DE19734438A1 - New crystal modification 2 of leflunomid has better water solubility than modification 1 and is stable over wide temperature range - Google Patents

Abstract

New crystal modification 2 of N-(4-trifluoromethylphenyl)-5-methyl-isoxazole-4-carboxamide (I) (leflunomid; HWA 486) has transmission lines (diffraction angles 2 eta ) in the X-ray diffraction graph using Cu-K alpha 1 radiation in the focusing Deybe-Scherrer radiation procedure and transmission, of strong intensity at 10.65, 14.20, 14.80, 16.10, 21.70, 23.15, 24.40, 24.85, 25.50, 25.85, 26.90 and 29.85 and of medium intensity at 7.40, 9.80, 13.10, 15.45, 16.80, 20.70, 21.45, 22.80, 23.85, 27.25 and 28.95. Also claimed is the production of crystal modification 1 of (I) having lines of strong intensity at 16.70, 18.90, 23.00, 23.65 and 29.05 and lines of medium intensity at 8.35, 12.65, 15.00, 15.30, 18.35, 21.55, 24.10, 24.65, 25.45, 26.65, 27.40, 28.00 and 28.30 measured and defined in the same way as for modification 2. (I) is known from US 4284786.

Description

The invention relates to a new readily soluble crystal modification (modification 2) of the compound of formula I.

which has lines in the X-ray diffraction diagram in transmission with a focusing Debye-Scherrer beam path and Cu-K _{α 1} radiation at the following diffraction angles 2Theta (°):
Strong intensity lines: 10.65; 14.20; 14.80; 16.10; 21.70; 23.15; 24.40; 24.85; 25.50; 25.85; 26.90; 29.85
Medium intensity lines: 7.40; 9.80; 13.10; 15.45; 16.80; 20.70; 21.45; 22.80; 23.85; 27.25; 28.95.

The X-ray diffraction diagram of modification 2 recorded with Cu-K _{α 1} radiation is shown in FIG. 1. The STADI P dual-circuit diffractometer from Stoe (Darmstadt, Germany) or the computer-supported single-crystal diffractometer R3 m / V from Siemens (radiation Mo K _α ) were used to record the diagram.

The infrared spectrum of modification 2 of the compound of formula I (1 mg in 300 mg KBr) recorded with an infrared spectrophotometer shows the following main bands (unit cm ^-1 ):

The specified wave numbers are arranged in increasing intensity. The infrared spectrum of modification 2 of the compound of formula I according to Example 1 is also shown in FIG. 3, the transmission in% being given in the ordinate and the wave number in cm ⁻¹ in the abscissa.

The compound of formula I crystallizes in modification 2 in space group P2 ₁ / c with 8 molecules in the unit cell. The molecules of the compound of the formula I are in the form of dimers which are formed from the individual molecules by formation of a -C = O. . .HN hydrogen bonding (2.938 Å), whereby the two molecular planes are practically perpendicular to each other (91.2 °). The two molecules have a very different conformation. The angles of the five and six rings with the central carbonyl group are 5.4 ° and 2.1 ° or 23.4 ° and 23.1 °. The latter twist creates the steric conditions for hydrogen bonding between the two molecules to be possible.

The compound of formula I is known per se and is also known as leflunomide (HWA 486). It can be obtained in the manner described in US 4,284,786. However, the crystals produced by recrystallization from, for example, toluene are obtained in crystal modification 1. The X-ray diffraction diagram (Cu-K _α1 radiation) of modification 1 is shown in FIG. 2 and has characteristic lines at the following diffraction angles 2 theta (°):
Strong intensity lines: 16.70; 18.90; 23.00; 23.65; 29.05
Medium intensity lines: 8.35; 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30.

The compound of formula I crystallizes in modification 1 in space group P2 ₁ / c with 4 molecules in the unit cell. The molecule is essentially planar. The angle between the planar atomic groups is less than 2.4 °. The molecules are arranged in stacks in the crystal. The molecules lie next to each other in stacks and are arranged in an anti-parallel manner. Very weak hydrogen bonds link the dimers in the crystal structure (NH. .N: 3.1444 Å). The C = O group is not involved in any hydrogen bond.

