SK512011A3 - Cocrystals of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one and their preparation and use - Google Patents

Abstract

The invention relates to co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one and co-crystallization partners selected nutraceuticals, such as quercetin, gallic acid, chlorogenic acid, 1,3,5- benzenetricarboxylic acid, 3,4-dihydroxybenzoic acid, taurine, vitamins such as nicotinamide and ascorbic acid, acid adipic, citric acid, tartaric acid, acid camphor-10-sulfonic acid, glycolic acid, aspartic acid, 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-acid carboxylic acid hydroquinone sulfonic acid 5-sulfosalicylic acid, acid 3- sulfobenzoic acid, tannic acid, acid-succinic acid, urea, imidazolidinethione, biuref 2-ketoglutaric acid, hydrochlorothiazide, aloxane, 2-hydroxysuccinic acid, 4-aminosalicylic acid, ethylenediaminetetraacetic acid, quinic acid, 4-acetamidophenol, folic acid, N (4) - acetylcytosine, lactic acid amide, acetamidine, D-mannitol, D-tocopherol succinate, D-tocopherol palmitate, choline chloride, D-glucose, D-fructose, trehalose, hidantoin, urazole, diacetamide, gluaric acid imide, glutaric acid, 2-imidazolidinone, caffeine, 1,2-benzisothiazole-3 (2i) - on- (1,1-dioxide), pyrrolidine-5-carboxylic acid, acid L-glutamic acid, N-acetyl-L-glutamic acid, L-carnitine, lactic acid, caffeic acid, ferulic acid, acid 3,3'-thiodipropionic acid, coenzyme Q10, acid koji, 2-methoxyisophthalic acid, maleic acid, L-lysine, donepezil. The invention also relates to a method of preparation these co-crystals as well as their use as therapeutic agents purposes and the preparation of medicinal products.

Description

Technical field

The present invention relates to novel 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one co-crystals and to a process for their preparation and use.

Antioxidants are substances that affect the activity of oxygen compounds. They limit their formation or transform them into a less reactive or inactive state. Oxygen radicals (e.g., superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen, and the like) can react with unsaturated fatty acids and amino acids in lipid micelles, cell membranes, or proteins. Antioxidants can be divided into natural (naturally occurring in nature or food) and synthetic (prepared by chemical or biotechnological processes). Antioxidants are specifically used to inhibit oxidative stress and related diseases. Consumption of substances containing them has a positive effect on the health of the organism in which they prevent oxidation, with multiple antioxidants exhibiting more than one mechanism of antioxidant activity. Many products contain natural antioxidants such as resveratrol, 3,4-dihydroxycinnamic acid derivatives, ascorbic acid and others. Antioxidants are not only important in the prevention of malignancy, but also in other civilization diseases (eg atherosclerosis, multiple sclerosis, various cysts and dysplasias, immune disorders, autoimmune diseases, etc.). Antioxidants in foods are reported by Schmid (Schmid, S. 2010. In: Antioxidants and oxidative changes in fats in foods). The lack of antioxidants in the diet can be compensated by nutraceuticals containing, for example, coenzyme Q, flavonoids, L-carnitine, acetylcamitin, vitamin C.

Most of the antioxidant agents are included in the class of nutraceuticals such as polyphenols, phenolic acids, phytoestrogens, phytosterols, phytates, some vitamins and polyunsaturated fatty acids.

One group of synthetic antioxidants is 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (Edaravone, norphenazone, CAS-89-25-8). The preparation is described by Knorr (Ann. 1887, 238, 137). It is a powerful antioxidant, a neuroprotective used to treat postischemic events and a free radical scavenger, protecting against oxidative stress and apoptosis. In human organism o.i. acts as an antioxidant, prevents autooxidation of unsaturated fatty acids. It was marketed in Japan by Mitsubishi Pharma in 2001 as an injection under the name Radicut. Its effects in testing against amyotrophic lateral sclerosis and other neurodegenerative diseases are documented (Journal of Stroke and Cerebrovascular Dioseases, 2011, 1; Experimental Neurology 213,2008,448; Recent Patents on Cardiovascular Drug Discovery, 2006, 1, 85).

The use of norphenazone as an antipyretic is disclosed in GB 1072262 and as an anti-inflammatory agent in US 4579844 and JP63132833.

Injectable forms are disclosed in CA 2504873 and US 2004/0162330.

