals were formed after 48 hrs.
  • the XRPD is set forth in 25;
  • the DSC is set forth in Figure 26;
  • the TGA is set forth in Figure 27.
  • Example-11 Preparation of caffeine: catechin (1 : 1) cocrystal: Caffeine (0.668 g) was dissolved in water (26 ml) at 25-35°C. To this solution, catechin hydrate (1 g) was added and slurried for 3.5 hrs at 25-35°C. The solid obtained was filtered and suck dried to get caffeine: catechin (1 : 1) cocrystal.
  • the XRPD is set forth in 28;
  • the DSC is set forth in Figure 29;
  • the TGA is set forth in Figure 30.

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Abstract

La présente invention concerne de nouveaux cocristaux de caféine et leur formes polymorphes.
PCT/IB2016/054252 2015-07-16 2016-07-16 Nouveaux co-cristaux de caféine et leur formes polymorphes WO2017009813A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020123625A1 (fr) * 2018-12-11 2020-06-18 The Regents Of The University Of Michigan Co-cristaux, leurs procédé et appareil de formation
CN111423444A (zh) * 2020-04-20 2020-07-17 广西中医药大学 白藜芦醇-替莫唑胺共晶及其制备方法和应用
EP3873941A4 (fr) * 2018-10-31 2022-07-27 Merck Sharp & Dohme Corp. Anticorps anti-pd-1 humain et procédés d'utilisation associés
US11633476B2 (en) 2017-05-02 2023-04-25 Merck Sharp & Dohme Llc Stable formulations of programmed death receptor 1 (PD-1) antibodies and methods of use thereof

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WO2008153945A2 (fr) * 2007-06-06 2008-12-18 University Of South Florida Compositions nutraceutiques de co-cristal

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11633476B2 (en) 2017-05-02 2023-04-25 Merck Sharp & Dohme Llc Stable formulations of programmed death receptor 1 (PD-1) antibodies and methods of use thereof
EP3873941A4 (fr) * 2018-10-31 2022-07-27 Merck Sharp & Dohme Corp. Anticorps anti-pd-1 humain et procédés d'utilisation associés
WO2020123625A1 (fr) * 2018-12-11 2020-06-18 The Regents Of The University Of Michigan Co-cristaux, leurs procédé et appareil de formation
CN111423444A (zh) * 2020-04-20 2020-07-17 广西中医药大学 白藜芦醇-替莫唑胺共晶及其制备方法和应用
CN111423444B (zh) * 2020-04-20 2024-05-28 广西中医药大学 白藜芦醇-替莫唑胺共晶及其制备方法和应用

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