RU2521595C2 - Crystalline form ii of tilorone and method of obtaining thereof (versions) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel stable crystalline polymorphic modification of form II of tilorone and to versions of a method of its obtaining. Tilorone is used as an anti-viral and immunomodulating substance. The crystalline form II of tilorone is characterised by a powder radiograph, which has characteristic peaks at the following values of 2θ (°): 4.39 8.82 10.53 11.94 12.14 12.37 12.73 13.10 13.29 15.14 16.43 20.72 22.57 23.89 24.11 24.49 24.71 25.70 26.28 26.55 27.42 28.78 30.82 31.60 31.95 33.27 34.82. The method of obtaining the crystalline form II of tilorone includes tilorone purification by dissolution at heating in a mixture of isopropanol and a polar solvent, selected from ethanol and water, separation of non-dissolved admixtures from the tilorone solution and spontaneous cooling of the solution with formation of crystals of the crystalline form II of tilorone, which are separated from admixtures, dissolved in the solution. Tilorone purification can also be performed by dissolution of tilorone at heating in the polar solvent, selected from ethanol and water, with separation of non-dissolved admixtures from the tilorone solution and precipitation of crystals of the crystalline form II of tilorone from the solution by isopropanol, with crystals being separated from admixtures, dissolved in the solution, in conditions of slow cooling.

EFFECT: obtaining the novel stable crystalline polymorphic modification of tilorone of form II.

14 cl, 5 tbl, 4 dwg, 6 ex

Description

This invention relates to a new crystalline form II of tilorone and to an industrial method for its preparation.

Tiloron, whose chemical name is 2,7-bis [2- (diethyl-amino) ethoxy] fluorenone dihydrochloride, is currently widely used in medical practice as an antiviral and immunomodulating substance.

US Pat. No. 3,592,819, published in 1971, describes crystalline tilorone, which is obtained from tilorone by recrystallization from a mixture of isopropanol and methanol in a 3: 1 ratio. At the same time, tiloron with a melting point of 232-233 ° C is isolated.

In the article DAN USSR, ser. B, "Geol., Chem., Biol. Science. ”- 1976, No. 7, pp. 610-611 - describes tilorone in the form of a crystalline orange powder with a melting point of 233-235 ° C, which is isolated by purification of tilorone by recrystallization from a mixture of isopropanol and methanol. The IR spectrum recorded in KBr presented in the article is characterized by absorption bands at the following values of cm ^-1 : 1715 C = O, 1615 CN (CH ₃ ) ₂ ⁺ , 1050 COC.

In the article Syn.Comm. - 1976, V.6, No. 5, pp.371-376 — a crystalline tiloron with a melting point of 232-234 ° C is described, its infrared spectrum recorded in KBr has characteristic absorption bands at the following values of cm ^-1 : 2930, 2600 , 1700, 1600, 1460, 1235. Tiloron is obtained after additional purification by recrystallization from a mixture of isopropanol and methanol in a ratio of 3: 1.

In J.Med.Chem. - 1978, V.21, No. 10, pp.1084-1086 — an orange crystalline tilorone with a melting point of 228-233 ° C is described, the IR spectrum of which is recorded in KBr, differs somewhat from that presented above and is characterized by absorption bands in the following cm ^-1 values: 3150, 2980, 2890, 2655, 1705, 1610, 1460, 1245, 795, 689. Tiloron obtained by the method described in article J. Med. Chem. - 1974, V.17, No. 8, pp.882-886, by recrystallization from a mixture of isopropanol with methanol in a ratio of 3: 1. However, crystalline tilorone with a melting point of 235-236 ° C is obtained in this article. Thus, in these articles, crystalline tilorone having a different melting point is obtained in the same way, which indicates poor reproducibility of this method of producing crystalline tilorone.

Patent RU 2076097 describes tilorone in the form of an orange with a pinkish tint powder with a melting point of 234-235 ° C, which is obtained from diiodofluorenone by alkylation in a solution of dimethylformamide followed by conversion of the tilorone base into the final product by suspension in water and treatment with 20% hydrochloric acid with the allocation of crystalline tilorone from the reaction mixture without recrystallization.

