Indian Patents. 208155:PROCESS FOR PREPARING CRYSTAL MODIFICATION C 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-QUINOLINECARBOXYLIC ACID (CCDC)

Title of Invention	PROCESS FOR PREPARING CRYSTAL MODIFICATION C 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-QUINOLINECARBOXYLIC ACID (CCDC)
Abstract	Process for preparing CCDC of the crystal modification C, characterized in that CCDC of unknown modification or amorphous CCDC is exposed to a relative atmospheric humidity of at least 92% until there is no further weight increase, then drying the product and subsequently heating it to a temperature above the rearrangement temperature.

Full Text	FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; Rule 13] BAYER AKTIENGESELLSCHAFT, a body corporate organised under the laws of Germany, D-51368 Leverkusen, Germany, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- GRANTED 13-1-2005 ORIGINAL IN/PCT/2001-00970/MUM 13/6/2001 The present invention relates to a process for preparing CCDC of the crystal modification C. The present invention generally relates to a defined crystal modification of 8-cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations. Hereinbelow, 8-cyano-l-cycloprppyI-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) is referred to as CCDC. CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4. According to these publications, it is prepared by reacting 7-chloro-8-cyano-l-cycIopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS,6S)-2,8-diaza-bicyclo[4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. Water is added to the mixture and CCDC is then extracted from water using dichloromethane and is isolated by removing the extractant. This gives a powder whose crystal modification is not unambiguous. On the contrary, the powder is largely amorphous and can contain mixtures of different crystal modifications. If, by chance, a uniform crystal modification is formed, it is not clear how it can be extracted and obtained in a defined form. However, it is the precondition for preparing medicaments that, for an active compound which can be present in different crystal modifications, it can be stated unamibiguously which of its crystal modifications is used for preparing the medicament. The partially amorphous powder which is obtained by the preparation process outlined above is furthermore hygroscopic. Amorphous solids, and in particular hygroscopic solids, are difficult to handle when being processed pharmaceutically since, for example, they may have low bulk densities and unsatisfactory flow properties. Moreover, the handling of hygroscopic solids requires special work techniques and apparatuses to obtain reproducible results, for example with respect to the active compound content or the stability of the solid formulations produced. It is therefore an object of the invention to prepare a crystalline form of a defined modification of CCDC which, owing to its physical properties, in particular its crystal properties, is easy to handle in pharmaceutical formulations. This object is achieved according to invention by a novel crystalline form of CCDC which is referred to as modification C hereinbelow. Accordingly, there is provided a process for preparing CCDC of the crystal modification C, characterized in that CCDC of unknown modification or amorphous CCDC is exposed to a relative atmospheric humidity of at least 92% until there is no further weight increase, then drying the product and subsequently heating it to a temperature above the rearrangement temperature. The invention accordingly provides the crystalline modification C of CCDC which is characterized in that it has an X-ray powder diffractogram with the reflection signals (2 theta) of high and medium intensity (> 15% relative intensity) listed in Table 1 below. Table 1: X-ray powder diffractogram of CCDC of the modification C A characteristic X-ray powder diffractogram of the modification C is also shown in Figure 1. Moreover, the CCDC modification C according to the invention differs from other 10 forms of CCDC in a number of further properties. These properties, on their own or together with the other parameters, may serve for characterizing the CCDC modification C according to the invention. CCDC of the modification C is characterized, inter alia, by a melting point, 1 5 determined with the aid of differential thermoanalysis (DTA), of from 235°C to 237°C. A characteristic differential thermodiagram is shown in Figure 2. CCDC of the modification C is further characterized in that it has an infrared spectrum, measured in KBr, as shown in Figure 3. CCDC of the modification C is further characterized in that it is obtainable by the preparation process given below. The crystal modification C of CCDC is obtained by storing CCDC of unknown modification or amorphous CCDC at room temperature at a relative atmospheric humidity of at least 92% for a number of days until there is no more weight increase, drying the resulting water-containing product and then heating to a temperature above the rearrangement temperature. The water-containing product can be dried by customary methods. Thus, the water-containing product can be dried, for example, at elevated temperature under reduced pressure. It is also possible to carry out the drying in the presence of a customary drying agent, such