SI23950A - Crystal forms of xanturinic acid and methods for their preparation - Google Patents

Abstract

The present invention relates to a new crystalline form of xanthuric acid (4.8 dihydroxyquinoline-2-carboxylic acid, C10H7NO4), to processes for its preparation and to the pharmaceutical forms it contains.

Description

Crystalline forms of xanthuric acid and methods for their preparation

FIELD OF THE INVENTION

The present invention relates to a new crystalline form of xanthuric acid (4,8 dihydroxyquinoline-2carboxylic acid, C ₁₀ H ₇ NO ₄ ), to processes for its preparation and to the pharmaceutical forms containing it.

A technical problem

Xanthuric acid (4,8 dihydroxyquinoline-2-carboxylic acid, C ₁₀ H ₇ NO ₄ ) has the structural formula:

OH

Hydroxyquinoline-type compounds are potentially very promising agents for the treatment of Alzheimer's disease; (A. Budimir, et al., J. Inorg. Biochem. 105 (2011) 490). Altered (disrupted) homeostasis of metals, notably Zn ²⁺ , Cu ²⁺ and Fe ³⁺ , is known to increase the concentration of these metals in the brain, and said metal ions are directly involved in the pathogenesis of Alzheimer's disease; (A. Rauk, Chem. Soc. Rev. 38 (2009) 2698; DG Smith et al., Biochim. Biophys. Acta 1768 (2007) 1976). Agents that, as chelate ligands, would allow the re-homeostasis of metals in the brain represent great potential in the treatment of this disease.

As a polyphenolic compound, xanthuric acid acts as an antioxidant and has the ability to reduce oxidative damage to DNA. With increasing concentration of xanthuric acid, DNA damage is reduced (Silvia Lopez-Burillo, Dun-Xian Tan, Juan C. Mayo, Rosa M. Sainz, Lucien C. Manchester

-2and Russel J. Reiter, J. Pineal Res. 34 (2003) 269-277). Xanthuric acid has been found to efficiently purify peroxyl radicals in antioxidant activity (S. Christen, E. Peterhans, R. Stocker, Proc. Natl. Acad. Sci. USA, 87 (1990) 2506).

Xanthuric acid has also been used in the preparation of a highly sensitive electrochemical measurement sensor (Francisco de Assis dos Santos Silva, Cleylton Bezerra Lopes, Erivaldo de Oliveira Costa, Phabyanno Rodrigues Lima, Lauro Tatsuo Kubota, Marilia Oliveira Fonseca Goulart, Electrochemistry Communications 12). 450-454). The polyfunctionality of xanthuric acid, which enables its antioxidant as well as its pro-oxidant activity, was the main reason that it was used to modify the electrode in the manufacture of the sensor for electrochemical measurements.

The chelating and antioxidant action of xanthuric acid represents a wide potential for the development of pharmaceutical applications. For incorporation into the pharmaceutical form, the active ingredients must have suitable physicochemical properties, such as e.g. high purity, adequate crystallinity, adequate thermodynamic as well as chemical stability, adequate solubility, adequate dissolution rate and compatibility with excipients. These properties depend largely on the crystalline form of the active substance. Similar to the development of pharmaceutical applications, the crystalline form of xanthuric acid plays an important role in the development of electrochemical sensors.

Therefore, there is a need for new crystalline forms of xanthuric acid, which have adequate thermodynamic stability, an adequate degree of crystallinity and are suitable for incorporation into pharmaceutical forms as well as for the production of electrochemical sensors.

The present invention satisfies this need, since the object of the invention is a novel crystalline form of xanthuric acid with improved thermodynamic stability and a high degree of crystallinity, the process of its preparation and the pharmaceutical forms containing it.

The state of the art

Xanthuric acid was first prepared as early as 1941 in a multi-step synthesis of the sodium salt of oxaloacetate ester and 2-methoxyaniline (L. Musajo, M. Minchilli, Ber., 74B, 1842 (1941)). The authors determined the melting point of the isolated compound at 283-285 ° C.