Patent RU 2218327 describes pure tilorone in the form of an orange crystalline powder with a melting point of 233-235 ° C, which is obtained from a tilorone base purified from impurities by washing with water, dissolving in hexane, then transferring it to acetone and treating with concentrated hydrochloric acid to isolate tilorone crystals, which are purified from impurities by recrystallization from isopropanol.

In the patent RU 2317974, crystalline tiloron is obtained with a melting point of 237-238 ° C from the reaction mixture of the toluene solution of the tilorone base treated with 35% hydrochloric acid, evaporation of the mixture until the water evolution ceases (in the form of an azeotropic toluene-water mixture) and crystallization from the reaction mixtures of toluene-water-hydrochloric acid.

RU 2375345 provides crystalline tiloron with a melting point of 234-235.5 ° C by treating the tiloron base in methylene chloride with dry gaseous hydrogen chloride or concentrated hydrochloric acid and subsequent crystallization from the reaction mixture.

In the documents described above, crystalline tilorone is obtained directly from the reaction mixture upon receipt of dihydrochloride and after further purification by recrystallization from a solvent, and the obtained tiloron differs in melting temperature, as well as in the values of the characteristic absorption bands of the infrared spectrum.

Studies of recent decades in the field of analysis of pharmaceutical substances obtained in the form of crystalline organic compounds have shown that organic compounds, depending on their crystal structure, have various physicochemical properties, such as solubility, hygroscopicity, electrostaticity, melting point and others, which , in turn, affect their biopharmacological and pharmacotechnological properties, as well as the stability of finished drugs containing e and substance. The establishment of polymorphism - the existence of a pharmaceutical substance in the form of several crystalline polymorphic modifications is of great importance in the identification and determination of the quality of finished drugs, which include this pharmaceutical substance.

At the moment, no data on the polymorphism of tilorone are found in an open publication; at the same time, tiloron is described in the cited sources, the infrared spectra of which have some differences, and the melting temperature is given in the range of 228-238 ° C, which may indirectly indicate the polymorphism of tiloron .

The objective of the invention is to obtain industrially tilorone in a stable crystalline form and the determination of its crystalline structure.

The problem is solved by the fact that two stable crystalline forms of tilorone are obtained industrially: the known crystalline form I of tilorone and the new crystalline form II of tilorone.

The problem is solved in that the crystal structure of I and II crystalline forms of tilorone is established and their characteristic distinguishing features are determined.

Crystalline polymorphic form I of tilorone, characterized by the following x-ray diffraction parameters:

2θ d (Å) I / I ° 4.03 21.9278 70 8.11 10.8972 eleven 10.57 8.3660 13 12.21 7.2410 53 12.64 6.9989 17 13.35 6.6259 27 14.70 6.0215 fifteen 16.14 5.4862 fifteen 16.36 5.4131 13 01/17 5.2095 77 17.41 5.0899 26 18.88 4.6967 21 19.50 4.5483 eleven 21.36 4.1557 47 22.83 3.8924 eleven 08/23 3.8502 12 23.65 3.7587 twenty 24.61 3.6146 7 25.19 3.5322 one hundred 25.47 3.4943 36 25.80 3.4505 32 26.46 3.3654 10 26.77 3.3269 12 27.18 3.2786 42 03/28 3.1810 13 28.35 3.1453 eighteen 29.60 3.0158 fifteen

The invention relates to a stable crystalline polymorphic form II of tilorone, characterized by the following parameters of x-ray diffraction:

2θ d (Å) I / I ° 4.39 20.1341 one hundred 8.82 10.0169 2 10.53 8.3979 12 11.94 7.4070 16 12.14 7.2833 10 12.37 7.1500 10 12.73 6.9510 10 13.10 6.7518 10 13.29 6.6587 eleven 15.14 5.8485 thirty 16.43 5.3919 26 20.72 4.2828 24 22.57 3.9372 29th 23.89 3.7218 eighteen 11/24 3.6878 29th 24.49 3.6326 39 24.71 3.6006 21 24.99 3.5600 8 25.70 3.4639 38 26.28 3.3888 12 26.55 3.3547 32 27.42 3.2499 9 28.78 3.1000 twenty 30.82 2.8991 10 31.60 2.8288 twenty 31.95 2.7985 21 33.27 2.6905 10 34.82 2.5742 10

The invention relates to an industrial method for producing crystalline polymorphic form II of tilorone.