The X-ray diffraction diagrams also allow the amount of the Modification 2 in a mixture containing both modifications. For quantitative Determination is suitable for the line at 8.35 ° 2 theta of modification 1 and the line at 16.1 ° 2 theta of modification 2. The ratio of the peak heights and if you correlate it with the content of the modification, you get a calibration line. The detection limit of this method is about 0.3% modification 2 in crystals with modification 1.

Modification 2 is more water-soluble than modification 1. At 37 ° C, 38 mg / l of modification 2 can be dissolved, while modification 1  25 mg / l go into solution. Furthermore, the modification 2 is in the temperature range from -15 ° C to + 40 ° C, preferably from 20 ° C to 40 ° C, stable and is not in Modification 1 converted.

The modification 2 according to the invention of the compound of the formula I is obtained, for example, by heating a suspension of the crystals of the modification 1 or mixtures of the modifications 1 and 2 of the compound of the formula I in a solvent to a temperature of about 10 ° C. to 40 ° C., preferably 15 ° C to 30 ° C, especially from 20 ° C to 25 ° C. The production speed is essentially dependent on the temperature. Solvents in which the compound of the formula I dissolves poorly are advantageous. For example, water can be used or aqueous solutions with (C ₁ -C ₄ ) alcohols, e.g. B. methanol, ethanol, propanol, isopropanol, butanol or isobutanol and / or with ketones such as acetone or methyl ethyl ketone. As a rule, the heating takes place in aqueous suspension, expediently with stirring or shaking. The temperature treatment is carried out until modification 1 is completely converted into modification 2.

The complete conversion of modification 1 into modification 2 is from Temperature dependent and usually lasts at a temperature of 20 ° C 36 hours to 65 hours, preferably from 48 hours to 60 hours. The The reaction is checked by X-ray or IR spectroscopy using samples taken during treatment.

Another method for producing modification 2 of the compound of formula I is to dissolve modification 1 or mixtures of modifications 1 and 2 in a solvent and then to flash-cool them to temperatures of about -5 ° C. to -25 ° C. Suitable solvents are, for example, water-miscible solvents such as (C ₁ -C ₄ ) alcohols, but also ketones such as acetone or methyl ethyl ketone or other solvents such as ethyl acetate, toluene or dichloromethane. The dissolving process takes place at room temperature from 20 ° C. to 25 ° C. or else elevated temperatures up to the boiling point of the solvent under normal pressure or under increased or reduced pressure. The solution obtained is optionally filtered in order to separate undissolved constituents or crystals of leflunomide. The filtered solution is then cooled so quickly that only crystals of modification 2 are formed. A sufficient cooling process is, for example, that the filtered solution is placed in a vessel that is cooled to -15 ° C, or by spraying the filtered solution in a room cooled to -10 ° C, or cooling the solution under vacuum condensation conditions . A preferred method is to introduce the compound of the formula I into methanol and to carry out the dissolution process at the boiling point of methanol under normal pressure or reduced pressure; then filter the hot solution and transfer the filtered solution so slowly into a vessel which has cooled to -15 ° C that the temperature of the crystal suspension obtained does not rise to more than -10 ° C. The precipitated crystals are then washed several times with methanol and dried under reduced pressure. Crystallization can take place without seeding with crystals of modification 2 or preferably by seeding with crystals of modification 2. The seeding takes place in the cooled vessel. The amount of inoculation material depends on the amount of solution and can be easily determined by a person skilled in the art. The abovementioned processes are also suitable for converting mixtures containing modification 1 and 2 into an essentially pure modification 2 of the compound of the formula I.

However, the invention also relates to new processes for the preparation of the compound of the formula in modification 1. The novel processes can also be used to specifically convert mixtures containing modification 1 and 2 to modification 1. For this purpose, for example, crystals of modification 2 or mixtures of modification 1 and 2 are dissolved in a solvent. Suitable solvents are, for example, water-miscible solvents such as (C ₁ -C ₄ ) alcohols, e.g. As methanol, ethanol, propanol, isopropanol, butanol or isobutanol, but also ketones such as acetone or methyl ethyl ketone. Mixtures of organic solvents with water, for example from about 40% to 90% isopropanol, have also proven successful. The dissolving process is preferably carried out at an elevated temperature up to the boiling point of the particular solvent. The hot solution is kept at boiling temperature for some time to ensure complete dissolution of the compound of formula I. The filtered solution is then cooled slowly enough that only crystals of modification 1 form. It is preferably cooled to end temperatures of 20 ° C. to -10 ° C., in particular to temperatures of 10 ° C. to -5 ° C., very particularly preferably to temperatures of 10 ° C. to 5 ° C. The crystals are separated and washed with isopropanol and then with water. The substance is dried at elevated temperature, preferably at 60 ° C. under reduced pressure or at normal pressure.