-3 Repeated synthesis by the same method (E. C. Miller, C. A. Baumann, J. Biol. Chem. 157 (1945) 551) resulted in the product having a melting point at 281-283 ° C. The same authors cite a melting point at 281-284 ° C in a later article (E. C. Miller, C. A. Baumann, J. Biol. Chem. 159 (1945) 173).

Xanthuric acid isolated from rat urine had a melting point at 250 ° C (C. C. Porter, I. Clark, R. H. Silber, J. Biol. Chem. 167 (1947) 573).

Subsequently, the original synthesis process was optimized. (A. D. Mebane, W. Oroshnik, J. Am. Chem. Soc., 73 (1951) 3520). The authors derived from the sodium salt of oxaloacetate ester and 2-methoxyaniline, and the isolation process was simplified. The authors state that at pH 6.95, xanthuric acid has two broad absorption bands in the ultraviolet part of the spectrum at 243 and 342 nm.

Further enhancement of the synthesis results from ethyl oxaloacetate ester and 2-methoxyaniline (A. Furst, C. Olsen, J. Org. Chem. 16 (1951) 412). The xanthuric acid obtained had a melting point at 284 ° C and two broad absorption bands in the UV part of the spectrum at about 240 and 340 nm. The authors also state that xanthuric acid forms anisotropic tile crystals, light to dark yellow in color.

Crystallization in 95% methanol prepared crystals of xanthuric acid monohydrate and determined its crystalline structure. The compound crystallizes in the monoclinic space group P2i (N. Okabe, J.Miura, A. Shimosaki, Acta Cryst. C52 (1996) 663).

There is one crystalline form of anhydrous xanthuric acid on the market, which we have called crystalline form I.

DETAILED DESCRIPTION OF THE INVENTION

The subject of the invention is a new crystalline form of xanthuric acid without bound water, with improved thermodynamic stability and a high degree of crystallinity, which enables easy handling, storage and incorporation of said crystalline form into pharmaceutical forms.

The subject of the invention is also a method of preparing a new crystalline form of xanthuric acid and pharmaceutical formulations containing a new crystalline form of xanthuric acid.

The invention also relates to electrochemical sensors containing a new crystalline form of xanthuric acid.

The new crystalline form of xanthuric acid, named in the present invention as crystalline form II, is characterized by deflections in the X-ray powder diagram at about 14.4, 26.9, 27.4, 29.0 ± 0.2 degrees two-theta. Crystalline form II of xanthuric acid is further characterized by x-ray deposition

powder diagram at about 14.4, 15.0, 15.5, 18.8, 21.0, 24.5, 25.2, 26.2, 26.9, 27.4, 29.0 ± 0, 2 degrees two-theta. Further, crystalline form II of xanthuric acid is indicated by an X-ray powder diffractogram as shown in Figure 2.

Crystalline form II of xanthuric acid can also be characterized by its existence as a twin ion in the orthorhombic crystal structure in the Pbca space group with dimensions of the base cell: a = 7,773 (10) A, b = 12,7 (2) A, c = 16.8 (2) A.

Furthermore, crystalline form II of xanthuric acid is characterized by having a melting point in the range of 290 ° C to 310 ° C, preferably at 297 ± 1 ° C.

Furthermore, crystalline form II of xanthuric acid is characterized in that, by thermogravimetric analysis, the compound is stable to the melting point and then 100% decomposes in two steps up to 700 ° C.

Data on the chemical equilibria of xanthuric acid in aqueous solutions show an extremely complex picture where it occurs in various chemical species. With such a complex system, different solvents and their combinations play a particularly important (decisive) role in the stabilization of individual crystalline forms. Only by choosing the right solvents can the corresponding crystalline form of xanthuric acid be obtained, which is a demanding, time-consuming and unpredictable process.

The subject of the invention is also a process for the preparation of crystalline form II of xanthuric acid, characterized in that it contains the steps of:

a) preparing a mixture of xanthuric acid in an appropriate solvent or solvent mixture,

b) crystallization of crystalline Form II xanthuric acid from a mixture of step a),

c) optional isolation of the resulting precipitate

Preferably, the xanthuric acid mixture of step a) is prepared in an organic solvent or a mixture of organic solvent and water, more preferably the solvent is a mixture of water and an organic solvent, the organic solvent preferably comprising acetone, acetonitrile or alcohol, the alcohol being preferably ethanol. Preferably, the ratio of water to organic solvent is greater than 1: 1, more preferably 3: 1.