Pharmaceutical compositions for ophthalmic treatment are disclosed in EP 0633025A1.

Formulations containing norphenazone and coenzyme Q are disclosed in WO2005 / 034945A1.

Emulsion compositions are described in US 2009 / 0131496A1.

WO2010 / 059727Al discloses the preparation of formulations using amphiphilic solubilizers.

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 host-type compounds (active molecule, eg, pharmacologically active compound, nutraceutical, etc.) - host (co-crystallization partner, inactive or active substance), formed from two or more components that are solid at room temperature. Not performed

2 / interfering with the primary molecular structure of the active substance, non-covalent bonds are formed. As co-crystal preparation techniques, co-crystallization of the components (co-crystallization) at stoichiometric ratios from solution is used, with great variability in the conditions for nuclei search and growth and solvent selection (if the co-crystal is less soluble).

Co-crystals of the same active ingredient may have substantially different properties (melting point, solubility, bioavailability, chemical stability, dissolution rate, etc.) depending on the other component (partner). The original physiological and biochemical effect and mechanism of action remain unchanged. 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).

By modifying the crystalline form in this way, substances with more favorable properties are obtained, in particular in terms of formulations for oral application, technological operations (grinding, drying), stability and solubility.

Drug co-crystals are reported by Sekhon, B.S. (In. Ars Pharm, 2009, Vol. 50, 2; p. 99-117) and U.S. Pat. Nos. 2008/45481, 2008/51453, WO 2010/17343.

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

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

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

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

US 2009/0258859 discloses metronidazole co-crystals of anutraceuticals (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).

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

A series of nutraceutical co-crystals is disclosed in US 2010/204204. This document also describes several co-crystals of antioxidants and vitamins (quercetin, diosmine, hesperetin) with phenolic acids, aliphatic acids, purine bases and isonicotin amide, ascorbic acid, 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 Laskorbic acid-sarcosine, nicotinic acid, betaine, catechol, and betaine-gallic acid, resveratrol and ferulic acid - baclofen published in Cryst. Growth Des., 2010, 10 (8), pp. 3568-3584.

Choline diepalrestat co-crystal is protected by US2009 / 055868.

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

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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 make it possible to estimate their efficiency and stability.

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.

Obviously, it is advantageous to obtain new forms of nutraceuticals with solubility that make it possible to achieve plasma levels faster or slower as needed. At the same time, adjusting the properties will allow specifically to improve product stability and processability. The aim is to obtain forms having low hygroscopicity and good processability for pharmaceutical operations and stabilization of the injectable drug form. The present invention solves the problems of preparing more technologically easier to handle, more soluble and more stable forms of the 5-methyl-1-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one (edavarone) antioxidant in combination with nutraceuticals, providing novel co-crystals as set forth in claim 1.

SUMMARY OF THE INVENTION

The present invention solves the above problems by preparing novel forms of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one as co-crystals.

A first object of the present invention are co-crystals which consist of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one as an active ingredient and a co-crystallization partner.

A second object of the present invention is to prepare 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystals by co-crystallization from a solvent.

It is a further object of the present invention to provide 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystals by co-milling the components.

A further object of the invention are co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3one, wherein the co-crystallization partner is a nutraceutical or a drug.

It is a further object of the invention to provide 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystals suitable for use in pharmaceutical compositions, in particular for use as an injection.

The discovery of novel co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and 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 invention also relates to solvates of co-crystals and polymorphic modifications thereof.

The present invention relates to 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystals and to a process for their preparation and use.

The co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one according to the invention are substances consisting of at least two non-identical solids 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 the antioxidant 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one (edavarone) and the selected nutraceutical as co-crystallization partner form a co-crystal, this has new unexpected properties. These new forms have altered solubility and increased stability as compared to the original form of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one or nutraceutical, whether in the form of a salt, hydrate or solvate. The changes are further reflected in the new morphology or habit, which allows for better processability than e.g. milling. For example, a co-crystalline form of a nutraceutical is preferred if the parent antioxidant molecule is insoluble in water. Conversely, a further advantage is provided by the co-crystal formation of the two active substances in the case of a combination of more soluble co-crystallization partners e.g. choline chloride, citric acid, ascorbic acid, etc.

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Especially preferred is the stabilizing effect of the co-crystallization partner for the preparation of an injectable form of edavarone, which is further associated with adjusting the appropriate pH of the injectable solution.

