RU2536484C1 - Cocrystalline form of niflumic acid with isonicotinamide ot caffeine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel cocrystals of niflumic acid with isonicotinamide or caffeine, where molar ratio of niflumic acid with isonicotinamide or caffeine constitutes 1:1, and cocrystal of niflumic acid with isonicotinamide has entothermic peak from 152 to 162°C according to the data of measurement by means of differential scanning calorimetry and peaks at 2θ(°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 by the data of measurement of X-ray radiation difraction on powder, and cocrystal of niflumic acid with caffeine has endothermic peak from 155 to 165°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 by the data of measurement of X-ray radiation diffraction on powder.

EFFECT: increase of solubility in water in comparison with indices of niflumic acid solubility in pure form.

12 dwg, 2 ex

Description

Introduction

The invention relates to the pharmaceutical industry, in particular to new co-crystals of niflumic acid, suitable for the manufacture of pharmaceutical preparations.

State of the art

2 - [[3- (Trifluoromethyl) phenyl] amino] -3-pyridinecarboxylic acid, also called niflumic acid,

It is a well-known pharmaceutical ingredient (API) with anti-inflammatory, analgesic, antipyretic effect, and also reduces platelet aggregation. Niflumic acid can be used for rheumatoid arthritis (an infectious allergic disease from the group of collagenoses, characterized by chronic progressive inflammation of the joints), osteoarthritis (joint disease), ankylosing spondylitis (spinal disease), acute gouty arthritis (acute inflammation of the joint tissue from the urine joint ) It is used in the treatment of diseases of the soft tissues of the musculoskeletal system, such as bursitis (inflammation of the joint bag), tendonitis (malnutrition of the tendon tissue, accompanied by inflammation), epicondylitis (inflammation of a limited area of the humerus, which is the site of attachment of muscles and tendons). It relieves pain from bone fractures, joint dislocations, sprains and muscles, soft tissue injuries, periostitis (inflammation of the periosteum); pain syndromes after surgical interventions: extraction (removal) of teeth, other dental procedures. Used for obstetric and gynecological interventions: the introduction and removal of the intrauterine device; with gynecological diseases: adnexitis (inflammation of the uterus), parametritis (inflammation of the peritoneal spaces). In addition, it is used for diseases of the ear, throat, nose: sinusitis (inflammation of the paranasal sinuses), pharyngolaryngitis (combined inflammation of the larynx and pharynx), otitis media (inflammation of the middle ear); acute superficial thrombophlebitis. Reduces capillary permeability, stabilizes lysosomes and prevents lysosomal enzymes from entering the cytoplasm and extracellular space, and inhibits the production of macroergic phosphates (primarily ATP). It inhibits cyclooxygenase and inhibits the synthesis of prostaglandins, inhibits platelet aggregation. Although the most significant characteristic of a drug compound, such as niflumic acid, is therapeutic efficacy, the forms of the intended drug are no less important in terms of pharmacokinetic parameters. For example, the amorphous form, salt, co-crystal, polymorphic modifications, because they have different physical and chemical properties, which affects the pharmaceutical API parameters, such as storage stability, compressibility and others. One of the determining factors of bioavailability is solubility and kinetic indicators of dissolution, since the low solubility of a drug compound in biological fluids leads to low drug efficacy and increased side effects. So the use of niflumic acid can lead to nausea, vomiting, diarrhea, pain in the stomach. Other side effects are dyspeptic symptoms, anorexia, with prolonged use - a stomach ulcer and / or duodenal ulcer, melena. In some cases, after several years of treatment with large doses - bone fluorosis. Local reactions: hyperemia, itching, rash, burning sensation. If a rash appears at the site of the cream and gel, stop treatment. Therefore, increasing the solubility of the drug is an urgent technical problem.

There are various ways to increase the speed and solubility of a drug compound:

- fine grinding to create a larger surface area of the soluble compound [Chaumeil J.C. Micronisation: a method of improving the Bioavailability of poorly soluble drugs // Methods Find. Exp. Clin. Pharmcol. - 1998 - 20 (3) - P.211-215],

- the use of salts of the studied objects with improved solubility [Agharkar S., Lindenbaum S., Higuchi T. Enhancement of solubility of drug salts by hydrophilic counter-ions: properties of organic salts of an anti-malarial drug // J. Pharm. Sci. - 1976 - 65 (5) - P.747-749],

- dissolution in complex [Amin K., Dannenfelser R.-M., Zielinski J., Wang B. Lyophilization of polyethylene glycol mixtures // J. Pharm. Sci. - 2004 - 93 (9) - P.2244-2249] and micellar solvents [Torchillin V.P. Micellar nanocarriers: pharmaceutical perspectives // Pharm. Res. - 2007 - 24 (1) - P.1-16],

- the formation of supramolecular complexes with cyclodextrins [Rajewski R.A., Stella V.J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery // J. Pharm. Sci. - 1996 - 85 (11) - P.1142-1169],

- the use of phospholipid vesicles filled with lipophilic compounds [Humberstone A.J., Charman W.N. Lipid-based vehicles for the oral delivery of poorly soluble drugs // Adv. Drug Deliv. Rev. - 1997 - 25 (1) - P.103-128].

