SK292011A3 - Flavonoids co-crystals, method for the preparation thereof and their use - Google Patents

Abstract

Flavonoid co-crystals selected from the group are described quercetin, rutin, hesperidin, hesperetin, naringin, diosmin, genistein, naringenin and their polymorphs and solvates. It is described and a method for preparing cocrystals and their use in therapy purposes

Description

Technical field

The present invention relates to flavonoid co-crystals, to a process for their preparation and to their use

BACKGROUND OF THE INVENTION

Flavonoids, as one class of nutraceuticals, are widespread in various types of plant material, particularly in vegetables, fruits, tea and wine. More than 4000 different flavonoids have been described, which are divided into several subgroups (Puupponen-Pimiä at all., 2001. In Journal of Applied Microbiology, p. 494-507). We include flavones, flavanols, flavanones, catechins, chalcones, dihydrochalones (Tripoli, E. et al., 2007. In Food Chemistry, 104, p. 466-479). These substances exhibit a wide range of biological activities and (bio) flavonoids, natural plant polyphenols, are a common part of the human diet. As antioxidants, various flavonoids are often added to foods to prevent radical reactions (Jayaprakasha et al., 2007). They are part of many nutraceutical products and OTC preparations.

Many studies describe the health benefits of flavonoids (Cook, NC, Samman, S. 1996. Flavonoids - Chemistry, metabolism, cardioprotective effects and dietary sources. In The Journal of Nutritional Biochemistry, 7, pp. 66-76; Peterson, J., Dwyer, J. 1998. In Nutrition Research, 18, 1995-2018).

They can act as antioxidants especially in cancer, cardiovascular and neurodegenerative diseases, asthma, diabetes, liver diseases and other inflammatory processes. In the paper (Safari, M.-R., 2003. In Prostaglandins, Leukotrienes and Essential Fatty Acids, 69, p. 73-77), they investigated the inhibitory effect of flavonoids on LDL oxidation. Of the flavonoids tested, quercetin was the most effective. Flavonoids with multiple hydroxyl groups such as e.g. quercetin, hesperetin showed peroxyl radical binding activity several times more potent than trolox, an alpha-tocopherol analog.

Quercetin, a flavone present in fruits and vegetables, exhibits antilipogenic effects by inhibiting insulin-mediated lipogenesis (Shisheva, A. and Shechter, Y. Biochemistry 1992, 31, 8059-8063)

Flavonoids such as quercetin, myricetin and morin have been shown to be trypsin inhibitors (Maliar, T. European Journal of Medicinal Chemistry, 2004, 39, p. 241-248).

The addition of lemon polyphenols to the diet had a beneficial effect on suppressing obesity, fat metabolism, and improving insulin resistance (Liang, Y.C., FEBS Lett., 2001,496, 12-18).

An overview of the occurrence of flavonoids in food is provided by Schmid (Schmid, S. 2010. In Antioxidants and Oxidative Changes of Fat in Food, p. 68-71)

In general, nutraceuticals may be administered in various forms e.g. as salts, derivatives or in various physical forms such as amorphous, crystalline polymorphs or co-crystals.

Co-crystals are stoichiometric multicomponent compounds of the host type (active molecule, eg pharmacologically active compound, nutraceutical, etc.): guest (co-crystallization partner, inactive or active substance), formed from two or more components which are solid at room temperature solid . There is no interference in the primary molecular structure of the active substance, non-covalent bonds are formed. The original physiological and biochemical effects and mechanism of action remain unchanged. Co-crystallization of the components (co-crystallization) at stoichiometric ratios from solution is used as the co-crystal preparation technique. In solid phase methods, co-milling is sometimes used with the addition of solvent, co-sublimation and standard crystallizations. A device for preparing co-crystals is disclosed in US 7763112.

Co-crystals of the same active ingredient may have substantially different properties (melting point, solubility, bioavailability, chemical stability, dissolution rate, crystal habitus, etc.) depending on the other component (partner). The preparation, definition and properties of co-crystals are reviewed by Brittain, H.G. (In Profiles of Drug Substances, Excipients and Related Methodology, 2010, Vol. 35, 373) and Krishnaiah S.R.Y. (J Bioequiv Availab. 2010.2 (2) 28-36).

Thus, by modifying the original form in such a way, the nutraceuticals will have more favorable properties, particularly in terms of formulations for oral administration, technological operations (grinding, drying), stability and solubility.

In nutraceuticals, co-crystals are described e.g. for caffeine (Jones, W. 2006, Int. J.Pharm., 31, 875-879) or WO2009 / 136408 discloses co-crystals for coenzyme Q10.