The present inventors have found that the novel 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one co-crystals described in this invention provide additional advantages. They show low hygroscopicity and good processability in technological operations and stability of edavarone injectable solutions.

A first object of this invention are co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and nutraceuticals. Among the nutraceuticals, the antioxidants quercetin, gallic acid, chlorogenic acid, 1,3,5-benzenetricarboxylic acid, 3,4-dihydroxybenzoic acid, taurine, vitamins such as nicotinamide and ascorbic acid, adipic acid, citric acid, tartaric acid, camphor-10sulfonic acid, glycolic acid, aspartic acid, 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid, hydroquinone sulfonic acid, 5sulfosalicylic acid, 3-sulfobenzoic acid, tannic acid, succinic acid, urea, imidazolidine trione, biuret, 2-ketoglutaric acid, hydrochlorothiazide, alloxane, 2-hydroxysuccinic acid, 4-aminosalicylic acid, ethylenediaminetetraacetic acid, quinic acid, 4-acetamidophenol, folic acid, N (4) acetylcytosyl, , acetamidine, D-mannitol, D-tocopherol succinate, Dtocopherol palmitate, choline chloride, D-glucose, D-fructose, trehalose, hydan toine, urazole, diacetamide, glutaric acid imide, glutaric acid, 2-imidazolidinone, caffeine, 1,2-benzisothiazol-3 (2H) -one (1,1-dioxide), pyrrolidine-5-carboxylic acid, Lglutamic acid, V-acetyl-L-glutamic acid, L-carnitine, lactic acid, coffee acid, ferulic acid, 3,3'-thiodipropionic acid, coenzyme Q10, kojic acid, 2-methoxyisophthalic acid, maleic acid, L-lysine, donepezil.

It is known that the effect of nutraceuticals increases when used together. Selected nutraceuticals are implicated in the prevention and treatment of diabetic cataract, improvement of brain metabolism, neuropathy and retinopathy. A combination of nutraceuticals, e.g. With vitamin C, a synergistic complex is formed, whereby vitamin C regenerates vitamin E. It affects the formation of red blood cells, the renewal and growth of muscle mass and other tissues, and often have diuretic effects, thereby lowering blood pressure.

It is therefore advantageous to prepare a common form of edavarone and a nutraceutical. It is particularly advantageous in some cases to influence the theological properties of the blood and the pathologies of the main arteries.

The preparation process according to the invention is characterized by:

a) dissolving 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one 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 C4-C6 ethers or alkanes such as hexane. The molar ratio of active component to co-crystallization partner used is 1: 1, although in some cases co-crystals are obtained by crystallization with a higher component ratio e.g. 1: 2, 1: 3, 1: 4.

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

(a) mixing a stoichiometric amount of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and a co-crystallization partner; and

b) occasionally by adding a small amount of solvent and co-milling 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 nutraceuticals and substances mentioned e.g. in the GRAS or EAFUS list or excipients applied in pharmacy. E.g. the co-crystallization partner may be an amine, amide, sulfonamide, carboxylic acid, sulfonic acid, heterocyclic compound, phenol or polyphenol. It will be appreciated that the compounds may also be in the form of pharmaceutically acceptable salts such as hydrochlorides or sodium salts. Quercetin, gallic acid, chlorogenic acid, 1,3,5-benzenetricarboxylic acid, acid are chosen as co-crystallization partners.

3,4-dihydroxybenzoic acid, taurine, vitamins such as nicotinamide and ascorbic acid, adipic acid, citric acid, tartaric acid, camphor-10-sulfonic acid, glycolic acid, aspartic acid, 3-oxo-4,7,7-trimethyl- 2oxabicyclo [2.2.1] heptane-1-carboxylic acid, hydroquinone sulfonic acid, 5sulfosalicylic acid, 3-sulfobenzoic acid, tannic acid, succinic acid, urea, imidazolidine trione, biuret, 2-ketoglutaric acid, hydrochlorothiazide, alloxane, 2-hydroxysuccinic acid 4-aminosalicylic acid, ethylenediaminetetraacetic acid, quinic acid, 4-acetamidophenol, folic acid, N (4) acetylcytosine, lactic acid amide, acetamidine, D-mannitol, D-tocopherol succinate, choline chloride, D-glucose, D-fructose, hydantoin , urazole, diacetamide, glutaric acid imide, glutaric acid, 2-imidazolidinone, caffeine, 1,2-benzisothiazol-3 (2/7) -one (1,1-dioxide), pyrrolidine-5-carboxylic acid, L- glutamic, Nacetyl-L-glutamic acid, L-carnitine, lactic acid, coffee acid, ferulic acid, 3,3'-thiodi (propionic acid), coenzyme Q10, kojic acid, 2-methoxyisophthalic acid, maleic acid, L-lysine, donepezil .