However, the known methods have disadvantages that limit the possibility of their use. So, although fine grinding increases the dissolution rate of the drug, however, it does not increase the equilibrium solubility of the substance. Often for medicinal compounds, an increase in van der Waals interactions between small particles and their electrostatic attraction lead to a decrease in the effective dissolution area and, thus, the limit of their biological activity is limited.

Increasing the solubility of a drug compound by creating its salts is unacceptable, since in pharmacy mainly weakly ionizable and neutral molecules are used, and salts are not included in this class of compounds.

The use of complex and micellar solvents suggests acceptable solubility and compatibility of the drug molecules with the solvent, which is not always achievable.

The increase in solubility through the formation of complexes with cyclodextrins, as well as the use of phospholipid vesicles, is applicable for drug compounds of prolonged action, however, fast-acting drugs, such as non-steroidal anti-inflammatory drugs, are often required.

It is also known that solubility can be increased by the formation of a co-crystalline form of API with a component that promotes increased dissolution. Co-crystals are supramolecular systems where one of the components is a poorly soluble active pharmaceutical ingredient, i.e. a molecule of a drug compound, while the second component is a molecule of a well-soluble compound, which is completely absorbed by the body and is involved in enzymatic processes [Lara-Ochoa F. and Espinosa-Pérez G. Cocrystals definitions // Supramolecular Chemistry. - 2007 - 19 (8) - P.553-557].

Co-crystals used in the pharmaceutical industry are attractive in that they make it possible to obtain new crystalline forms of the active pharmaceutical ingredient with special properties, such as improved solubility, thermal stability, improved mechanical properties, etc. Moreover, the choice of co-crystal components greatly facilitates, so to speak, “Fine-tuning” the physical properties of the cocrystal.

Only one co-crystal of niflumic acid is described in the literature - with nicotinamide [Fábián L., Hamill N., Eccles K.S., Moynihan H.A., Maguire A.R., McCausland L., Lawrence S.E., Cocrystals of Fenamic acids with Nicotinamide. Crystal Growth & Design, 2011, 11, p. 3522-3528].

However, the work of Fabian et al. Does not mention any increase in the solubility of niflumic acid in the obtained co-crystal, therefore, the use of this co-crystal in the pharmaceutical industry is impractical.

Isonicotinamide and caffeine were selected as components of the co-crystalline form of niflumic acid. Isonicotinamide is known to increase transcriptional silence at loci regulated by Sir2, which slows down aging. Caffeine is a psychostimulant and is used in medicine as a remedy for headaches and migraines, as a stimulant for breathing and cardiac activity in colds, to increase mental and physical performance, and to eliminate drowsiness.

Thus, co-crystals of niflumic acid with isonicotinamide or caffeine can be used for pharmaceutical purposes.

SUMMARY OF THE INVENTION

The technical task of the invention is to search for a co-crystalline form of niflumic acid with isonicotinamide or caffeine, which allows to increase its solubility and is suitable for use in the pharmaceutical industry.

The invention consists in the following.

A co-crystalline form of niflumic acid with isonicotinamide or caffeine, where the molar ratio of niflumic acid with isonicotinamide or caffeine is 1: 1, and the co-crystal of niflumic acid with isonicotinamide has an endothermic peak of 152 to 162 ° C according to measurements using differential scanning calorimetry and peaks at 2 (°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 according to the X-ray powder diffraction measurement data, and the co-crystal of niflumic acid with caffeine has an endothermic peak from 155 to 165 ° C according to the data measured minutes using differential scanning calorimetry, and peaks at 2θ (°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 as measured by X-ray diffraction powder.

The claimed invention allows to obtain the following advantage - an increase in solubility in water of 1.7 with isonicotinamide and 1.4 times with caffeine compared to pure solubility of niflumic acid. Solubility data was obtained for an aqueous solution at room temperature in an apparatus for measuring the solubility of solid compounds by isothermal saturation. Samples were taken at points of about 0.1, 0.15, 0.2, 0.25, 0.33, 0.5, 0.6, 0.75, 1, 1.25, 1.4, 1.75, 2, 2.5, 3, 3.5 hours and were analyzed using a VARIAN CARY 50 spectrophotometer in the ultraviolet region of the spectrum, operating wavelength range λ = 190 ÷ 400 nm.

The claimed new co-crystalline form - solid crystalline stable substances, do not disintegrate, are not affected by moisture and are convenient for the preparation of stable pharmaceutical preparations.