as, for example, phosphorus pentoxide. The temperature required for converting the dried sample into modification C can be determined by DTA of the dried substance. In general, the temperature is between 150°C and 180°C. CCDC of the crystal modification C is surprisingly stable and does not change into another crystal modification or the amorphous form, even on prolonged storage. For these reasons, it is highly suitable for preparing tablets or other solid formulations. Owing to its stability, it gives these formulations the desired long-lasting storage stability. Using the crystal modification C, it is therefore possible to prepare, in a defined and targeted manner, stable solid preparations of CCDC. CCDC of the crystal modification C is highly active against pathogenic bacteria in the area of human or veterinary medicine. Its broad area of use corresponds to that of CCDC. The X-ray powder diffractogram for characterizing the crystal modification C of CCDC was obtained using a transmission diffractometer STADI-P with a location-sensitive detector (PSD2) from Stoe. The melting point of the differential thermoanalysis was obtained using the DSC 820 unit from Mettler-Toledo. Here, the sample of CCDC of the crystal modification C was heated exposed to the atmosphere in an aluminium crucible at 10 K/min. The KBr 1R spectrum was obtained using the 881 unit from Perkin-Elmer. The examples below illustrate the invention without limiting it. The diluent/base systems described in the examples below are particularly preferred. Comparative Example A mixture of 3.07 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.39 g of (lS,6S)-2,8-diazabicyclo[4.3.0]nonane, 2.24 g of l,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml dimethylformamide and 29.5 ml of acetonitrile is stirred at room temperature for 16 hours. The reaction mixture is concentrated at a bath temperature of 60°C using a rotary evaporator, and the residue is taken up in 10 ml of water. The resulting solution is adjusted to pH 7 using dilute hydrochloric acid, and the solid is filtered off. The filtrate is extracted three times using 20 ml of dichloromethane each time. The organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated at a bath temperature of 60°C using a rotary evaporator. This gives 2.4 g of a light-brown solid which has the X-ray powder diffractogram shown in Figure 4 and is therefore predominantly amorphous. Example 1 1012 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3- quinolinecarboxylic acid are initially charged in a mixture of 3300 ml of ethanol, 1980 ml of N-methyl-pyrrolidone and 534 g of Hunig base. The mixture is heated to reflux, and 459 g of (lS,6S)-2,8-diazabicyclo[4.3.0]nonane are then added dropwise. After the dropwise addition has ended, the mixture is stirred under reflux for another 3 hours and then allowed to cool to room temperature, and the solid is filtered off with suction and washed with a total of 1800 ml of ethanol. The resulting solid is suspended in a mixture of 4650 ml of ethanol and 41 g of Hunig base, and the reaction mixture is heated under reflux for 3 hours. The reaction mixture is allowed to cool again to room temperature, and the solid is filtered off with suction, washed with a total of 1000 ml of EtOH and dried at from 60 to 70°C in a vacuum drying cabinet until the weight remains constant. This gives 1130 g of a beige solid which has the powder X-ray diffractogram shown in Figure 5. An amount of 500 mg of the solid prepared according to this procedure is stored at room temperature at a relative atmospheric humidity of from 95% (established using a saturated solution with sediment of Na2HP04 x 12 H20 in water) for 11 days. This gives 695 mg of product. 200 mg of the resulting solid are dried at 100°C in a vacuum drying cabinet over P,05 for 24 hours. This gives 134 mg of a solid which, according to powder X-ray diffractogram (Fig. 6), is substantially amorphous and has the DTA shown in Fig. 7. Under nitrogen, 30 mg of the resulting solid are heated at 180°C for 2 hours. This gives 27 mg of a solid which has the powder X-ray diffractogram shown in Figure 1, the differential thermodiagram shown in Figure 2 and the IR spectrum shown in Figure 3. WE CLAIM: 1. Process for preparing CCDC of the crystal modification C, characterized in that CCDC of unknown modification or amorphous CCDC is exposed to a relative atmospheric humidity of at least 92% until there is no further weight increase, then drying the product and subsequently heating it to a temperature above the rearrangement temperature. Dated this 13th day of August, 2001 JAYANTA PAL] OF Remfry & Sagar ATTORNEY FOR THE APPLICANT]

Full Text

FORM 2
THE PATENTS ACT, 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10; Rule 13]

BAYER AKTIENGESELLSCHAFT, a body corporate organised under the laws of Germany, D-51368 Leverkusen, Germany,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-
GRANTED
13-1-2005
ORIGINAL
IN/PCT/2001-00970/MUM
13/6/2001

The present invention relates to a process for preparing CCDC of the crystal modification C.
The present invention generally relates to a defined crystal modification of 8-cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.
Hereinbelow, 8-cyano-l-cycloprppyI-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) is referred to as CCDC.

CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4. According to these publications, it is prepared by reacting 7-chloro-8-cyano-l-cycIopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS,6S)-2,8-diaza-bicyclo[4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. Water is added to the mixture and CCDC is then extracted from water using dichloromethane and is isolated by removing the extractant. This gives a powder whose crystal modification is not unambiguous. On the contrary, the powder is largely amorphous and can contain mixtures of different crystal modifications. If, by chance, a uniform crystal modification is formed, it is not clear how it can be extracted and obtained in a defined form. However, it is the precondition for preparing medicaments that, for an active compound which can be

present in different crystal modifications, it can be stated unamibiguously which of its crystal modifications is used for preparing the medicament.
The partially amorphous powder which is obtained by the preparation process outlined above is furthermore hygroscopic. Amorphous solids, and in particular hygroscopic solids, are difficult to handle when being processed pharmaceutically since, for example, they may have low bulk densities and unsatisfactory flow properties. Moreover, the handling of hygroscopic solids requires special work techniques and apparatuses to obtain reproducible results, for example with respect to the active compound content or the stability of the solid formulations produced.
It is therefore an object of the invention to prepare a crystalline form of a defined modification of CCDC which, owing to its physical properties, in particular its crystal properties, is easy to handle in pharmaceutical formulations.
This object is achieved according to invention by a novel crystalline form of CCDC which is referred to as modification C hereinbelow.
Accordingly, there is provided a process for preparing CCDC of the crystal modification C, characterized in that CCDC of unknown modification or amorphous CCDC is exposed to a relative atmospheric humidity of at least 92% until there is no further weight increase, then drying the product and subsequently heating it to a temperature above the rearrangement temperature.
The invention accordingly provides the crystalline modification C of CCDC which is characterized in that it has an X-ray powder diffractogram with the reflection signals (2 theta) of high and medium intensity (> 15% relative intensity) listed in Table 1 below.

Table 1:
X-ray powder diffractogram of CCDC of the modification C

A characteristic X-ray powder diffractogram of the modification C is also shown in Figure 1.
Moreover, the CCDC modification C according to the invention differs from other
10 forms of CCDC in a number of further properties. These properties, on their own or
together with the other parameters, may serve for characterizing the CCDC modification C according to the invention.
CCDC of the modification C is characterized, inter alia, by a melting point,
1 5 determined with the aid of differential thermoanalysis (DTA), of from 235°C to
237°C. A characteristic differential thermodiagram is shown in Figure 2.
CCDC of the modification C is further characterized in that it has an infrared spectrum, measured in KBr, as shown in Figure 3.
CCDC of the modification C is further characterized in that it is obtainable by the preparation process given below. The crystal modification C of CCDC is obtained by

storing CCDC of unknown modification or amorphous CCDC at room temperature at a relative atmospheric humidity of at least 92% for a number of days until there is no more weight increase, drying the resulting water-containing product and then heating to a temperature above the rearrangement temperature.
The water-containing product can be dried by customary methods. Thus, the water-containing product can be dried, for example, at elevated temperature under reduced pressure. It is also possible to carry out the drying in the presence of a customary drying agent, such as, for example, phosphorus pentoxide.
The temperature required for converting the dried sample into modification C can be determined by DTA of the dried substance. In general, the temperature is between 150°C and 180°C.
CCDC of the crystal modification C is surprisingly stable and does not change into another crystal modification or the amorphous form, even on prolonged storage. For these reasons, it is highly suitable for preparing tablets or other solid formulations. Owing to its stability, it gives these formulations the desired long-lasting storage stability. Using the crystal modification C, it is therefore possible to prepare, in a defined and targeted manner, stable solid preparations of CCDC.
CCDC of the crystal modification C is highly active against pathogenic bacteria in the area of human or veterinary medicine. Its broad area of use corresponds to that of CCDC.
The X-ray powder diffractogram for characterizing the crystal modification C of CCDC was obtained using a transmission diffractometer STADI-P with a location-sensitive detector (PSD2) from Stoe.