The co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one obtained according to the invention can be used for the prevention or treatment of various diseases. Their primary activity is their ability to quench free radicals and their antioxidant activity

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it generally increases with the number of hydroxyl groups and is also potentiated by their presence in the co-crystallization partner molecule. Their use for treatment or prevention includes, but is not limited to, neurodegenerative diseases such as Alzheimer's disease, rheumatoid arthritis, recovery from ischemic stroke, or infectious diseases caused by bacteria.

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 I have available for formulation design.

The stability of the new co-crystals was monitored by exposure to defined moisture. These 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 co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and a nutraceutical such as nicotine amide, ascorbic acid, choline chloride, isoascorbic acid or N-acetylcytosine is substantially less hygroscopic than nicotinamide alone, ascorbic acid, isoascorbic acid, respectively. N-acetylcytosine at 65% r.h. and a temperature of 25 ° C.

A sample of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and N-acetylcytosine co-crystal was found to sorb 1.1% in a load chamber after exposure to 75% RH, at 25 ° C. water, with N-acetylcytosine alone absorbing 11% water. Analogously, in the case of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and isoascorbic acid, a value of 0.4% was achieved with isoascorbic acid absorbing 5% of water. The adsorption isotherms of some other co-crystals and co-crystallization partners are shown in graph no. 1. Where the adsorption isotherms of the co-crystals of edaravone and co-crystallization partners are in ascending order: sulfosalicylic acid (top line), lactamide, edaravonlactamide, 3,5-dihydroxybenzoic acid, gallic acid, edaravon-sulfosalicylic acid, edaravon-gallic acid, edaravone 5-dihydroxybenzoic acid (bottom line).

The lower hygroscopicity of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystals and nutraceuticals is advantageous for processing and storage in crystalline form. Accordingly, a further advantage of the co-crystals of the present invention is the uniformity of the product and the stability thereof, as a result of which their mechanical processing properties (filtration, drying, milling, etc.) are improved. When used as pharmaceuticals, the co-crystals of edavarone of the invention are administered in the form of pharmaceutical compositions. The compositions may be formulated for any route of administration, and the preparation of a suitable pharmaceutical composition for a particular mode of administration is well known to those skilled in the art of pharmacy. Accordingly, the present invention also relates to pharmaceutical compositions comprising a therapeutically significant amount of edavarone co-crystals together with a pharmaceutically acceptable diluent or carrier. Of note is the stabilizing effect of the co-crystallization partner in the preparation of the injectable dosage form. The aqueous-ethanolic co-crystals of edavarone prepared according to the invention have been found to be stable, without degradation reactions in the injectable solution.

In a preferred form, the pharmaceutical compositions of the invention are formulated for injection, e.g. for intravenous administration. A typical composition for administration comprises a sterile isotonic aqueous solution and a co-solvent e.g. ethanol, polyethylene glycol. Such a formulation may include a chelating agent and an antioxidant, but an advantage of the invention is the use of a co-crystal of edavarone whose co-crystallization partner combines the above properties.

In another aspect of the invention, compositions comprising novel co-crystals of nutraceuticals are disclosed. The method of preparation according to the invention depends on the skill of the person skilled in the art. The co-crystals of the present invention can advantageously be formulated into pharmaceutical compositions. In this case, the main active ingredient is used in combination with some of the elements such as binders, fillers, diluents, stabilizers, chelating agents, disintegrants, lubricants as desired.

It is advantageous to combine novel nutraceutical co-crystals with other known nutraceuticals or ingrowths such as vitamins, flavonoids, coenzens Q, as in the case of the food supplements hitherto used with the active ingredient bioflavonoids.

Solid oral dosage forms are, for example, hard gelatin capsules and tablets.