The structure of the claimed cocrystal is proved by two methods, all of which are sufficient to confirm the formation of a new compound:

- X-ray diffraction (XPRD),

- differential scanning calorimetry (DSC).

Figure 1 shows a typical XPRD profile of a niflumic acid cocrystal: isonicotinamide (1: 1).

Figure 2 shows a typical XPRD profile of a niflumic acid cocrystal: caffeine (1: 1).

Figure 3 presents a typical profile of XPRD niflumic acid in pure form.

Figure 4 presents a typical profile of XPRD isonicotinamide in its purest form.

Figure 5 presents a typical profile of XPRD caffeine in its purest form.

Figure 6 presents a typical thermogram DSC cocrystal niflumic acid: isonicotinamide (1: 1).

Figure 7 presents a typical thermogram DSC cocrystal niflumic acid: caffeine (1: 1).

On Fig presents a typical thermogram DSC niflumic acid in its pure form.

Figure 9 presents a typical thermogram DSC of isonicotinamide in its purest form.

Figure 10 presents a typical thermogram DSC of caffeine in its purest form.

Figure 11 presents the solubility data for the cocrystal niflumic acid: isonicotinamide (1: 1) and its components in pure form.

On Fig presents solubility data for cocrystal niflumic acid: caffeine (1: 1) and its components in pure form.

Information confirming the reproducibility of the invention

To obtain the claimed cocrystal used the following substances:

- niflumic acid - manufacturer Sigma-Aldrich, lot N0630, CAS 4394-00-7, ReagentPlus®;

- isonicotinamide - manufacturer company "Sigma-Aldrich", lot I17451, CAS 1453-82-3, purity 99%;

- caffeine - manufacturer "Sigma-Aldrich", lot C0750, CAS 58-08-2, ReagentPlus®;

- Methanol - analytical reagent, manufacturer Labscan, ChemMed;

- Acetone (dimethyl ketone), ChDA, GOST 2603-79, Himmed.

The new co-crystals of niflumic acid are substantially characterized by the XPRD results shown in FIGS. 1-5, and are substantially described by the DSC thermogram data shown in FIGS. 6-10. The claimed co-crystalline forms can be obtained in the solid phase.

Example 1

A mixture of 34.90 mg (0.124 mmol) of niflumic acid and 15.10 mg (0.124 mmol) of isonicotinamide was placed in an agate grinding cell in a planetary micromill, 0.05 ml of ethanol was added to the mixture (according to the ratio of 1 μl of solvent per 1 mg of mixture). 10 agate beads with a diameter of 3 mm were placed in the cell. The grinding process at a speed of 600 rpm lasted twice for half an hour with a break of 5 minutes. After grinding, the cell was left in a fume hood until the solvent residue completely evaporated. The remaining powder was a co-crystal of niflumic acid: isonicotinamide (1: 1), which was confirmed by XPRD and DSC. The resulting XPRD profile of the final product substantially corresponded to that shown in FIG. The resulting DSC thermogram of the final product substantially corresponded to that shown in Fig.6.

Example 2

A mixture of 29.62 mg (0.105 mmol) of niflumic acid and 20.38 mg (0.105 mmol) of caffeine was placed in an agate grinding cell in a planetary micromill, 0.05 ml of ethanol was added to the mixture (according to the ratio of 1 μl of solvent per 1 mg of mixture). 10 agate beads with a diameter of 3 mm were placed in the cell. The grinding process at a speed of 600 rpm lasted twice for half an hour with a break of 5 minutes. After grinding, the cell was left in a fume hood until the solvent residue completely evaporated. The remaining powder was a co-crystal of niflumic acid: isonicotinamide (1: 1), which was confirmed by XPRD and DSC. The resulting XPRD profile of the final product substantially corresponded to that shown in FIG. 2. The obtained DSC thermogram of the final product substantially corresponded to that shown in Fig. 7.

The claimed cocrystals of niflumic acid can be used to produce an agent for the treatment of rheumatoid arthritis, osteoarthrosis, ankylosing spondylitis, acute gouty arthritis; in the treatment of diseases of the soft tissues of the musculoskeletal system, such as bursitis, tendonitis, epicondylitis, etc.

Claims (1)

A co-crystalline form of niflumic acid with isonicotinamide or caffeine, where the molar ratio of niflumic acid with isonicotinamide or caffeine is 1: 1, and the co-crystal of niflumic acid with isonicotinamide has an endothermic peak of 152 to 162 ° C according to measurements using differential scanning calorimetry and peaks at 2 (°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 according to the X-ray powder diffraction measurement data, and the co-crystal of niflumic acid with caffeine has an endothermic peak from 155 to 165 ° C according to the data measured minutes using differential scanning calorimetry, and peaks at 2θ (°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 as measured by X-ray diffraction powder.

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