The co-crystals of nutraceuticals and pterostilbene are described by Schultheiss N. (CrystEngComm, 2010, 12, 2436-2442).

Aboaray A. D. (2009, In Theses and Dissertations, Crystal Engineering of Nutraceutical Cocrystal) describes co-crystals of resveratrol, citric acid and flavone.

Kapildev A. (2009, In Theses and Dissertations, Nutraceutical and Pharmaceutical Co-Crystals) describes the preparation of co-crystals from various combinations of nutraceuticals such as epigallocatechin gallate, quercetin, hesperetin, gallic acid, L-ascorbic acid with various pyridine derivatives.

Pujar T. A. (2009, In Theses and Dissertations, Cocrystals of Nutraceuticals; Protocatechuic Acid and Quercetin) discloses co-crystals of quercetin and isonicotinic acid, respectively. theobromine.

US 2009/0258859 discloses co-crystals of metronidazole and nutraceuticals (gallic, filmaric and gentisic acids)

Co-crystals of 4-oxopimelic acid and 4,4'-bipyridine are reported by Halasz, (New J. Chem., 2011, 35, 24-27).

Cancerostatically active co-crystals of N '- (7-fluoropyrrolo [1,2a] quinoxalin-4-yl) pyrazine-2-carbohydrazide and oxalic acid are disclosed in US 20110034473.

Paracetamol-citric acid co-crystals are reported by Elbagerma, M. A. (CrystEngComm, 2011, 13, 1877-1884)

A series of nutraceutical co-crystals is disclosed in US 2010/204204. This document also describes several cocrystals of flavonoids (quercetin, diosmin, hesperetin) with phenolic acids, aliphatic acids, purine bases and isonicotin amide respectively. nicotinic acid.

Co-crystals of quercetin-caffeine and hesperetin-isonicotin amide respectively. nicotinic acid and their methanolic solvates are also reported by Kavuru P. (2008, In Thesis. Crystal Engineering of Flavonoids). Results supplemented with co-crystals of other nutraceuticals such as L-ascorbic acid-sarcosine, nicotinic acid, betaine, catechol, and betaine-gallic acid, resveratrol, and ferulic acid - baclofen author published in Cryst. Growth Des., 2010, 10 (8), pp. 3568-3584.

The synergistic effect of co-crystal formation of two biologically active substances is described in WO 2009/136408.

The low solubility and unsatisfactory physicochemical properties of some drugs may be improved o.i. using an alternative co-crystalline form. A large number of new forms for a single active ingredient can be obtained depending on the number of components tested according to literature procedures. The result is new patentable forms of API, with new features. Quantified differences of some physicochemical parameters (solubility, dissolution rate, hydroscopicity ...) to the input forms allow to estimate their efficiency and stability. It is known from the application e.g. stabilization as disclosed in US 2008/234371 for stabilizing hygroscopic carnitine.

From the point of view of the pharmaceutical company, the preparation of new formulations resp. co-crystals of active substances positively manifest in the lifecycle management of the drug.

One of the motives for the preparation of co-crystals in the case of aglycone flavonoids is, in particular, an increase in solubility and dissolution rate. Obviously, it is advantageous to obtain new forms of nutraceuticals with a variation in solubility which makes it possible to achieve plasma levels faster or slower as needed. At the same time, the adjustment of the property makes it possible to specifically improve product stability and processability for pharmaceutical formulations into solid dosage forms, especially in the form of capsules or tablets.

SUMMARY OF THE INVENTION

The present invention solves the problems of preparing more technologically easier to handle, more soluble and more stable forms of nutraceuticals of the flavonoid family, providing novel co-crystals as set forth in the claim

First

A first object of the present invention are nutraceutical co-crystals as well as polymorphs and solvates thereof which consist of flavonoids as the active ingredient and a co-crystallization partner, preferably also a nutraceutical.

A second object of the present invention is the preparation of co-crystals by co-crystallization from a solvent.

Another object of the invention is the preparation of co-crystals by co-milling the components.

Another object of the invention are nutraceutical co-crystals, wherein the co-crystallization partner is another nutraceutical or medicament.

It is a further object of the invention to provide nutraceutical co-crystals suitable for use in solid release formulations, in particular for use in the form of tablets.

The discovery of new co-crystals of flavonoid nutraceuticals as pharmaceutically usable forms provides opportunities to improve the properties and effects of pharmaceutical products. This expands the range of forms whose formulations are available for formulation design.