In the compositions of the present invention, the amount of co-crystal 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. Preferred binders are starches, sugars, cellulose and derivatives thereof, gelatin and polyvinylpyrrolidone. Starch and microcrystalline cellulose have

11, preferably 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.

Preferred for administration are injections containing 3 to 60 mg / ml edavarone co-crystal per total injection volume. Water and pharmaceutically acceptable solvents in a volume of 10 to 70% by volume of injection are used as diluent. As pharmaceutically acceptable solvents, ethanol, propylene glycol, polyethylene glycol and the like are used. It is preferred to maintain the pH of the injection in the range of 2.0 to 6.5, and a pharmaceutically acceptable stabilizer may also be used. For pH adjustment, e.g. citric acid, tartaric acid, ascorbic acid, ethylenediaminetetraacetic acid and salts thereof. The injections may further comprise a pharmaceutically acceptable stabilizer. Also in this case it is suitable to use as a pharmaceutically acceptable stabilizer of the co-crystallization partner e.g. L-cysteine, 3,3'-thiodipropionic acid, ascorbic acid, gallic acid, ethylenediaminetetraacetic acid and salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Picture no. 1a-p represents Fourier transform infrared spectra of FTIR of selected co-crystals measured on a Spectrometer Nicolet, Impact 410. ATR measurement technique, Omnic program version 5.2 was used.

Picture no. 1a: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one aspartic acid (2: 1), co-crystal (upper line), 5-methyl-2-phenyl- L-aspartic acid 2,4-dihydro-3 H -pyrazol-3-one (lower line)

Picture no. 1b: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one-urea cocrystal (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 // - pyrazol-3-one urea (lower line)

Picture no. 1c, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one-3,4-dihydroxybenzoic acid co-crystal (upper line), 5-methyl-2-phenyl-2,4- dihydro-3H-pyrazol-3-one 3,4-dihydroxybenzoic acid (lower line)

Picture no. 1d, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one gallic acid (upper line), 5-methyl-2-phenyl-2,4-dihydro- 3 H -pyrazol-3-one gallic acid (lower line)

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Picture no. 1e, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and nicotinamide (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 H- -pyrazol-3-one nicotinamide (lower line)

Picture no. 1f, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal adonepezil hydrochloride (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 // - pyrazol-3-one and donepezil hydrochloride (lower line)

Picture no. 1g, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystal and D-fructose (upper line), 5-methyl-2-phenyl-2,4-dihydro- 3 H -pyrazol-3-one and Dructose (lower line)

Picture no. 1h, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and lactic acid (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro- 3 H -pyrazol-3-one and lactic acid (lower line)

Picture no. 1i, a co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and Lglutamic acid (upper line), a mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro- 3 / Z-pyrazol-3-one and L-glutamic acid (lower line)

Picture no. 1j, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and coffee acid (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro- 3 H - pyrazol-3-one and coffee acid (lower line)

Picture no. 1k, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and 3,3'-thiodipropionic acid (upper line), 5-methyl-2-phenyl-2 mechanical mixture , 4dihydro-3 H -pyrazol-3-one and 3,3'-thiodipropionic acid (lower line)

Picture no. 11, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and kojic acid (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro- 3 H -pyrazol-3-one and kojic acid (lower line)

Picture no. Im, 5-methyl-2-phenyl-2,4-dihydro-37 H -pyrazol-3-one cocrystal and potassium hydroquinone sulfonic acid potassium salt (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 H- -pyrazol-3-one and the hydroquinone sulfonic acid potassium salt (lower line).

Picture no. In, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and glutaric acid (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro- 3 H -pyrazol-3-one and glutaric acid (lower line).

Picture no. lo, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and acetamidine hydrochloride (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 1 H -pyrazol-3-one and acetamidine hydrochloride (lower line).

Picture no. 1p, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and caffeine (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4-dihydro-3 1 H -pyrazol-3-one and caffeine (lower line).

Picture no. 2a-f shows photographs from a polarizing microscope (Nikon Eclipse LV IPOPOL) of selected co-crystals and corresponding co-crystallization partners (left).

