MXPA01008650A - Crystal modification d of 8-cyano-1-cyclopropyl-7- (1s, 6s- 2,8- diazabicyclo- [4.3.0]nonan-8-yl) -6-fluoro -1,4-dihydro -4-oxo -3-quinoline carboxylic acid - Google Patents

Abstract

The invention relates to a defined crystal modification of 8-cyano -1-cyclopropyl -7- (1S, 6S- 2,8- diazabicyclo [4.3.0]nonan-8-yl) -6-fluoro -1,4- dihydro -4-oxo-3- quinoline carboxylic acid, to methods for producing the same and to the use thereof in pharmaceutical formulations. The crystal modification can be distinguished from other crystal modifications of 8-cyano -1-cyclopropyl -7-(1S, 6S-2,8- diazabicyclo [4.3.0]nonan-8-yl) -6-fluoro -1,4-dihydro -4-oxo -3-quinoline carboxylic acid of formula (I) by its characteristic X-ray powder diffractogram and its differential thermodiagram.

Description

CRYSTALLINE MODIFICATION D ACID 8-Cyano-1-cyclopropyl-7- (1S, 6S-2,8-DIAZABICICLOG4.3.01-nonan-8-yl) -6-fluoro-1.4-dihydro-4- oxo-3-quinolinecarboxylic acid . FIELD OF THE INVENTION The present invention relates to a defined crystal modification of the acid 8-cyano- 1-cyclopropyl-7- (1 S, 6S, 2, 8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro- 1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid , to procedures for its preparation and its use in pharmaceutical preparations. 8-cyano-1-cyclopropyl-7- (1S, 6S, 2, 8-di-azabicyclo- [4.3.0] nonan-8-yl) -6-fluoro, 4-dihydro-4 Oxo-3-quinolinecarboxylic acid of the formula (I) will be referred to below as CCDC.

Description of the prior art The CCDC is known from DE-A 19 633 805 or from PCT application No. 97 903 260.4. It is prepared by the reaction of 7-halogeno-8-cyano-l-ciclopro-pil-6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS, 6S) -2,8-diazabicyclo - [4.3.0] nonane in a mixture consisting of dimethylformamide and acetonitrile in the presence of an auxiliary base. After combining with water, the CCDC is extracted from the water with dichloromethane and isolated by removal of the extraction agent. In this case a powder is obtained, which does not show a clear crystalline modification. On the contrary, the powder is mostly amorphous and may contain mixtures of various REF: 131990 crystalline modifications. If a unitary crystalline modification were formed by chance, it is not clear how it could be extracted and obtained in a definite way. For the obtaining of medicines is, however, a precondition that is clearly indicated, for an active product, which can be presented in various crystalline modifications, which is the crystalline modification that is used for the manufacture of the agent. The powder, partly amorphous, obtained according to the process of obtaining previously schematized is, moreover, hygroscopic. However, the amorphous solid products and especially the hygroscopic solid products are difficult to manipulate in galenic processing since they have, for example, low bulk weights and defective yield properties. In addition, special work techniques and facilities are required for the handling of hygroscopic solid products, in order to achieve reproducible results, for example as regards the content of active product or stability in the solid formulations produced. DETAILED DESCRIPTION OF THE INVENTION Thus, the invention has as its task the preparation of a crystalline form of defined modification of the CCDC, which is perfectly manipulable due to its physical properties, especially its crystalline properties and its behavior against water, in formulations galenicas. This task is solved according to the invention by means of a new crystalline form of the CCDC, which is referred to below as modification D. Thus, the object of the invention is the crystalline modification D of the CCDC, characterized in that it has a powder diffraction diagram to the X-rays, with the reflection layers (2 Theta) indicated in Table 1 below of high and medium intensity (relative intensity> 30%). Table 1: X-ray powder diffraction diagram of modification D of the CCDC The powder diffraction diagram has also been given to the X-rays of modification D in figure 1. Modification D of the CCDC according to the invention is further distinguished by a series of other properties of the other forms of the CCDC. These properties can also serve individually or in conjunction with the other parameters for the characterization of modification D of the CCDC according to the invention. The CCDC of modification D is characterized by having a melting point of 261 ° C to 265 ° C, determined with the help of differential thermal analysis (DTA). Figure 2 shows a characteristic differential thermal analysis diagram.

The CCDC of modification D is characterized, moreover, because it has an infra-red spectrum, measured in KBr, like the one shown in figure 3. Crystal modification D of CCDC is obtained because it dissolves in water CCDC of an unknown or amorphous crystalline modification, this solution is allowed to stand until a solid product precipitates, this solid product is separated by filtration, the hydrated product, obtained in this way, is dried and then heated to a temperature located at above the transformation temperature.

The drying of the hydrated product can be carried out according to usual methods. In this way, for example, the hydrated product can be dried at a high temperature under vacuum. It is also possible to carry out drying in the presence of a conventional drying agent such as, for example, phosphorus pentoxide. The temperature necessary for the transformation in the modification D of the dried sample can be determined by means of a DTA of the dried substance. As a rule it is between 130 ° C and 160 ° C. The CCDC of the crystalline modification D is surprisingly stable and neither is it transformed, on the occasion of prolonged storage, into another different crystalline modification or into the amorphous form. For these reasons it is excellent for obtaining tablets or other solid formulations. Through its stability it provides these formulations with storage stability that is durable over time, desirable. Thus, with the crystalline modification D, solid and specific stable CCDC preparations can be prepared. The CCDC of crystal modification D is active in an excellent manner against pathogenic bacteria in the field of human and veterinary medicine. Its broad field of application corresponds to that of the CCDC.