The present invention relates to flavonoid co-crystals, to a process for their preparation and to their use.

The flavonoid co-crystals of the invention are crystalline materials consisting of at least two non-identical solids generally in a stoichiometric ratio. The co-crystals may also include one or more solvent or water molecules in the crystalline lattice.

It has been found that when a nutraceutical of the flavonoid family and a selected co-crystallization partner form a co-crystal, this has new unexpected properties. These new forms have altered solubility and increased stability when compared to the original flavonoid form, regardless of whether it was in the form of a salt, a hydrate or a solvate. Changes also manifest themselves in new morphology or habit. For example, a co-crystalline form of a nutraceutical is preferred if the parent nutraceutical molecule is insoluble in water. On the other hand, the co-crystal formation of the two active ingredients provides a further advantage in the case of a combination of more soluble glucosidic flavonoids and water-soluble co-crystallization partners e.g. edavarone, hydrochlorothiazide, etc.

The present inventors have found that the novel flavonoid co-crystals described in this invention provide considerable advantages. They exhibit low hygroscopicity and good processability for pharmaceutical formulations into solid dosage forms, especially in the form of capsules or tablets.

A first object of the present invention are co-crystals of nutraceuticals of the flavonoid family. Quercetin, rutin, hesperidin, hesperetin, naringin, diosmin, genistein, naringenin are selected from the group of flavonoids.

Selected flavonoids are involved in the prevention and treatment of diabetic cataract, neuropathy and retinopathy. In particular, quercetin is a potent reductase inhibitor.

The preparation process according to the invention is characterized by:

a) dissolving the flavonoid in a solvent and heating at a defined temperature

b) adding a stoichiometric amount of the host molecule (cocrystallization partner) and heating at a defined temperature to form a solution

c) cooling the mixture and isolating the co-crystalline form and occasionally

d) micronizing the crystals to the desired size

According to the present invention, in step (a), solvents selected from the group of hexane, toluene, acetonitrile, dimethylformamide, alcohols C 1 -C 5, acetic acid, tetrahydrofuran, ketones C 3 -C 6, diethylene glycol, ethoxyethanol, ethyl lactate and water or their or mixture. In step (a), a temperature of 40 to 160 ° C, preferably the boiling point of the solvent, is used.

It is understood that a large amount of additional solvent may result in the exclusion of the substance in oily form. It is therefore advantageous to add it while stirring. Conversely, in some cases, a large amount of solvent may lead to a dilute solution from which the product crystallizes only after a long time, respectively. up to partial concentration. It will be appreciated that it is also possible to add the individual components dissolved in different solvents. In step (b), a temperature of 40 to 140 ° C, preferably the boiling point of the reaction mixture, is used. In step (c), the crystallization mixture is cooled to a temperature of 0 ° C to 40 ° C, preferably to a temperature of 10 ° C to 20 ° C.

The isolation in step (c) is carried out by filtration, preferably under reduced pressure, or by centrifugation. The filter cake may be washed with an inert solvent under isolation conditions such as ethers C 4 -C 6 or esters such as ethyl acetate. The molar ratio of active component to co-crystallization partner used is 1: 1, although in some cases co-crystals can be obtained with a higher component ratio e.g. 1: 2, 1: 3.

Alternatively, the compounds of the invention may be prepared by:

(a) mixing the stoichiometric amount of flavonoid and the co - crystallization partner; and

b) occasionally adding a small amount of solvent and co-grinding the solid phase to form a co-crystal

c) and isolating the cocrystalline form

Hexane, toluene, acetonitrile, dimethylformamide, alcohols C 1 to C 5, acetic acid, tetrahydrofuran, ketones C 3 to C 6, diethylene glycol, ethoxyethanol, ethyl lactate and water or mixtures thereof are used as a solvent to accelerate the preparation of the co-crystals.