The mixture of step a) of the present invention can preferably be heated under reflux for at least 1 hour, more preferably for at least 4 hours, or exposed to stirring for at least 1 hour, preferably at room temperature (about 25 ° C).

-5Crystallisation of crystalline Form II xanthuric acid in step b) may occur spontaneously or may be induced, preferably by evaporation of the solvent, lowering of the temperature of the reaction mixture, or a combination of both. More preferably crystallization is achieved by keeping the mixture under controlled conditions (preferably in an incubator at about 37 ° C, preferably for more than 1 day, more preferably for more than 1 week) by simultaneously evaporating the solvent slowly or by cooling the mixture and subsequently storing it at a temperature of about 5 ° C (preferably more than 1 day, more preferably more than 1 week) or by feeding the mixture under controlled conditions (preferably in an incubator at about 37 ° C, preferably more than 1 day, more preferably more than 1 week) with slow evaporation of the solvent and subsequent cooling of the mixture and keeping it at a temperature of about 5 ° C (preferably more than 1 day, more preferably more than 1 week).

Further, the present invention is a process for the preparation of crystalline Form II xanthuric acid, characterized in that it contains the steps of:

a) preparing a mixture of xanthuric acid in the presence of tetrabutylammonium bromide in a suitable solvent or solvent mixture,

b) crystallization of crystalline Form II xanthuric acid from a mixture of step a),

c) optional isolation of the resulting precipitate

Preferably, the xanthuric acid mixture of step a) is prepared in an organic solvent or a mixture of organic solvent and water, more preferably the solvent is an alcohol or a mixture of alcohol and water, preferably the alcohol is ethanol. Preferably, the amount ratio of xanthuric acid to tetrabutylammonium bromide is 1: 1.

The mixture of step a) of the present invention can preferably be heated under reflux for at least 1 hour, more preferably for at least 4 hours, or exposed to stirring for at least 1 hour, preferably at room temperature (about 25 ° C).

Crystallization of crystalline Form II xanthuric acid in step b) can occur spontaneously or can be induced, preferably by solvent evaporation, lowering of the reaction mixture temperature, or a combination of both. More preferably crystallization is achieved by keeping the mixture under controlled conditions (preferably in an incubator at about 37 ° C, preferably for more than 1 day, more preferably for more than 1 week) by simultaneously evaporating the solvent slowly or by cooling the mixture and subsequently storing it at a temperature of about 5 ° C (preferably more than 1 day, more preferably

-6 more than 1 week) or by keeping the mixture under controlled conditions (preferably in an incubator at about 37 ° C, preferably for more than 1 day, more preferably for more than 1 week) by simultaneously evaporating the solvent and subsequently cooling the mixture and storing it at at a temperature of about 5 ° C (preferably more than 1 day, more preferably more than 1 week).

Preferably, the process for the preparation of crystalline Form II xanthuric acid according to the present invention is characterized in that it contains the steps of:

a) preparation of a mixture of xanthuric acid in a mixture of water and acetone,

b) heating the mixture from step a) under reflux, preferably for 6 hours,

c) storing the mixture under controlled conditions (preferably in an incubator at about 37 ° C) with simultaneous slow evaporation of the solvent and subsequently cooling the mixture and keeping it at a temperature of about 5 ° C;

d) isolating the resulting precipitate

The present invention also relates to pharmaceutical forms containing crystalline form II of xanthuric acid, or to pharmaceutical forms where, in the process of preparing such forms, crystalline form II of xanthuric acid is used, or to pharmaceutical forms containing crystalline form II prepared by the processes subject to of this invention. The pharmaceutical forms of the present invention may be e.g. tablets, capsules, pellets, granules or combinations thereof. These may be immediate-form and modified-release pharmaceutical forms. The pharmaceutical forms of the present invention further comprise at least one other pharmaceutically acceptable excipient.