A preferred method consists in the compound of formula I in 80% Isopropanol and boiling temperature of isopropanol under normal pressure or to release reduced pressure and then slowly release the hot solution cool so that the crystallization at temperatures of more than 40 ° C, preferably from 40 ° C to 85 ° C, particularly preferably from 45 ° C to 80 ° C, in particular from 50 ° C to 70 ° C, takes place. The precipitated crystals are then washed several times with isopropanol and dried under reduced pressure. Crystallization can take place without seeding with crystals of modification 1 or preferably in the presence of crystals of modification 1, which by Inoculating into the solution containing the compound of formula I introduced become. Inoculation can also take place several times at different temperatures respectively. The amount of inoculation material depends on the amount of solution and can easily be determined by a specialist.

Another method for producing modification 1 from modification 2 or a mixture containing the modification 1 and 2 is that the Crystals are heated to a temperature of above 40 ° C to 130 ° C, preferred from 50 ° C to 110 ° C, especially from 70 ° C to 105 ° C, very particularly preferably 100 ° C. The transfer of modification 2 to 1 is from temperature dependent and lasts for example at 100 ° C. from 2 to 5 hours, preferably from 2 to 3 hours.  

Another method for producing modification 1 consists in the production a suspension containing crystals of modification 2 or a mixture of Crystals containing modification 1 and 2, and a solvent.

Modification 1 of the compound of the formula I is obtained by heating the suspension of the crystals in a solvent to a temperature of more than 40 ° C., preferably 41 ° C. to 100 ° C., in particular 50 ° C. to 70 ° C. The production essentially depends on the temperature. Solvents in which the compound of the formula I dissolves poorly are advantageous. For example, water can be used or aqueous solutions with (C ₁ -C ₄ ) alcohols and / or with ketones such as methyl ethyl ketone or acetone. As a rule, the heating takes place in aqueous suspension, expediently with stirring or shaking. The temperature treatment is carried out until modification 2 has been completely converted into modification 1.

The complete transfer of modification 2 into modification 1 is from Temperature dependent and usually lasts at a temperature of 50 ° C 20 hours to 28 hours, preferably 24 hours. The control of the reaction is done by X-ray or IR spectroscopy using during the treatment taken samples.

Modification 2 according to the invention of the compound of formula I is suitable, for example, for the treatment of

• - acute immunological events such as sepsis, allergy, graft versus host and host versus graft responses
• - Autoimmune diseases, especially rheumatoid arthritis, systemic Lupus erythematosus, multiple sclerosis
• - Psoriasis, atopic dermatitis, asthma, urticaria, rhinitis, uveitis
• - Type II diabetes
• - liver fibrosis, cystic fibrosis, colitis  
• - cancers such as lung cancer, leukemia, ovarian cancer, sarcomas, Kaposi's sarcoma, meningioma, colon cancer, lymph node cancer, brain tumors, Breast cancer, pancreatic cancer, prostate cancer or skin cancer.

The invention also relates to medicinal products characterized by an effective one Content of modification 2 of the compound of formula I, together with a pharmaceutically suitable and physiologically compatible carrier, additive and / or active substances and auxiliary substances.

The invention further relates to a method for producing the medicament, the characterized in that modification 2 of the compound of Formula I and a pharmaceutical carrier to a pharmaceutical Dosage form processed.

The medicament according to the invention can be used as a dosage unit in the form of Dosage forms such as capsules (including microcapsules), tablets (including Dragees and pills) or suppositories are present, with the use of capsules the capsule material perform the function of the carrier and the content z. B. as Powder, gel, emulsion, dispersion or suspension can be present. Especially However, it is advantageous and simple to use oral (peroral) formulations with the To produce modification 2 of the compound of formula I, the calculated Amounts of active ingredients along with any desired pharmaceutical Carrier included. Also a corresponding formulation (suppository) for the rectal Therapy can be applied. The transdermal application is also in shape of ointments, creams or oral application of tablets or suspensions that contain the preparation according to the invention possible.