Preferably, the co-crystallization partner is selected from the group of substances listed in the GRAS or EAFUS list, or preferably substances already applied as nutraceuticals. E.g. the co-crystallization partner may be an amine, amide, sulfonamide, carboxylic acid, sulfonic acid, heterocyclic compound, phenol or polyphenol. Quinic acid, ferulic acid, coffee acid, hydrochlorothiazide, choline chloride, tannic acid, 4-acetamidophenol, 1,3,5-benzenetricarboxylic acid, 2-methoxyisophthalic acid, 3,4-dihydroxybenzoic acid, L-carnitine, acid are selected as co-crystallization partners. folic acid, arginine, isoascorbic acid, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one, choliniumsalicylate, N, N-acetylcytosine, acetamidine, lactic acid amide, 2-ketoglutaric acid, camphor-10sulfonic acid, 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2. l] heptane-1-carboxylic acid, 5-sulfosalicylic acid, D-tocopherol succinate, D-tocopherol polyethylene glycol succinate, L-lactic acid, glycolic acid, hydroxyurea, imidazolidine trione, biuret, alloxane, urazole, diacetamide, 3-glutaric acid imide sulfobenzoic acid, 2-imidazolidinone, 2,5-dihydroxybenzene sulfonic acid, glutaric acid, 1,2-benzisothiazol-3 (277) -one- (1,1-dioxide), (E) -1-propene-1,2,3-tricarboxylic acid galactaric acid, N-acetyl-L-glutamic acid, 3,3'-thiodi (propionic acid), etofibrate, 5-oxo-proline, coenzyme Q10. It will be appreciated that, where possible, the compounds may also be in the form of pharmaceutically acceptable salts such as e.g. hydrochlorides, hydrogen sulphates or salts of alkali metals or alkaline earths. The following table shows a representative combination of flavonoids and a co-crystallization partner.

flavonoid Co-crystallization partner quercetin quinic acid, quercetin ferulic acid, quercetin coffee acid, quercetin hydrochlorothiazide quercetin choline chloride, quercetin tannic acid, quercetin 4-acetamidophenol. quercetin 1,3,5-benzenetricarboxylic acid, quercetin 2-methoxyisophthalic acid, quercetin 3,4-dihydroxybenzoic acid, quercetin L-carnitine, quercetin folic acid, quercetin arginine, quercetin isoascorbic acid, quercetin 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one; quercetin cholíniumsalicylát, quercetin A / Rev-acetylcytosine, quercetin acetamidine quercetin Lactic acid amide quercetin 2-ketoglutaric acid, quercetin Camphor-10-sulfonic acid, quercetin 3-Oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid quercetin 5-sulfosalicylic acid quercetin D-tocopherol succinate quercetin D-tocopherol polyethylene glycol succinate quercetin L-lactic acid quercetin glycolic acid quercetin hydroxyurea quercetin imidazolidíntrión quercetin biuret

quercetin aloxán quercetin offend quercetin diacetamido quercetin glutaric acid imide quercetin 3-sulfobenzoic acid quercetin 2-imidazolidinone quercetin 2,5-dihydroxybenzene sulfonic acid quercetin glutaric acid quercetin 1,2-benzisothiazol-3 (2H) -one (1,1-dioxide) quercetin (E) -1-propene-1,2,3-tricarboxylic acid quercetin Galactaric acid quercetin N -acetyl-L-glutamic acid quercetin 3,3'-thiodi (propionic acid) quercetin etofibrate quercetin 5-oxo-proline quercetin coenzyme Q10 routines N (4) -acetycytosine, routines L-carnitine, routines 2,5-dihydroxybenzene sulfonic acid routines isoascorbic acid, hesperetin choline chloride, hesperetin L-carnitine, hesperetin Lactic acid amide hesperetin cholíniumsalicylát, diosmin choline chloride, diosmin L-carnitine, naringin 3,3'-thiodi (propionic acid) naringin L-carnitine, naringin Lactic acid amide naringin choline chloride, genistein choline chloride,

genistein L-carnitine, genistein AF4) -acetylcytozín. naringenin L-carnitine, naringenin choline chloride,

The nutraceutical co-crystals obtained by the process of the invention can be used for the prevention or treatment of various diseases. Their primary activity lies in the ability to quench free radicals and their antioxidant activity generally increases with the number of hydroxyl groups and is potentiated by their presence in the co-crystallization partner molecule. Their use for treating or preventing includes, but is not limited to, neurodegenerative diseases such as Alzheimer's disease, rheumatoid arthritis, or infectious diseases caused by bacteria. Prepared flavonoid co-crystals are involved in the prevention and treatment of diabetic cataract, neuropathy and retinopathy.

The invention also relates to solvates of co-crystals and polymorphic modifications thereof. The discovery of new co-crystals as pharmaceutically useful compounds provides new opportunities for improving the properties and effects of pharmaceutical products. This expands the repertoire of the formulations we have available for formulation design.