Figure 1 presents a powder x-ray diffraction pattern of crystalline polymorphic form I of tilorone.

Figure 2 presents the x-ray powder diffraction pattern of crystalline polymorphic form II tilorone.

Figure 3 presents the IR spectrum of crystalline polymorphic form I of tilorone.

Figure 4 presents the IR spectrum of crystalline polymorphic form II of tilorone.

When developing an industrial method for obtaining a stable crystalline form of tilorone, it was necessary to take into account current trends in the use of the least toxic reagents in the technological process, which allows one to obtain a stably reproducible crystalline form of pharmacopoeial tilorone that does not contain residual toxic solvents. Studies have been conducted on the preparation of pharmacopoeial tilorone by a method involving the purification of tilorone from impurities obtained at the stage of salt formation by recrystallization of tilorone from a solution of a mixture of polar non-toxic solvents. For recrystallization, mixtures of two polar protic solvents were used, one of which is isopropanol, the other ethanol or water.

In determining the most optimal conditions for a method of obtaining a stable crystalline form of pure tiloron, which is stably reproduced under industrial conditions, unexpectedly two crystalline products were obtained that visually differed in color, shape and size of crystals, as well as the values of characteristic absorption bands of the infrared spectrum. By the method of X-ray diffraction analysis based on the data of powder X-ray diffraction patterns, the crystal structure of these products was established and it was proved that stable crystalline forms of tilorone were obtained - crystalline form I and crystalline form II (Figs. 1 and 2).

By comparing the infrared spectra of crystalline forms I and II with a commercial sample from Sigma-Aldrich (melting point 230-233 ° C), the spectra of crystalline forms I and commercial samples are identical, as a result of which tilorone crystalline form I is recognized.

A method of obtaining a stable crystalline form I of tilorone is as follows.

Tiloron is dissolved by heating in a mixture of isopropanol and a non-toxic polar solvent with a ratio of tiloron: isopropanol 1: 3 ÷ 8 and a ratio of tiloron: non-toxic polar solvent 1: 0.2 ÷ 3.5. The hot tilorone solution is separated from insoluble impurities and forcedly cooled to form crystals of stable crystalline form I tilorone, which are separated from impurities dissolved in the solution.

In the course of research, alternative industrial methods for the preparation of a new crystalline form of tilorone II were developed.

A method of obtaining a stable crystalline form II of tilorone is as follows.

Tiloron is dissolved by heating in a mixture of isopropanol and a non-toxic polar solvent with a ratio of tiloron: isopropanol 1: 3 ÷ 8 and a ratio of tiloron: non-toxic polar solvent 1: 0.2 ÷ 3.5. The hot tilorone solution is separated from insoluble impurities and spontaneously cooled to form crystals of stable crystalline form II of tilorone, which are separated from impurities dissolved in the solution.

An alternative method of obtaining a stable crystalline form II of tilorone is as follows.

Tiloron is dissolved by heating in a nontoxic polar solvent, with a ratio of tiloron: nontoxic polar solvent 1: 0.5 ÷ 3.0. The tiloron solution is separated from insoluble impurities and crystals of stable crystalline form II of tiloron are precipitated from the solution with isopropanol, which are separated from impurities dissolved in the solution with slow cooling.

Ethanol or water is used as a non-toxic polar solvent.

Comparison of the characteristics of the most significant peaks of powder X-ray diffraction patterns of crystalline forms I and II of tilorone (Tables 1 and 2).