(a) gallic acid, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one gallic acid (b) 3-oxo-4,7,7-trimethyl-2 -oxabicyclo [2.2.1] heptane-1-carboxylic acid 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal 3-oxo-4,7,7-trimethyl- 2oxabicyclo [2.2.1] heptane-1-carboxylic acid (c) urea, 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystal, urea 2 (d) camphorsulfonic acid, co-crystal 5 -methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one camphorsulfonic acid (e) isoascorbic acid, co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazole- 3-one isoascorbic acid (f) succinic acid, co-crystal 5-methyl-2-phenyl-2,4-dihydro-3 H- pyrazol-3-one antaric acid

Picture no. 3a-e represent selected diffractograms (XRPD-X-ray powder diffraction). The measurement was performed on a powder diffractometer: Bragg-Brentano diffractometer Philips PW 1730/1050, with cobalt lamp: β-filtered CoKa radiation, voltage 40 kV / 35 mA, range 3 ° - 51 ° 2Θ, step 0.02 °. Key inter-plane distances and relative intensities to the figures are shown in the accompanying table.

3a: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one (upper line), 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3 co-crystal -one and 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid (1: 1) (centerline), 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] Heptane-1-carboxylic acid (lower line).

3b: 5-methyl-2-phenyl-2,4-dihydro-37H-pyrazol-3-one cocrystal and urea (1: 1)

3c: camphorsulfonic acid (lower line), 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one (middle line), 5-methyl-2-phenyl-2,4- dihydro-377-pyrazol-3-one; and camphorsulfonic acid (1: 1) (upper line).

3d: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and gallic acid (2: 1).

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3e: 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one (lower line), quercetin (midline), co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 1 H -pyrazol-3-one akvercetine (1: 1) (upper line).

Picture no. Figures 4a-b show records from a dispersive Raman DXR Smart Microscope with an excitation laser (532 nm).

Figure 4a, Raman spectrum: co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and D-tartaric acid (upper line), 5-methyl-2-phenyl-2, 4-dihydro-3 H -pyrazol-3-one (centerline), 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one mechanical mixture and D-tartaric acid (lower line).

Figure 4b, Raman spectrum: co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3Z / pyrazol-3-one and citric acid (upper line), mechanical mixture of 5-methyl-2-phenyl-2,4- dihydro-3 H -pyrazol-3-one and citric acid (lower line).

Figures 5a-c show records obtained by Differential Compensation Calorimetry (DSC). DSC measurements were performed using a Perkin-Elmer DSC-7 instrument (PerkinElmer, USA) with Pyris software. The temperature scale was calibrated using In, Sn and Zn. The enthalpy scale was calibrated for the enthalpy of melting In. The 3-4 mg samples were placed in a standard molded aluminum dish using nitrogen as the purge gas. Endothermic peaks are upward on the recordings. Records are corrected to baseline. The heating rate was 10 C / min, in the temperature range 100-250 C. Figure 5a, DSC record: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one co-crystal and quercetin (lower line), 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one (middle line) and quercetin (upper line)

Figure 5b, DSC entry: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and gallic acid (lower line), 5-methyl-2-phenyl-2, 4-dihydro-3 H -pyrazol-3-one (middle line) and gallic acid (upper line)

Figure 5c, DSC entry: 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and camphorsulfonic acid (lower line), 5-methyl-2-phenyl-2, 4-dihydro-37 H -pyrazol-3-one (middle line) and camphorsulfonic acid (upper line)

The compounds of the invention were characterized by FT-IR spectrum, Raman spectrum, melting point, DSC / TGA and XRPD.

The following examples describe the process for preparing co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one according to the present invention. The examples serve to further illustrate the present invention without limiting its practice to the examples described herein.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 5-methyl-2-phenyl-2,4-dihydro-37 H -pyrazol-3-one cocrystal and nicotine amide.

To 100 mg of 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one in a 10 ml (stainless steel) grinding vessel, 72.5 mg of nicotinamide is added and the mixture is mixed with a spatula. Then add 10 μΐ of methanol and a 9 mm grinding ball (stainless steel). The vessel is blown with nitrogen and sealed. Subsequently, the mixture is subjected to a vibrating ball mill (25 / s) for 1 hour and allowed to stand overnight. The product is removed. 160 mg of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-377-pyrazol-3-one and nicotine amide (1: 1) were obtained. Melting point: ~ 99 ° C, (Kofler block). The substance was characterized by XRPD, IR, DSC and X-ray (single crystal) structure analysis. The loss on drying was determined by thermogravimetry (TG) <0.15%.