For verification, the stability behavior of the nutraceutical co-crystals was monitored by exposure to a defined moisture. These crystalline forms were left in the stability chamber to the point where equilibrium was reached. The water content was determined gravimetric for each form (% of the water content was determined by the feedstock). It has been observed that the quercetin-cocrystal and nutraceuticals such as choline chloride, carnitine, ascorbic acid, isoascorbic acid or N-acetylcytosine are substantially less hygroscopic than quercetin, choline chloride, carnitine, ascorbic acid, isoascorbic acid, respectively. N-acetylcytosine at 65% r.h. at 25 ° C.

It was found that in the load chamber after exposure to 68% r.h., at 25 ° C a sample of quercetin and choline chloride co-crystal absorbed 10.1% water, with choline chloride alone absorbing 32% water and spilling the sample. Analogously, in the case of the quercetin and akamitin cocrystals, a value of 3.7% was reached, with camitin alone absorbing 55% of the water and flowing.

The lower hygroscopicity of the co-crystals is advantageous for processing and storage in crystalline form. Accordingly, a further advantage of the co-crystals of the present invention is the stability (low hygroscopicity) of the product, as a result of which their mechanical processing properties (filtration, drying, grinding, etc.) improve the moisture limit processing conditions.

In another aspect of the invention, compositions comprising novel co-crystals of nutraceuticals are disclosed. The co-crystals of the present invention can advantageously be formulated into pharmaceutical compositions. The method of preparation according to the invention depends on the skill of the person skilled in the art. In this case, the main active ingredient is used in combination with some of the elements such as binders, fillers, diluents, disintegrants, lubricants and coatings as desired. It is advantageous to combine novel nutraceutical co-crystals with other known nutraceuticals or ingrowths such as vitamins, coenzene Q, and, as with the food supplements previously used, with bioflavonoids as active ingredients.

Solid oral dosage forms, such as hard gelatin capsules and tablets, are preferred. In the compositions of the present invention, the amount of salt ranges from 5% to 85%, most preferably 5% to 35% by weight.

Diluents that may be included in the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and microcrystalline cellulose. Similarly, preferred binders are starches, sugars, cellulose and derivatives thereof, gelatin and polyvinylpyrrolidone. Starch and microcrystalline cellulose are preferred in use as good disintegrants. Particularly preferred is Avicel (TM), a type of commercial microcrystalline cellulose.

Lubricants used for solid dosage forms are selected from the group consisting of talc, silica, magnesium stearate, glidant, aerosol, stearic acid and stearin. Magnesium stearate is particularly preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1a-p represent selected Fourier transform infrared spectra of FTIR co-crystals measured on a Nicolet Spectrometer, Impact 410. ATR measurement technique, Omnic version 5.2 program was used for measurement.

Figure No. 1, FT IR spectrum: Quercetin-camitin co-crystal (upper line), quercetin-camitin mechanical mixture (lower line)

Figure 1b, FT IR spectrum: Quercetin hydrochlorothiazide cocrystal (upper line), quercetin hydrochlorothiazide mechanical mixture (lower line)

Figure 1c, FT IR spectrum: quercetin-ketoglutaric acid co-crystal, solvent used MeOH (upper line), quercetin-ketoglutaric acid mechanical mixture (lower line)

Figure No. 1d, FT IR spectrum: Quercetin-acid (2S, 3R, 4S, 5R) -2,3,4,5-tetrahydroxyhexanedioic acid cocrystal, MeOH solvent (upper line), quercetin-acid mechanical mixture (25,3R, 45 ', 57?) - 2,3,4,5-tetrahydroxyhexanedio (lower line)

Figure 1e, FT IR spectrum: Quercetin-3-sulfobenzoic acid co-crystal, MeOH solvent (upper line) used, quercetin-3-sulfobenzoic acid mechanical mixture (lower line)

Figure 1 f, FT IR spectrum: Quercetin-biuret co-crystal, DMF solvent (upper line), quercetin-biuret mechanical mixture (lower line)

Figure 1 g, FT IR spectrum: quercetin-alloxane, solvent DMF (red line) used, mechanical mixture quercetin-alloxane monohydrate (blue line)

Figure 1 h, FT IR spectrum: Quercetin-urazole co-crystal, solvent DMF (red line) used, quercetin-urazole mechanical mixture (blue line)

Figure No. 1, FT IR spectrum: Quercetin-diacetamide cocrystal, solvent used water (upper line), quercetin-diacetamide mechanical mixture (lower line)

Figure 1 i, FT IR spectrum: Quercetin-camphor-10-sulfonic acid co-crystal, MeOH solvent (upper line), quercetin-camphor-10-sulfonic acid mechanical mixture (lower line)