Table 1 table 2 Characterization of the most significant peaks of form I Characterization of the most significant peaks of form II 2θ d (Å) I / I ° 2θ d (Å) I / I ° 4.03 21.9278 70 4.39 20.1341 one hundred 8.11 10.8972 eleven 8.82 10.0169 2 10.57 8.3660 13 10.53 8.3979 12 12.21 7.2410 53 11.94 7.4070 16 12.64 6.9989 17 12.14 7.2833 10 13.35 6.6259 27 12.37 7.1500 10 14.70 6.0215 fifteen 12.73 6.9510 10 16.14 5.4862 fifteen 13.10 6.7518 10 16.36 5.4131 13 13.29 6.6587 eleven 01/17 5.2095 77 15.14 5.8485 thirty 17.41 5.0899 26 16.43 5.3919 26 18.88 4.6967 21 20.72 4.2828 24 19.50 4.5483 eleven 22.57 3.9372 29th 21.36 4.1557 47 23.89 3.7218 eighteen 22.83 3.8924 eleven 11/24 3.6878 29th 08/23 3.8502 12 24.49 3.6326 39 23.65 3.7587 twenty 24.71 3.6006 21 24.61 3.6146 7 24.99 3.5600 8 25.19 3.5322 one hundred 25.70 3.4639 38 25.47 3.4943 36 26.28 3.3888 12 25.80 3.4505 32 26.55 3.3547 32 26.46 3.3654 10 27.42 3.2499 9 26.77 3.3269 12 28.78 3.1000 twenty 27.18 3.2786 42 30.82 2.8991 10 03/28 3.1810 13 31.60 2.8288 twenty 28.35 3.1453 eighteen 31.95 2.7985 21 29.60 3.0158 fifteen 33.27 2.6905 10 34.82 2.5742 10

Where I / I ° is the relative intensity (expressed as a percentage of the most intense beam).

X-ray powder diffraction patterns from 2 to 40 ° 2θ (for CuKα), obtained on a Huber / Guinier G670 diffractometer, CuK _α1 - radiation, λ = 1.54059 Å, light transmission survey in the angular range 4-80 ° 20Ө voltage 45 kV, current 35 mA , the slit width after the curved germanium monochromator is 2 mm, the coordinate fixed detector in the form of a plate sensitive to x-ray radiation (IP, Image Plate).

Processing of experimental data, determination and refinement of the crystal structure was carried out using the MRIA software package.

The crystallographic data characterizing the unit cell parameters in the form of values of a, b, c, α, β, γ, obtained as a result of X-ray diffraction analysis of a single crystal of powder of form I and form II, clearly demonstrate the differences between the studied polymorphic modifications of tilorone (Table 3).

Table 3 Crystallographic data of crystalline forms of tilorone Unit Cell Parameters of Form I Unit Cell Parameters Form II a 8.35 a 7.38 b 43.22 b 39.82 c 7.07 c 8.56 α 90 α 90 β 93.77 β 90 γ 90 γ 90 z four z four Volume 2546 A ³ Volume 2516 A ³ Syngonia Symmetry Group Monoclinic P21 / C Syngonia Symmetry Group Rhombic Pna21

As a result of the study, the distinctive features of crystalline forms of tilorone were found and it was found:

- crystalline form I is a pale orange crystalline powder;

- crystalline form II is a bright orange crystalline powder;

- crystalline form I and crystalline form II are stable and do not spontaneously pass one into another, including during mechanical action (mixing and grinding of these forms);

- in the drying process to remove residual organic solvents in the case of crystalline form II, you can use more gentle drying modes than for crystalline form I;

- crystalline form II is more hygroscopic than crystalline form I, the values of which are determined by the following formula: (m ₃ -m ₂ / m ₂ -m ₁ ) × 100, where m ₁ , m ₂ , m ₃ is the weight of the box, the weight of the original crystalline form and a weighed sample of the corresponding crystalline form after exposure to a saturated solution of ammonium chloride in a desiccator at 25 ° C for 24 hours (table 4);

- crystalline form I and crystalline form II are very soluble in water and soluble in absolute ethanol in accordance with GP XII (solubility in absolute ethanol has the following meanings: form I - 1:19 g / ml; form II - 1:18, g / ml);

- crystalline form II, less electrostatic than crystalline form I, therefore, crystalline form II is more convenient for the manufacture of finished medicines, in the form of tablets, capsules, powders.

Table 4. Hygroscopicity characteristic of crystalline forms of tilorone Crystalline form m ₁ , g m ₂ , g m ₃ , g Actual hygroscopicity,% European Pharmacopoeia EP 7, c 637 Form I 29.9735 30.9616 31.0513 9.08 Hygroscopic Form II 29,9851 30.9060 31,1156 22.7 Very hygroscopic

The difference between crystalline form I and crystalline form II of tilorone is confirmed by infrared spectroscopy (Table 5).