Example 2

Preparation of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and gallic acid. To 100 mg of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one in a 10 ml (stainless steel) grinding vessel was added 48.8 mg of gallic acid and mixed with a spatula. Subsequently, 10 μΐ DMF and a 9 mm grinding ball (stainless steel) are added. The vessel is sealed and the contents are cooled with liquid nitrogen. Subsequently, the mixture is ground in a vibratory ball mill (25 / s) for 30 minutes and allowed to stand overnight. The product is removed. 128 mg of co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and gallic acid (2: 1) were obtained. Melting point: 154-155 ° C (Kofler block). Drying loss determined by thermogravimetry (TG) <0.15%.

Example 3

Preparation of 5-methyl-2-phenyl-2,4-dihydro-37 H -pyrazol-3-one cocrystal and 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid.

16 '

To 100 mg of 5-methyl-2-phenyl-2,4-dihydro-37 H -pyrazol-3-one in a 10 ml (stainless steel) grinding vessel was added 113 mg of 3-oxo-4,7,7- trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid and mix with a spatula. Subsequently, 10 μΐ of DMF and a 9 mm grinding ball (stainless steel) are added. The vessel is sealed and the contents are cooled with liquid nitrogen. Subsequently, the mixture is milled for 0.5 hours and allowed to stand overnight. The finely crystalline product is removed from the container. 200 mg of a co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2. 1] hepan-1-carboxylic acid (1: 1). Melting point: 124 ° C (Kofler block). The substance was characterized by XRPD as shown in Figure 3 and by X-ray (single crystal) structure analysis. Drying loss determined by thermogravimetry (TG) <0.15%.

Example 4

Preparation of the injection form

1.0 g of the co-crystal of edavarone and ascorbic acid was dissolved in 50 ml of ethanol. Subsequently, 50 ml of water for injection was added and the mixture was filtered through a microbial aseptic filter. The sterile solution was dispensed into 10 ml vials under a nitrogen atmosphere and then sealed (edavarone concentration: 5mg / ml).

Example 5-17

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

Example 5-methyl-2-phenyl-2,4-di hydro-377-pyrazol-3-one solvent Co-crystallization partner Example 5 100 mg methanol citric acid Example 6 100 mg DMF tartaric acid, Example 7 100 mg acetone quinic acid Example 8 100 mg DMF hydrochlorothiazide Example 9 100 mg Water EDTANa Example 10 100 mg methanol urea Example 11 100 mg toluene 1,3,5-benzenetricarboxylic acid Example 12 100 mg DMF 3,4-dihydroxybenzoic acid Example 13 100 mg methanol glutaric acid

Example 14 100 mg Water isoascorbic acid Example 15 100 mg Water ascorbic acid Example 16 100 mg acetone glutamic acid Example 17 100 mg DMF / water aspartic acid,

Example 18

Preparation of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one cocrystal and 3-oxo-4, 7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid .

200 mg of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one are dissolved in an ultrasonic bath in 5.5 ml of methanol. 226 mg of 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane-1-carboxylic acid is then added. The mixture is heated to boiling and then filtered through a Nylon filter (0.45 µm). Water is added to the filtrate until turbidity and the mixture is allowed to crystallize freely. After a few days, the precipitate was filtered off through frit S3, washed with 2 x 1.7 mL hexane and dried at 20 ° C under a water pump vacuum in a desiccator. 375 mg of co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and 3-oxo-4,7,7-trimethyl-2-oxabicyclo [2.2.1] heptane- 1-carboxylic acid (1: 1).

Example 19

Preparation of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and quercetin.

57.6 mg of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and 100 mg of quercetin are dissolved in 1.2 ml of dimethylformamide at 85-90 ° C. 3.8 ml of ethanol are then added with stirring. The mixture was heated to boiling and quickly filtered through a Nylon filter (0.45 pm). The mixture was allowed to freely crystallize in an open 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. 110 mg of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and quercetin (1: 1) were isolated.

Example 20

Preparation of a dispersion of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and tocopherol polyethylene glycol succinate for solid dosage forms.

500 mg of tocopherol polyethylene glycol succinate (TPGS, Eastman-Kodak) was melted in a water bath at 65 ° C in a flask. Subsequently, 250 mg of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one is introduced with stirring. The mixture was stirred under a nitrogen atmosphere for 0.5 h at 65-70 ° C. After stopping the heating, add 18

PVP (BASF) followed by Cab-O-Sil (Cabot) in the form of aqueous solutions. The gradually crystallized mass is lyophilized for 6 hours and then crushed in a mortar. The resulting solid dispersion of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one tocopherol polyethylene glycol succinate and PVP-Cab-O-Silu was used to prepare a solid dosage form.