Figure 1j, FT IR spectrum: Quercetin-imidazolidine trion co-crystal, solvent DMF (upper line) used, quercetin-imidazolidine trion mechanical mixture (lower line)

Figure 1k, FT IR spectrum: Quercetin-3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid cocrystal, solvent DMF (upper line), quercetin-acid mechanical mixture 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid (lower line)

Picture no. 11, FT IR spectrum: Quercetin-lactic acid co-crystal, solvent DMF (upper line), quercetin-lactic acid mechanical mixture (lower line)

Figure No. FT, FT IR spectrum: Quercetin-3,3'-thiodipropionic acid cocrystal, DMF solvent (upper line), quercetin-3,3'-thiodipropionic acid mechanical mixture (lower line)

Picture no. In, FT IR spectrum: Hesperetin-choline chloride co-crystal, solvent DMF (upper line) used, hesperetin-choline chloride mechanical mixture (lower line)

Figure 1 o, FT IR spectrum: Hesperetin-lactic acid cocrystal, solvent methanol (upper line), hesperetin-lactic acid mechanical mixture (lower line)

Figure 1 p, FT IR spectrum: hesperetin-L-carnitine cocrystal, solvent DMF (upper line), hesperetin-L-carnitine mechanical mixture (lower line)

Figures 2a-e show selected photographs of co-crystals from a polarizing microscope (Nikon Eclipse L IN IPOPOL). The co-crystallization partner in the picture on the left.

2a lactic acid amide, quercetin-lactic acid cocrystal b choline chloride, (quercetin-choline chloride cocrystal)

2c hydrochlorothiazide, quercetin hydrochlorothiazide co-crystal

2d L-carnitine, quercetin-carnitine co-crystal

2e acetylcytosine, quercetin-acetylcitosine co-crystal

Figures 3a-b show selected records from Differential Compensation Calorimetry (DSC). The DSC-7 Perkin-Elmer instrument, a temperature scale calibrated to the melting points In, Sn and Zn, enthalpy to the melting enthalpy In, was used. The purge gas was nitrogen with a flow rate of 50 ml / min, the heating rate was 15 K / min. Records were corrected to baseline. The sample weight was about 3 mg, the sample was pressed in a standard aluminum pan. The endothermic peaks are up, exothermic down.

and, Quercetin-acetylcytosine co-crystal

3b, loaded cocrystal quercetin-carnitine,

The compounds of the invention were characterized by FT-IR spectrum, Raman spectrum, melting point, DSC / TGA and X-ray powder diffraction (XRPD).

The following examples describe the process for preparing the co-crystals of the nutraceuticals of the present invention. The examples serve only to further illustrate the present invention without limiting its practice to the described examples within the meaning of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of co-crystal of quercetin and L-carnitine

To 100 mg quercetin in a 10 ml (stainless steel) grinding vessel was added 53.3 mg of L-carnitine and mixed with a spatula. Subsequently, 10 µl of isopropanol and a 9 mm grinding ball (stainless steel) are added. The vessel is sealed and cooled with liquid nitrogen. Subsequently, it is ground (frequency 25 / s) for 1/2 hour, mixed, isopropanol (1 µl) is added and ground for 1/2 hour. The product is removed. 150 mg of co-crystal of quercetin and L-carnitine were obtained. Melting point: ~ 120 ° C (Kofler block). Drying loss determined by thermogravimetry (TG) <0.15%.

Example 2

Preparation of co-crystal of quercetin and N-acetylcytosine

To 100 mg quercetin in a MM200 grinding vessel, 10 ml volume (stainless steel), add 50.7 mg of N-acetylcytosine and mix with a spatula. Then add 10μ1 DMF and a 9 mm grinding ball (stainless steel). The vessel is sealed and cooled with liquid nitrogen. It is then milled for 1 hour and allowed to stand overnight. The product is removed. 150 mg of quercetin and N-acetylcytosine co-crystal were obtained. Melting point: 237-241 ° C (Kofler block). Drying loss determined by thermogravimetry (TG) <0.15%.

Example 3

Preparation of co-crystal of routine and carnitine

To 100 mg of trihydrate routine in an MM200 grinding vessel of 10 ml volume (stainless steel) was added 24.7 mg of camitin and mixed with a spatula. Then add 10μ1 of water and a 9 mm grinding ball (stainless steel). The vessel is sealed and cooled with liquid nitrogen. It is then milled for 0.5 hours and allowed to stand overnight. The finely crystalline product is removed from the vessel and dried at 55 ° C under water pump vacuum. 60mg co-crystal of rutin and acarnitine was obtained. Melting point; ~ 145 ° C (Kofler block). Drying loss determined by thermogravimetry (TG) - 8.35%.