Table 5. Characterization of the infrared spectrum of crystalline forms of tilorone Groups and types of vibrations Form I Form II Wavelength, cm ^-1 Wavelength, cm ^-1 (C-H) 2975 cf. 2943 cf. 2974 cf. 2941 cf. (R3N ⁺ H) 2594 s. 2526 cf. 2484 p. 2565 s. 2526 cf. 2461 s. (C = O) 1710 s. 1708 p. 1602 cf. 1610 cf. 1593 cf. 1475 s. 1446 cf. 1463 s. 1419 cl. 1411 cf. 1398 cl. 1400 cf. (C-O-C) 1298 cf. 1261 cf. 1288 p. 1238 cf. 1217 p. 1215 cl. 1170 cl. 1174 c. 1135 pp. 1137 cl. 1064 words 1040 cf. 1033 S. 1031 cf. 939 words 968 words 908 words 945 cl. 827 words 885 words 784 words 821 cf. 784 cf. 612 words 514 words

Fourier transform infrared spectra were recorded on a Shimadzu FTIR 8400 IR spectrometer, in the range of 4600-400 cm ^-1 , with a resolution of 2 cm ^-1 in a KBr tablet.

When comparing the infrared spectra of form I and form II of tilorone, significant differences can be noted in the region having the following absorption bands (cm ^-1 ):

crystalline form I tilorone:

2594, 2484, 1602, 1475, 1446, 1298, 1261, 1238

crystalline form II tilorone:

2565, 2461, 1610, 1593.1463, 1288, 1217, 1040, 1031, 821, 784

The following examples describe the invention without limiting it.

Example 1. Obtaining form I of tilorone.

112 l of toluene, 8 kg of 2,7-dihydroxyfluoren-9-one are successively charged into the reactor, then 65 kg of a 35% sodium hydroxide solution and 26.2 kg of 2-diethylaminoethyl chloride hydrochloride are added with stirring. The reaction mass is heated to boiling in a nitrogen atmosphere and maintained at this temperature for 20 hours, then the mass is cooled to 25 ° C and the organic layer is separated, which is washed successively with 20% sodium hydroxide solution (30 kg) and water (25 l). The resulting solution was dried with sodium sulfate and evaporated in vacuo. The residue is dissolved in 50 l of isopropanol and 7 kg of hydrochloric acid are added to the resulting mass with stirring. The precipitate formed is filtered off and 25 kg of tilorone containing impurities formed at the stage of salt formation are obtained. The obtained tilorone is dissolved by heating in a mixture of 60 l of isopropanol and 60 l of ethanol. The hot solution of tilorone is separated from insoluble impurities by filtration through a cartridge filter (1 μm) and forced to cool to 18-20 ° C with the formation of crystals that are separated by filtration from the mother liquor containing impurities. After drying, crystals of a stable crystalline form I of tilorone of pale orange color with a melting point of 235.3-235.7 ° C are obtained. Yield: 13.6 kg (76%).

Example 2

25 kg of tilorone, obtained as in example 1, is dissolved by heating in a mixture of 143 l of isopropanol and 5 l of water. The hot solution of tilorone is separated from insoluble impurities by filtration through a cartridge filter (1 μm) and forced to cool to 0-10 ° C with the formation of crystals that are separated by filtration from the mother liquor containing impurities. After drying, crystals of a stable crystalline form I of tilorone of pale orange color with a melting point of 234.3-235.5 ° C are obtained. Yield: 14.5 kg (80%).

Example 3

25 kg of tilorone, obtained as in example 1, is dissolved by heating in a mixture of 160 l of isopropanol and 10 l of water. The hot solution of tilorone is separated from insoluble impurities by filtration through a cartridge filter (1 μm) and spontaneously cooled to 0-20 ° C to form crystals, which are filtered by filtration from the mother liquor containing impurities. After drying, crystals of stable crystalline form II of tilorone of bright orange color with a melting point of 234.4-235 ° C are obtained. Yield: 11.9 kg (66%).