The melting point of the differential thermoanalysis was obtained using the DSC 820 unit from Mettler-Toledo. Here, the sample of CCDC of the crystal modification C was heated exposed to the atmosphere in an aluminium crucible at 10 K/min.
The KBr 1R spectrum was obtained using the 881 unit from Perkin-Elmer.
The examples below illustrate the invention without limiting it. The diluent/base systems described in the examples below are particularly preferred.

Comparative Example
A mixture of 3.07 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.39 g of (lS,6S)-2,8-diazabicyclo[4.3.0]nonane, 2.24 g of l,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml dimethylformamide and 29.5 ml of acetonitrile is stirred at room temperature for 16 hours. The reaction mixture is concentrated at a bath temperature of 60°C using a rotary evaporator, and the residue is taken up in 10 ml of water. The resulting solution is adjusted to pH 7 using dilute hydrochloric acid, and the solid is filtered off. The filtrate is extracted three times using 20 ml of dichloromethane each time. The organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated at a bath temperature of 60°C using a rotary evaporator. This gives 2.4 g of a light-brown solid which has the X-ray powder diffractogram shown in Figure 4 and is therefore predominantly amorphous.
Example 1
1012 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-
quinolinecarboxylic acid are initially charged in a mixture of 3300 ml of ethanol, 1980 ml of N-methyl-pyrrolidone and 534 g of Hunig base. The mixture is heated to reflux, and 459 g of (lS,6S)-2,8-diazabicyclo[4.3.0]nonane are then added dropwise. After the dropwise addition has ended, the mixture is stirred under reflux for another 3 hours and then allowed to cool to room temperature, and the solid is filtered off with suction and washed with a total of 1800 ml of ethanol.
The resulting solid is suspended in a mixture of 4650 ml of ethanol and 41 g of Hunig base, and the reaction mixture is heated under reflux for 3 hours. The reaction mixture is allowed to cool again to room temperature, and the solid is filtered off with suction, washed with a total of 1000 ml of EtOH and dried at from 60 to 70°C in a vacuum drying cabinet until the weight remains constant. This gives 1130 g of a beige solid which has the powder X-ray diffractogram shown in Figure 5.

An amount of 500 mg of the solid prepared according to this procedure is stored at room temperature at a relative atmospheric humidity of from 95% (established using a saturated solution with sediment of Na2HP04 x 12 H20 in water) for 11 days. This gives 695 mg of product.
200 mg of the resulting solid are dried at 100°C in a vacuum drying cabinet over P,05 for 24 hours. This gives 134 mg of a solid which, according to powder X-ray diffractogram (Fig. 6), is substantially amorphous and has the DTA shown in Fig. 7.
Under nitrogen, 30 mg of the resulting solid are heated at 180°C for 2 hours. This gives 27 mg of a solid which has the powder X-ray diffractogram shown in Figure 1, the differential thermodiagram shown in Figure 2 and the IR spectrum shown in Figure 3.

WE CLAIM:

1. Process for preparing CCDC of the crystal modification C,
characterized in that CCDC of unknown modification or amorphous CCDC is exposed to a relative atmospheric humidity of at least 92% until there is no further weight increase, then drying the product and subsequently heating it to a temperature above the rearrangement temperature.
Dated this 13th day of August, 2001
JAYANTA PAL]
OF Remfry & Sagar
ATTORNEY FOR THE APPLICANT]

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Patent Number

208155

Indian Patent Application Number

IN/PCT/2001/00970/MUM

PG Journal Number

42/2008

Publication Date

17-Oct-2008

Grant Date

18-Jul-2007

Date of Filing

13-Aug-2001

Name of Patentee

BAYER AKTIENGESELLSCHAFT

Applicant Address

D-51368 LEVERKUSEN,

Inventors:

#	Inventor's Name	Inventor's Address
1	HUBERT RAST	AUF DEM BRUCH 77 A, D -51381 LEVERKUSEN,
2	THOMAS HIMMLER	SCHONE AUSSICHT 1B, D-51519 ODENTHAL,

PCT International Classification Number

C07D 471/04

PCT International Application Number

N/A

PCT International Filing date

2000-02-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	199 08 449.1	1999-02-26	Germany