Example 4

Preparation of a pharmaceutical formulation

Co-crystal of Example 3 86mg

Silica dioxide lmg

Crosspovidone 16mg

Klucel 9mg

Magnesium stearate 2mg

Avicel 86mg

All components were weighed together, mixed and tableted.

Example 5

Preparation of the co-crystal of diosmin and lactic acid amide

To 300 mg of diosmin in a MM200 grinding vessel, 10 ml volume (stainless steel), add 88.8 mg of lactic acid amide and mix with a spatula. Subsequently, 10 µl of methanol and two 9 mm grinding balls (stainless steel) are added. The vessel is sealed and cooled with liquid nitrogen. It is then milled for 0.25 hours, and cooled again with nitrogen and milled for another 0.25 hours. The finely crystalline product is removed from the container. 350mg of diosmin-lactic acid amide was isolated. Melting point: ~ 155 ° C (Kofler block). Drying loss determined by thermogravimetry (TG) <0.15%.

Examples 6 to 18

A series of co-crystals are prepared analogously to Example 2, using the above solvent.

Example flavonoid solvent Co-crystallization partner Example 6 quercetin methanol 4-acetamidophenol. Example 7 quercetin DMF biuret Example 8 quercetin acetone quinic acid, Example 9 quercetin DMF hydrochlorothiazide Example 10 quercetin Water acetamidine hydrochloride, Example 11 quercetin methanol choline chloride,

Example 12 quercetin toluene 1,3,5-benzenetricarboxylic acid, Example 13 quercetin DMF 3,4-dihydroxybenzoic acid, Example 14 quercetin methanol 5-methyl-2-phenyl-2,4-dihydro-3 // - pyrazol-3-one Example 15 quercetin acetone cholíniumsalicylát, Example 16 diosmin DMF 2,5-dihydroxybenzene sulfonic acid Example 17 genistein methanol choline chloride, Example 18 genistein Water A-acetylcytosine,

Example 19

Preparation of a co-crystal of rutin and 5-methyl-2-phenyl-2,4-dihydro-37 H -pyrazol-3-one 200 mg of rutin trihydrate are dissolved in an ultrasonic bath in 5 ml of methanol and 1 ml of water is subsequently added 53 mg of 5-methyl- 2-phenyl-2,4-dihydro-3 H -pyrazol-3-one. The mixture was heated to boiling and then filtered through a Nylon filter (0.45pm). The filtrate is allowed to crystallize freely in an unclosed vial. After a few days, the precipitate was filtered off through a frit S3, washed with 2 x 1.7 ml ethyl acetate and dried at 20 ° C under a water pump vacuum in a desiccator. 185mg of the co-crystal of rutin and 5-methyl-2-phenyl-2,4-dihydro-37H-pyrazol-3-one was isolated. The structure was subsequently confirmed by IR, DSC, XRPD.

Example 20

Preparation of co-crystal of diosmin and L-carnitine

200 mg of diosmin and 53 mg of L-carnitine are dissolved in 1.2 ml of dimethylformamide at 85-90 ° C, and then 2.1 ml of ethanol are added with stirring. The mixture is allowed to crystallize freely in an unclosed vial. After a few days, the precipitate was filtered off through a frit S3, washed with 2 x 1.5 ml of ether and dried at 45 ° C under a water pump vacuum in a desiccator. 190mg of the co-crystal of diosmin and L-carnitine were isolated. The structure was subsequently confirmed by IR, DSC, XRPD.

Examples 21-29

A series of co-crystals were prepared analogously to Example 20, using the above solvent

Example flavonoid solvent Co-crystallization partner Example 21 rutin Water-ethanol isoascorbic acid

Example 22 rutin The water-methanol 2,5-dihydroxy benzene sulfonic acid potassium salt Example 23 diosmin DMF-water L-carnitine Example 24 naringin ethanol Choline chloride Example 25 naringin ethanol carnitine Example 26 naringin ethanol Lactic acid amide Example 27 rutin methanol Choline chloride Example 28 diosmin DMF-ethanol Choline chloride Example 29 rutin The water-methanol carnitine

Example 20

Coercal load of quercetin and L-carnitine

The sample obtained by the procedure of Example 1 is placed in a vapor sorption (DVS) t-25 ° C, 68% r.o. and after equilibration, the water content was determined to be 3.7%. A slightly yellow crystalline co-crystal of quercetin and L-carnitine was obtained. The DSC trace in Figure 3b shows a broad endothermic peak associated with solvent leakage. Above 189 ° C decomposition begins.