The X-ray powder diffraction diagram for the characterization of crystal modification D of the CCDC was obtained with a STADI-P transmission diffractometer with locally sensitive detector (PSD2) from Stoe. The point of departure of the differential thermal analysis was obtained with the DSC 820 device from Mettler-Toledo. In this case, the CCDC sample of crystalline modification D was heated in an aluminum crucible with 5 K / minute. The IR spectrum was obtained with the device 881 from Perkin-Elmer in KBr. The following examples illustrate the invention without limiting it in any way. The solvents / base systems used in the following examples are especially preferred. Comparative Example A mixture of 3.07 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3 acid is stirred for 16 hours at room temperature. -quinoline-linocarboxylic acid, 1.39 g of (lS, 6S) -2,8-diazabicyclo [4.3.0] nonane, 2.24 g of 1,4-di-azabicyclo [2.2.2] octane (DABCO) ), 29.5 ml of dimethylformamide and 29.5 ml of acetonitrile. The reaction mixture is concentrated by evaporation at 60 ° C of bath temperature in the rotary evaporator and the residue is taken up in 10 ml of water. The resulting solution is adjusted to pH 7 with dilute hydrochloric acid and the solid product is separated by filtration. The filtrate is shaken three times with 20 ml of dichloromethane each time. The organic phase is dried over sodium sulfate, filtered and the filtrate is concentrated by evaporation in a rotary evaporator at 60 ° C bath temperature. 2.4 g of light brown solid product are obtained, which has the X-ray powder diffraction diagram shown in FIG. 4 and which, therefore, is mostly amorphous. Example 1 1012 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid are prepared in a mixture of 3300 ml of ethanol , 1980 ml of N-methyl-pyrrolidone and 534 g of Hünig base. The mixture is refluxed and 459 g of (lS, 6S) -2,8-diazabicyclo [4.3.0] nonane are then added dropwise. Once the addition is complete, drop by drop, stir for another 3 hours at reflux, it is allowed to cool to room temperature, the solid product is separated by suction filtration and washed with a total of 1800 ml of ethanol. The solid product obtained is suspended in a mixture consisting of 4650 ml of ethanol and 41 g of Hünig's base and the reaction mixture is refluxed for 3 hours. The reaction mixture is allowed to cool again to room temperature, the solid product is separated by suction filtration, washed further with a total of 1000 ml of EtOH and dried at 60 to 70 ° C in the drying cabinet. in vacuum until weight constancy. 1130 g of a beige solid product are obtained, which shows the X-ray powder diffraction diagram shown in FIG. 5. From 450 g of this solid product and 29,450 g of double-distilled water, an aqueous solution is prepared as described in FIG. 1.5% (weight / weight), which is filtered through a 0.2 μm filter, to remove particles that may not be dissolved. This solution is then stored for 4 weeks at room temperature with the exclusion of light in polyethylene drums. At the end of this time, the precipitated solid product is filtered off through a 0.8 μm filter and dried overnight. 2 g of solid product are obtained, which is amorphous according to the powder diffraction diagram to the X rays (figure 6) and having the DTA shown in figure 7. 30 mg of the solid product, obtained in this way, are heated under nitrogen for 2 hours at 160 ° C. 28 mg of solid product are obtained, which shows the X-ray powder diffraction diagram shown in figure 1, the differential thermal diagram shown in figure 2 and the IR spectrum shown in figure 3. It is stated that, in relation to this date, the best method known by the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (6)

1. CLAIMS Having described the invention as above, it is claimed as property contained in the following: 1.- 8-cyano-l-cyclopropyl-7- (lS, 6S-2,8-di-azabicyclo [4.3.0] nonane -8-yl) -6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC) of the crystal modification D, characterized in that it presents a powder diffraction diagram to the X rays with the reflection layers following (2 Theta) of high and medium intensity
2. 2. - 8-cyano-l-cyclopropyl-7- (lS, 6S-2,8-di-azabicyclo [4.
3. 3.0] nonane-8-yl) -6-fluoro-l, 4-dihydro-4-oxo- 3-quinolinecarboxylic acid (CCDC) of the crystal modification D, characterized in that it presents a powder diffraction diagram to the X-rays with the following reflection layers (2 Theta) of high intensity and medium and a melting point, determined by DTA, from 261 ° C to 265 ° C. 15 3. - 8-Cyano-1-cyclopropyl-7- (1S, 6S-2, 8-di-azabicyclo [
4. 4.3.0] nonane-8-yl) -6-fluoro-l, 4-dihydroxy acid 4-oxo-3-quinolinecarboxylic acid (CCDC) of crystal modification D, characterized in that CCDC of an unknown or amorphous crystalline modification is dissolved in 1 to 3 weight percent, the The solid product precipitated after some time, dried and heated to a temperature above the transformation temperature. 4. Process for obtaining CCDC of modification D, characterized in that CCDC of an unknown or amorphous crystalline modification is dissolved in 1 to 3 weight percent, the solid product precipitated at the end is filtered off. for some time, it is dried and heated to a temperature above the transformation temperature.
5. 5. Medicament characterized in that they contain, in addition to the usual auxiliary agents and excipients, CCDC of modification D according to one of claims 1 and 2.
6. 6. Use of CCDC of modification D according to one of claims 1 and 2 for the manufacture of medicines. 7 '.- Use of the CCDC of modification D according to one of claims 1 and 2 in antibacterial agents.