In addition to the active ingredients, ointments, pastes, creams and powders can be the usual ones Contain carriers, e.g. B. animal and vegetable fats, waxes, paraffins, Starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Talc, zinc oxide, milk sugar, silica, aluminum hydroxide, calcium silicate and Polyamide powder or mixtures of these substances.  

The tablets, pills or granules can be prepared using conventional methods such as Pressing, dipping or fluidized bed processes or boiler coating are produced and contain carriers and other common additives such as gelatin, agarose, Starch (e.g. potato, corn or wheat starch), cellulose such as ethyl cellulose, Silicon dioxide, various sugars such as milk sugar, magnesium carbonate and / or Calcium phosphates. The coating solution usually consists of sugar and / or Corn syrup and mostly still contains gelatin, gum arabic, Polyvinyl pyrrolidone, synthetic cellulose esters, surface-active substances, Plasticizers, pigments and similar additives according to the state of the Technology. For the preparation of the preparations, any customary flow regulation, Lubricants or lubricants such as magnesium stearate and release agents can be used.

The dosage to be used is of course dependent on different ones Factors such as the living being to be treated (i.e. human or animal), age, Weight, general health, the severity of symptoms, the treating disease, any concomitant diseases (if any) of Type of concomitant treatment with other medicines, or the frequency of Treatment. The doses are generally several times a day and preferably administered once to three times a day.

The appropriate therapy is z. B. in the administration of one, two or 3 single doses of a preparation consisting of N- (4-trifluor methylphenyl) -5-methyl-isoxazole-4-carboxamide in modification 2 in one amount from 2 to 150 mg, preferably 10 to 100 mg, in particular 10 to 50 mg.

The amount of active components naturally depends on the number of Individual doses and also depending on the illness to be treated. The Single dose can also consist of several, administered simultaneously Dosing units exist.  

example 1 Production of modification 2

About 40 mg of the compound of the formula I prepared in accordance with US 4,284,786 were shaken with 40 ml of water in bottles (volume 45 ml). The sealed bottles were shaken at 15-25 ° C in a water bath. After 48 hours, a sample was taken, filtered, dried and a powder X-ray diffraction pattern was made. The measurement was carried out using the STADI P dual-circuit diffractometer from Stoe (Darmstadt, Germany) with Cu-K _{α 1} radiation in the Debye-Scherrer beam path and transmission. Fig. 1 shows the X-ray diffraction chart obtained and is typical of modification 2 of the compound of formula I.

Example 2 Production of modification 1

The preparation was carried out as in Example 1, but was shaken at 50 ° C. for 24 hours. Fig. 2 shows the X-ray diffraction pattern obtained and is typical of modification 1 of the compound of formula I.

Example 3 solubility in water

Apparatus: standing flask, magnetic stirrer, water bath 37 ° C ± 0.5 ° C
Medium: water (+ 37 ° C)
Sampling: 5 hours
Preparation: Modifications 1 and 2 according to Examples 1 and 2 were transferred to water and stirred vigorously at 37 ° C
Detection: UV spectroscopy at a wavelength of 258 µm
Result: Modification 1: 25 mg dissolve in 1 liter of water at 37 ° C
Modification 2 38 mg dissolve in 1 liter of water at 37 ° C

Example 4 Stability of the modification

Modification 2 samples were prepared as in Example 1 and at different temperatures and humidity stored. According to the above Samples were taken at times and an X-ray diffraction chart was like made in Example 1. Table 1 shows the results.

Table 1

¹ ) A calibration curve was used to determine modification 1. To create the calibration curve for the quantitative determination, the reflex at 8.35 ° 2ϑ was used for phase 1 and the reflex at 16.1 ° 2ϑ for phase 2. The ratios of the corresponding peak heights were formed and correlated with the contents of phase 2. The limit of the method is 0.3%. According to this method, the sample at + 60 ° C and storage for 1 month contains about 76% of modification 1.