Example 21

Preparation of co-crystal of quercetin and isoascorbic acid

Analogous to Example 1, except that 2 molar fold of isoascorbic acid is used. A co-crystal of quercetin and isoascorbic acid of the formula C15H10O7.2C6H8O6 is obtained.

Example 22

Preparation of the co-crystal of diosmin and tocopherol polyethylene glycol succinate

0.5 g of tocopherol polyethylene glycol succinate (TPGS, Eastman-Kodak) was melted in a water bath at 65 ° C in a flask, and 0.3 g of quercetin was then added with stirring. The mixture was stirred under a nitrogen atmosphere at 65-70 ° C for 0.5 h and the heating was stopped. PVP (BASF) is added followed by Cab-O-Sil (Cabot) as aqueous solutions. The gradually crystallized mass is lyophilized for 6 hours and then crushed in a mortar. A water-soluble co-crystal of diosminutocopherol polyethylene glycol succinate -PVP suitable for hard gelatine capsules is obtained.

Industrial usability

The invention is useful in the pharmaceutical industry in the manufacture of nutraceuticals and medicaments for the prevention and treatment of chronic venous insufficiency, allergy, arthritis, atherosclerosis, diabetes, high cholesterol, high blood pressure, inflammation, stroke, digestive ulcer disease and viral infections.

Claims (8)

Flavonoid co-crystals, wherein the flavonoids are selected from the group of quercetin, rutin, hesperidin, hesperetin, naringin, diosmin, genistein, naringenin, and the co-crystallization partner is selected from quinic acid, ferulic acid, caffeic acid, hydrochlorothiazide, choline chloride, tannic acid, 4-acetamidophenol, 1,3,5benzenetricarboxylic acid, 2-methoxyisophthalic acid, 3,4-dihydroxybenzoic acid, L-carnitine, folic acid, arginine, isoascorbic acid, 5-methyl-2-phenyl-2,4-dihydro-37 / - pyrazol-3-one, choliniumsalicylate, VfT1-acetylcytosine, acetamidine, lactic acid amide, 2-ketoglutaric acid, camphor-10-sulfonic acid, 3oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane- 1-carboxylic acid, 5 sulfosalicylic acid, D-tocopherol succinate, D-tocopherol polyethylene glycol succinate, L-lactic acid, glycolic acid, hydroxyurea, imidazolidine trione, biuret, alloxane, urazole, diacetamide, glutaric acid imide ej, 3-sulfobenzoic acid, 2imidazolidinone, 2,5-dihydroxybenzene sulfonic acid, glutaric acid, 1,2-benzisothiazol-3 (277) -one- (1,1-dioxide), (E) -1-propene-1, 2,3-tricarboxylic acid, galactaric acid, A-acetyl-L-glutamic acid, 3,3'-thiodi (propionic acid), etofibrate, 5-oxo-proline, coenzyme Q10 and their pharmaceutically acceptable salts, as well as polymorphs and solvates of co-crystals . A process for the preparation of co-crystals according to claim 1, characterized in that the flavonoid and the co-crystallization partner are reacted to form hydrogen bonds in a molar ratio of components from 0.8 to 1.0 to 1.0 to 3.2 and subsequently recover the resulting co-crystal. A process for preparing co-crystals according to claim 2, characterized in that the flavonoid and the co-crystallization partner are allowed to interact in a grinding machine wherein the flavonoid and the co-crystallization partner are solid, occasionally with the addition of a solvent. A process for preparing co-crystals according to claim 2, characterized in that the flavonoid and the co-crystallization partner are allowed to interact with each other in a solvent, followed by slow evaporation. Process for preparing co-crystals according to claims 3 and 4, characterized in that the solvent selected from the group of hexane, toluene, acetonitrile, dimethylformamide, alcohols C 1 to C 5, acetic acid, tetrahydrofuran, ketones C 3 to C 6, diethylene glycol, ethoxyethanol, ethyl lactate and water or mixtures thereof. Use of co-crystals according to claim 1, for the preparation of nutraceuticals and medicaments for the prevention and treatment of chronic venous insufficiency, allergy, arthritis, atherosclerosis, diabetes, high cholesterol, high blood pressure, inflammation, stroke, digestive ulcer disease and viral infections. A satin composition comprising at least one co-crystal according to claim 1. 8. A formulation comprising at least one co-crystal according to claim 6, wherein said formulation is a solid oral dosage form.