Example 4

25 kg of tilorone, obtained as in example 1, are dissolved by heating in a mixture of 70 l of isopropanol and 70 l of ethanol. The hot solution of tilorone is separated from insoluble impurities by filtration through a cartridge filter and spontaneously cooled to a temperature of 18-20 ° C with the formation of crystals, which are filtered by filtration from the mother liquor containing impurities. After drying, crystals of stable crystalline form II of tilorone bright orange are obtained with a melting point of 235-236 ° C. Yield: 12.8 kg (71%).

Example 5

25 kg of tilorone obtained as in example 1, dissolved in 15 l of water when heated (~ 60 ° C) and a hot solution of tiloron from insoluble impurities is separated by filtration through a cartridge filter (1 μm). While stirring, the hot filtrate is added to 150 L of isopropanol heated to 50 ° C, and crystals immediately precipitate, which, after spontaneous cooling of the solution by filtration, is separated from the mother liquor containing impurities. After drying, pure tilorone crystals are obtained in stable crystalline form II of a bright orange color with a melting point of 235-236 ° C. Yield 12 kg (66.7%).

Example 6

25 kg of tilorone obtained as in example 1, dissolved in 60 l of ethanol by heating (~ 74 ° C) and filtered through a cartridge filter. While stirring, the hot filtrate is added to 90 L of isopropanol heated to 50 ° C, and crystals immediately precipitate, which, after spontaneous cooling of the solution by filtration, is separated from the mother liquor containing impurities. After drying, pure tilorone crystals are obtained in stable crystalline form II of a bright orange color with a melting point of 235-236 ° C. Yield 13.9 kg (77%).

Claims (14)

1. Crystalline form II of tilorone, characterized by a powder X-ray diffraction pattern, which has characteristic peaks at the following values of 2θ (°): 4.39 8.82 10.53 11.94 12.14 12.37 12.73 13.10 13.29 15.14 16.43 20.72 22.57 23.89 24.11 24.49 24.71 25.70 26.28 26.55 27.42 28.78.28 30.8 . 2. The crystalline form II of tilorone according to claim 1, characterized by an infrared spectrum, which exhibits a characteristic absorption expressed in cm ^-1 at the following values: 2974, 2941, 2565, 2526, 2461, 1708, 1610, 1593, 1463, 1411, 1400 , 1288, 1217, 1174, 1137, 1040, 1031, 821, 784, 514. 3. The crystalline form II of tilorone according to claim 1, characterized by a powder x-ray in accordance with figure 2. 4. The crystalline form II of tilorone according to claim 1, characterized by an infrared spectrum in accordance with figure 4. 5. The method of obtaining crystalline form II of tilorone, characterized by a powder x-ray according to claim 1, which includes the purification of tilorone by dissolving when heated in a mixture of isopropanol and a polar solvent selected from ethanol and water, separating insoluble impurities from the tiloron solution and spontaneous cooling of the solution with the formation crystals of crystalline form II tilorone, which are separated from impurities dissolved in solution. 6. The production method according to claim 5, characterized in that the tilorone is dissolved at a ratio of tiloron: isopropanol 1: 3 ÷ 8. 7. The production method according to claim 5, characterized in that the tilorone is dissolved at a ratio of tiloron: polar solvent 1: 0.2 ÷ 3.5. 8. The production method according to claim 5, characterized in that ethanol is used as the polar solvent. 9. The production method according to claim 5, characterized in that water is used as a polar solvent. 10. The method of obtaining crystalline form II of tilorone, characterized by a x-ray powder diffraction pattern according to claim 1, which includes purification of tilorone by dissolving when heated in a polar solvent selected from ethanol and water, separating insoluble impurities from the solution of tilorone and precipitating crystals of crystalline form II from isopropanol tilorone, which is separated from impurities dissolved in solution by slow cooling. 11. The method according to claim 10, characterized in that the tilorone is dissolved in a polar solvent with a ratio of tiloron: polar solvent 1: 0.5 ÷ 3.0. 12. The method according to claim 10, characterized in that the tilorone is planted from the solution with isopropanol with a ratio of polar solvent: isopropanol 1: 2 ÷ 6. 13. The method according to claim 10, characterized in that ethanol is used as the polar solvent. 14. The method according to claim 10, characterized in that water is used as the polar solvent.

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