The present invention also relates to electrochemical sensors containing crystalline form II of xanthuric acid.

The present invention is further illustrated by way of example examples and figures.

Short description of the pictures

Figure 1 is an X-ray powder diffractogram of crystalline Form I xanthuric acid.

Figure 2 is an X-ray powder diffractogram of crystalline Form II xanthuric acid.

-7Figure 3 represents a single crystal of crystalline form II of xanthuric acid.

Figure 4 is an ORTEP image of a xanthuric acid crystalline Form II twin ion.

Figure 5 is an ORTEP image of a xanthuric acid crystalline Form II twin ion with hydrogen bonds shown.

Figure 6 shows the IR spectrum of crystalline form I xanthuric acid.

Figure 7 shows the IR spectrum of crystalline form II xanthuric acid.

Figure 8 shows a comparison of the IR spectra of crystalline forms I and II of xanthuric acid.

Figure 9 shows the thermal decay curves of crystalline forms I and II of xanthuric acid.

Figure 10 shows the DSC curves of crystalline forms I and II of xanthuric acid.

Analytical methods

1. X-ray powder diffraction (XRD-P)

Samples were taken on a PANalytical X'Pert PRO MPD powder diffractometer (CuKa radiation, 1.54178 A). Two-theta angles were measured in degrees, the error at peak positions is up to ± 0.2 degrees. X-ray powder diffractograms of xanthuric acid crystalline Form II samples show, regardless of the method of preparation, typical deviations at about 14.4, 26.9, 27.4, 29.0 ± 0.2 degrees two-theta, or about 14.4, 15.0, 15.5, 18.8, 21.0, 24.5, 25.2, 26.2, 26.9, 27.4, 29.0, 44.0, 56.6, 60, 0 ± 0.2 degrees dwt. Xanthuric acid crystalline Form I is characterized by x-ray powder diagram at about 10.4, 14.8, 15.3, 17.9, 18.5, 20.1, 20.8, 21.9, 25.8 , 26.1, 26.5, 27.2 ± 0.2 degrees two-theta The characteristic diffractograms of crystalline forms I and II of xanthuric acid are shown in Figures 1 and

2.

2. X-ray structural analysis of single crystals (XRD-M)

Monocrystals of crystalline form II xanthuric acid, suitable for X-ray structural analysis, were prepared by recrystallization in acetone-water. The single crystals are presented in Figure 3. The data for the X-ray structural analysis on the single crystal were recorded on a Nonius Kappa CCD diffractometer

-8 Using monochromatic Μο-Κα radiation. The compound crystallizes in the orthorhombic space group Pbca with the dimensions of the base cell:

a 7,773 (10) A b 12.7 (2) A c 16.8 (2) A

Figure 4 shows the ORTEP image of the xanthuric acid twin ion. The crystal structure of xanthuric acid is built by twin ions. In these ions, the carboxyl group is deprotonated and the nitrogen in the quinoline ring is protonated. Both hydroxyl groups still have hydrogen. The hydrogen bonds formed by the twin ion are shown in Figure 5. Interestingly, there is no hydrogen bond between the protonated nitrogen in the quinoline ring and the deprotonated carboxyl group. The hydrogen bonds form oxygen from both hydroxyl groups and, as can be seen from Figure 5, both oxygen from the carboxylate.

The distances between the donor and acceptor atoms involved in hydrogen bonds are short, indicating that the hydrogen bonds are strong.

3. Infrared spectroscopy (FT-IR)

The infrared spectra of both crystal modifications were recorded by ATR technique on a PerkinElmer Paragon 1000 FTIR spectrometer in the range of 4000-600 cm ^-1 . Figure 6 shows the IR spectrum of crystalline Form I, Figure 7 shows the IR spectrum of polymorphic Form II, and Figure 8 compares the two IR spectra of crystalline Form I and Form II xanthuric acid. In the IR spectrum of both crystalline forms, a sharp peak of about 3300 cm ^{-1 is} observed for N ⁺ -H longitudinal wave oscillation. The spectra differ in peak at 3073 cm ^-1 for CH aromatic valence oscillation, which is pronounced in shape I, while it is not observed in the spectrum of form II because it is hidden in a wide range of 3200-2300 cm ^-1 , where it occurs longitudinal wave oscillation of the quinoline and phenolic OH groups. The difference between the two IR spectra is also observed in the rest of the FT-IR fingerprint range. From the IR spectrum of the two acids, it is evident that both crystalline forms appear as twin ions, since we do not find a peak for the COOH group but a peak for the COO 'and N ⁺ -H oscillations.