Example 21

Preparation of the co-crystal of 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and L-aspartic acid.

Analogous to Example 1, except that 2 eq. L-aspartic acid.

Example 22

Preparation of the injection form

Dissolve 500 mg of edavarone-ethylenediaminotetraacetic acid (4: 1) cocrystal in 30 ml ethanol in a flask. A solution of 210 mg of citric acid and 150 mg of trisodium citrate in 65 ml of water for injection is then added and the pH adjusted to

3.6 by addition of hydrochloric acid. Make up the volume to 100 ml with water for injections and filter through an aseptic membrane filter. The solution is dispensed into 10 ml vials under a nitrogen atmosphere. The solution for injection was transparent and colorless after 14 days storage at 65 ° C.

Claims (10)

Co-crystals of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one and a co-crystallization partner, wherein the co-crystallization partner is selected from the group of quercetin, gallic acid, chlorogenic acid, 1,3,5- benzenetricarboxylic acid, 3,4-dihydroxybenzoic acid, taurine, vitamins such as nicotine amide and ascorbic acid, adipic acid, citric acid, tartaric acid, camphor-10-sulfonic acid, glycolic acid, aspartic acid, 3-oxo-4,7,7- trimethyl-2-oxabicyclo [2.2 l] heptane-1-carboxylic acid, hydroquinone sulfonic acid, 5sulfosalicylic acid, 3-sulfobenzoic acid, tannic acid, succinic acid, urea, imidazolidine trione, biuret, 2-ketoglutaric acid, hydrochlorothiazide, aloxane, 2-hydroxyisuccinic acid, 4-hydroxyamisuccinic acid, 4-succinic acid ethylenediaminetetraacetic acid, quinic acid, 4-acetamidophenol, folic acid, N (4) acetylcytosine, lactic acid amide, acetamidine, D-mannitol, D-tocopherol succinate, Dtocopherol palmitate, choline chloride, D-glucose, D-fructose, trehalose, trehalose, hydantoin, urazole, diacetamide, glutaric acid imide, glutaric acid, 2-imidazolidinone, caffeine, 1,2benzisothiazol-3 (2/7) -one- (1,1-dioxide), pyrrolidine-5-carboxylic acid, Lglutamic acid, V-acetyl-L-glutamic acid, L-carnitine, lactic acid, coffee acid, ferulic acid, 3,3'-thiodipropionic acid, coenzyme Q10, kojic acid, 2-methoxyisophthalic acid, maleic acid new, L-lysine, donepezil and their pharmaceutically acceptable salts. A process for the preparation of co-crystals according to claim 1, characterized in that 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and a 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 4.2 and subsequently recover the co-crystal formed. A process for the preparation of co-crystals according to claim 2, characterized in that the 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one and the co-crystallization partner are allowed to interact with each other in a ball mill preferably with the addition of a solvent. A process for preparing co-crystals according to claim 2, characterized in that the 5-methyl-2-phenyl-2,4-dihydro-3 H -pyrazol-3-one and the co-crystallization partner are allowed to interact with each other in a solvent followed by slow evaporation. A process for the preparation of co-crystals according to claim 3 and 4, characterized in that the solvent is selected from hexane, toluene, acetonitrile, dimethylformamide, alcohols C 1 -C 5, acetic acid, tetrahydrofuran, ketones C 3 -C 6, diethylene glycol, ethoxyethanol, ethyl lactate and water; mixtures thereof. Use of co-crystals according to claim 1, characterized in that they are used for the preparation of nutraceuticals and medicaments for the prevention and treatment of chronic venous insufficiency, allergies, arthritis, atherosclerosis, diabetes, high cholesterol, high blood pressure, inflammation, stroke, digestive ulcer disease. . A composition comprising at least one co-crystal according to claim 1. A preparation comprising at least one co-crystal according to claims 6 and 7, characterized in that it is an injectable dosage form. The composition of claim 8, wherein the dosage form comprises a co-crystallization partner as a pharmaceutically acceptable stabilizer. The composition of claim 8 and 9, wherein the pharmaceutically acceptable stabilizer is a chelating agent.