Claims (16)

1. Modification 2 of the compound of formula I.
which has lines in the X-ray diffraction diagram in transmission with a focusing Debye-Scherrer beam path and Cu-K _{α 1} radiation at the following diffraction angles 2Theta (°):
Strong intensity lines: 10.65; 14.20; 14.80; 16.10; 21.70; 23.15; 24.40; 24.85; 25.50; 25.85; 26.90; 29.85
Medium intensity lines: 7.40; 9.80; 13.10; 15.45; 16.80; 20.70; 21.45; 22.80; 23.85; 27.25; 28.95. 2. Process for the preparation of modification 2 of the compound of formula I. according to claim 1, characterized in that a solution containing the Compound of formula I which is not in modification 2 or mixtures Modification 1 and 2, shock to a temperature of less than -5 ° C to -25 ° C is cooled. 3. Process for the preparation of modification 2 of the compound of Formula I according to claim 1, characterized in that a suspension, containing the compound of formula I, which is not in modification 2 or Mixtures of modification 1 and 2, at a temperature of 10 ° C to 40 ° C. is heated. 4. The method according to claim 3, characterized in that an aqueous Suspension is heated.   5. The method according to claim 2, characterized in that as a solvent with water-miscible solvents such as (C ₁ -C ₄ ) alcohols, for. B. methanol, ethanol, propanol, isopropanol, butanol or isobutanol, especially isopropanol, but also ketones such as acetone or methyl ethyl ketone, or mixtures of the solvents with water or water-immiscible solvents such as ethyl acetate, toluene or dichloromethane. 6. The method according to claims 2 and 5, characterized in that a aqueous mixture with about 40% to 90% isopropanol is used. 7. The method according to claims 2, 5 and 6, characterized in that crystallization in the presence of crystals of modification 2 of the compound of formula I is carried out. 8. Process for the preparation of modification 1 of the compound of formula I,
which has lines in the X-ray diffraction diagram in transmission with a focusing Debye-Scherrer beam path and Cu-K _{α 1} radiation at the following diffraction angles 2 theta (°):
Strong intensity lines: 16.70; 18.90; 23.00; 23.65; 29.05
Medium intensity lines: 8.35; 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30;
characterized in that the compound of formula I which is not in modification 1 or mixtures of modification 1 and modification 2 according to claim 1 is heated in solid form to a temperature of 50 ° C to 130 ° C. 9. Process for the preparation of modification 1 of the compound of formula I. according to claim 8, characterized in that the compound of formula I, the is not in modification 1 or mixtures of modification 1 and 2, in Suspension to a temperature of more than 40 ° C, especially from 41 ° C to 100 ° C, preferably 50 ° C to 70 ° C, is heated. 10. The method according to claim 9, characterized in that an aqueous Suspension is present. 11. Process for the preparation of modification 1 of the compound of formula I. according to claim 8, characterized in that the compound of formula I, the is not in modification 1 or mixtures containing modifications 1 and 2, in an organic solvent or mixtures of organic Solvent and water is dissolved and at temperatures of more than 40 ° C, preferably from 41 ° C to 80 ° C, in particular from 50 ° C to 70 ° C, is crystallized. 12. The method according to claim 11, characterized in that as a solvent with water-miscible solvents such as (C ₁ -C ₄ ) alcohols, for. As methanol, ethanol, propanol, isopropanol, butanol or isobutanol, especially isopropanol, but also ketones such as acetone or methyl ethyl ketone, or mixtures of the solvents with water can be used. 13. The method according to claims 11 and 12, characterized in that an aqueous mixture with about 40% to 90% isopropanol is used. 14. The method according to claims 11 to 13, characterized in that the Crystallization in the presence of crystals of modification 1 of the compound of Formula I is carried out. 15. Medicament, characterized by a content of modification 2 of Compound of formula I according to claim 1 and a physiologically acceptable Carrier.   16. Use of modification 2 of the compound of formula I according to Claim 1 for the manufacture of a medicament for the treatment of acute immunological events such as sepsis, allergy, and graft versus host Host-versus-graft reactions, autoimmune diseases, especially rheumatoid Arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, atopic dermatitis, asthma, urticaria, rhinitis, uveitis, type II diabetes, Liver fibrosis, cystic fibrosis, colitis, cancers such as lung cancer, Leukemia, ovarian cancer, sarcomas, Kaposi's sarcoma, meningioma, colon cancer, Lymph node cancer, brain cancer, breast cancer, pancreatic cancer, prostate cancer or Skin cancer.