4. Thermal analysis (thermogravimetry, TG and dynamic differential calorimetry, DSC)

Figure 9 shows the TG curves of thermal decay of crystalline forms I and II of xanthuric acid in the range of 25 to 700 ° C, and Figure 10 shows the DSC curves for both modifications. The compounds merge in

temperature range 250 - 310 ° C, as shown in the DSC curve, where a sharp, endothermic band is observed. This is followed by the breakdown of the compounds. The breakup takes place in two stages. The DSC curve shows that the first stage of thermal decay is endothermic and the second is exothermic. Both compounds decompose completely because the weight loss is 100% and the crucibles were empty after completion of thermogravimetric analysis.

Comparison of thermograms shows that Form II is more thermally stable than Form I because it melts at a higher temperature (Form II at ~ 300 ° C, Form I at ~ 280 ° C).

Implementing examples:

Crystalline Form I xanthuric acid was purchased from Sigma-Aldrich (AL-D120804-5G, Lot .: STBB6490).

Example 1 (Formation of crystalline Form II xanthuric acid in water-acetone mixture) mg of xanthuric acid Form I was suspended in a mixture of 225 ml of distilled water and 75 ml of acetone (H ₂ O: acetone = 3: 1). The reflux was refluxed for 6 hours, with the crystals dissolving. Cover the beaker with parafilm, into which three holes are made with a needle and placed in an incubator at 37 ° C. After 20 days of slow evaporation of the solvent, the brown (olive green) crystals of xanthuric acid form II precipitate. Yield 22-24 mg.

Example 2 (Formation of crystalline Form II xanthuric acid in water-acetone mixture) mg of xanthuric acid Form I was suspended in a mixture of 150 ml of distilled water and 50 ml of acetone (H ₂ O: acetone = 3: 1). The reflux was refluxed for 6 hours, with the crystals dissolving. Cover the beaker with parafilm, into which three holes are made with a needle and placed in an incubator at 37 ° C. After 20 days of slow evaporation of the solvent, the brown (olive green) crystals of xanthuric acid form II precipitate. Yield 46-48 mg.

-10Example 3 (Formation of crystalline Form II xanthuric acid in water-acetone mixture) mg of xanthuric acid Form I was suspended in a mixture of 225 ml of distilled water and 75 ml of acetone (H _Z O: acetone = 3: 1). The reflux was refluxed for 6 hours, with the crystals dissolving. Cover the beaker with parafilm, into which three holes are made with a needle and placed in a refrigerator at 5 ° C. After five weeks, yellow-brown form II xanthuric acid crystals begin to appear. After two months, filter and dry. Yield 8-13 mg.

Example 4 (Formation of crystalline form II xanthuric acid in an alcohol solution of tetrabutylammonium bromide) mg of xanthuric acid form I was added 39.3 mg of tetrabutylammonium bromide (xanthuric acid: tetrabutylammonium bromide = 1: 1) and 150 mL of ethanol (96%) and stirred for 4 hours at room temperature with a magnetic stirrer. When the crystals are dissolved, place them in an incubator at 37 ° C. After 20 days of slow evaporation, a yellow precipitate disappears. Yield 5-10 mg.

Example 5 (Formation of crystalline Form II xanthuric acid in an alcohol solution of tetrabutylammonium bromide) mg of xanthuric acid form I was added 39.3 mg of tetrabutylammonium bromide (xanthuric acid: tetrabutylammonium bromide = 1: 1) and a mixture of water ethanol (120 mL distilled water) ethanol). Reflux for 4 hours. After refluxing, cover the beaker with parafilm, make three holes in parafilm and place the beaker in an incubator at 37 ° C. After 20 days of slow evaporation, a light yellow precipitate appears. Yield 5-10 mg.

Example 6 (Formation of crystalline Form II by admixture of Form I xanthuric acid in aqueous ethanol) mg of xanthuric acid Form I was suspended in a mixture of 225 ml of distilled water and 75 ml of ethanol (H ₂ O: ethanol = 3: 1). The reflux was refluxed for 6 hours, with the crystals dissolving. Glass

-11 cover with parafilm into which three holes are made with a needle and placed in an incubator at 37 ° C. After 20 days of slow evaporation of the solvent, brown (olive green) crystals of xanthuric acid li form. The product is xanthuric acid Form II with Form I admixture. Yield 1015 mg.

Example 7 (Formation of crystalline Form II in aqueous acetonitrile) mg of xanthuric acid Form I was suspended in a mixture of 225 ml of distilled water and 75 ml of acetonitrile (H ₂ O: acetonitrile = 3: 1). The reflux was refluxed for 6 hours, with the crystals dissolving. Cover the beaker with parafilm, into which three holes are made with a needle and placed in an incubator at 37 ° C. After 20 days of slow evaporation of the solvent, the brown (olive green) crystals of xanthuric acid form II precipitate. The product is xanthuric acid form II with a formulation admixture

Claims (9)

Patent claims 1. The crystalline form of xanthuric acid having the following characteristics: - by x-ray powder diffraction at 14.4, 26.9, 27.4, 29.0 ± 0.2 degrees two-theta; and / or - by x-ray powder diffraction at 14.4, 15.0, 15.5, 18.8, 21.0, 24.5, 25.2, 26.2, 26.9, 27.4, 29, 0 ± 0.2 degrees two-theta; and / or - by X-ray powder diffraction pattern as shown in Figure 2. The crystalline form of xanthuric acid according to claim 1, further characterized in that it exists in the orthorhombic crystal structure in the space group Pbca with the dimensions of the base cell: a = 7,773 (10) A, b = 12,7 (2) A, c = 16.8 (2) A. The crystalline form of xanthuric acid according to claim 1 or 2, further characterized by a melting point in the range of 290 ° C to 310 ° C, preferably at 297 ± 1 ° C. The crystalline form of xanthuric acid according to any one of claims 1 to 3, further characterized in that, by thermogravimetric analysis, the compound is stable to the melting point and then 100% decomposes in two steps up to 700 ° C. 5. A process for the preparation of the crystalline form of xanthuric acid according to claims 1-4, characterized in that it contains the steps of: a) preparing a mixture of xanthuric acid in an organic solvent or a mixture of an organic solvent and water, more preferably a mixture of water and an organic solvent, preferably comprising acetone, acetonitrile or alcohol, the alcohol being preferably ethanol; b) crystallization of crystalline Form II xanthuric acid from a mixture of step a); and c) optional isolation of the resulting precipitate. Method for the preparation of the crystalline form of xanthuric acid according to claims 1 - 4, characterized in that it contains the steps of: a) preparation of a mixture of xanthuric acid in the presence of tetrabutylammonium bromide in an organic solvent or a mixture of organic solvent and water, more -13 preferably the solvent is alcohol or a mixture of alcohol and water, preferably the alcohol is ethanol; b) crystallization of the crystalline form of xanthuric acid according to claims 1-4 from the mixture of step a); and c) optional isolation of the resulting precipitate. A process for the preparation of the crystalline form of xanthuric acid according to claims 1-4, characterized in that it contains the steps of: a) preparation of a mixture of xanthuric acid in a mixture of water and acetone; b) heating the mixture from step a) under reflux, preferably for 6 hours; c) storing the mixture under controlled conditions (preferably in an incubator at about 37 ° C) with the simultaneous slow evaporation of the solvent and subsequent cooling of the mixture and keeping it at a temperature of about 5 ° C; and d) isolating the resulting precipitate. A pharmaceutical form comprising the crystalline form of xanthuric acid according to any one of claims 1 to 4. A pharmaceutical form comprising the crystalline form of xanthuric acid prepared by the method of any one of claims 5 to 7. Intensity = Intensity