Indian Patents. 207886:CRYSTAL MODIFICATION OF A 8-CAYNO-1-CYCLOPROPYL-7-(1S,6S-2,8-DIAZABICYCLO[4.3.0]NONAN-8-YL)-6-FLUORO-1,4-DIHYDRO-4-OXO-3-QUINOLINECARBOXLYIC ACID

Title of Invention	CRYSTAL MODIFICATION OF A 8-CAYNO-1-CYCLOPROPYL-7-(1S,6S-2,8-DIAZABICYCLO[4.3.0]NONAN-8-YL)-6-FLUORO-1,4-DIHYDRO-4-OXO-3-QUINOLINECARBOXLYIC ACID
Abstract	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 (CCDC) of the crystal modification A, characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity 20 (2 theta) 6.70 8.92 12.44 13.66 15.96 17.60 21.42 21.78 28.97

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "CRYSTAL MODIFICATION OF A 8-CAYNO-l-CYCLOPROPYL-7-(IS,6S-2,8-DIAZABICYCLO[4.3.0]NONAN-8-YL)-6-FLUORO-l,4-DIHYDRO-4-OXO-3-QUINOLINECARBOXLYIC ACID" BAYER AKTIENGESELLSCHAFT, a company of Germany, D-51368, Leverkusen, Germany, GRANTED The following specification particularly describes the invention and the manner in which it is to be performed: 15-5-2006 ORIGINAL 134/MUMNP/2005 The present invention relates to a defined crystal modification of 8-cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yI)-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-1 -cyclopropyl-7-( 1 S,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-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS,6S)-2,8-diaza-bicyclo[4.3.0jnonane 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 unambiguously which of its crystal modifications is used for preparing the agent. 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 and its behaviour towards water, is easy to handle in pharmaceutical formulations. This object is achieved according to the invention by a novel crystalline form of CCDC which is referred to as modification A hereinbelow. The invention accordingly provides the crystalline modification A of CCDC which is characterized by an X-ray powder diffractogram having the reflection signals (2 theta) of high and medium intensity (> 30% relative intensity) listed in Table 1 below. ' Le A 33 269-Foreign Countries Table 1: X-ray powder diffractogram of CCDC of the modification A 2 0 (2 theta) 6.70 8.92 12.44 13.66 15.96 17.60 21.42 21.78 28.97 A characteristic X-ray powder diffractogram of the modification A is also shown in Figure 1 Moreover, the CCDC modification A according to the invention differs from other 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 A according to the invention. The CCDC of the modification A is, inter alia, characterized by a melting point, determined with the aid of differential thermoanalysis (DTA), of from 249 to 252°C. A characteristic differential thermodiagram is shown in Figure 2. CCDC of the modification A is also characterized in that it has an infrared spectrum, measured in KBr, as shown in Figure 3. CCDC of the modification A is furthermore characterized in that it is obtainable by Le A 33 269-Foreign Countries the preparation process given below. The crystal modification A of CCDC is obtained by dissolving CCDC of unknown modification or amorphous CCDC in hot water or a hot alcohol/water mixture, subsequently adding an alcohol and, after cooling to room temperature, isolating the precipitated solid. In a preferred embodiment, the alcohol used is ethanol or isopropanol. CCDC of the crystal modification A is surprisingly stable and does not change into another crystal modification or the amorphous form, even on prolonged storage. In addition, compared with amorphous CCDC, the modification A tends to absorb much less water from the atmosphere. 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 A, it is therefore possible to prepare, in a defined and targeted manner, stable solid preparations of CCDC. CCDC of the crystal modification A is highly active against pathogenic bacteria in the field 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 A 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 A was heated exposed to the atmosphere in an aluminium crucible at 10 K/min. The KBr ER spectrum was obtained using the FTS 60A unit from Biorad. The examples below illustrate the invention without limiting it. The solvent/base systems used in the examples below are particularly preferred. Le A 33 269-Foreign Countries Comparative Example A mixture of 3.07 g of 7-chIoro-8-cyano-l-cycIcpropyI-6-fluoro-I,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, 1.39g 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 of 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. At a relative atmospheric humidity of 95% (established using a saturated solution of Na2HP04 x 12 H20 with sediment in water), the solid obtained according to this procedure absorbs approximately 17 % by weight of water within one day. Example 1 617 g of CCDC of any modification are dissolved in 6170 ml of chloroform. 100 g of sodium sulphate are added, ihe mixture is stirred for 5 minutes and then filtered through 50 g of kieselguhr, which is then washed with 100 ml of chloroform. The solvent is distilled off on a rotary evaporator up to a residual pressure of 10mbar, resulting in a glass-like residue. 740 ml of water and 740 ml of ethanol are added to this residue, and the mixture is heated at 60°C until the entire residue has been dissolved. This solution is then added to 17 litres of boiling ethanol. This mixture is boiled for a further 5 minutes and then cooled to 35°C over a period of one hour. The precipitated crystals are filtered off with suction and dried at 20°C for.approximately Le A 33 269-Foreign Countries 16 hours and then at 30°C under reduced pressure until the weight remains constant. This gives 530 g of a solid which has the X-ray powder diffractogram shown in Figure 1, the differential thermodiagram shown in Figure 2 and the DR spectrum shown in Figure 3. At a relative atmospheric humidity of 95% (established using a saturated solution of Na2HP04 x 12 H20 with sediment in water), the solid obtained according to this procedure absorbs approximately 3% by weight of water within one day. Example 2 2 g of CCDC of unknown modification are dissolved in 4 ml of water. 4 ml of isopropanol are added, the reaction mixture is slowly heated with stirring and a further 32 ml oi' isopropanol are then added. The resulting clear solution is brought to the boil. The solution becomes turbid, and within a short period of time, crystals precipitate out. After 3 minutes at reflux, the heating is removed and the mixture is allowed to stand without stirring for 3 to 4 hours. The solid is then Filtered off with suction, washed with isopropanol and dried in the atmosphere until the weight remains constant. This gives 1.54 g of a solid which has an X-ray powder diffractogram identical to that shown in Figure 1, a differential thermodiagram identical to that shown in Figure 2 and an [R spectrum identical to that shown in Figure 3. WE CLAIM: 1. 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 (CCDC) of the crystal modification A, characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity 20 (2 theta) 6.70 8.92 12.44 13.66 15.96 17.60 21.42 21.78 28.97 2. 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 (CCDC) of the crystal modification A,v characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity 2 6 (2 theta) 6.70 8.92 . 12.44 13.66 15.96 17.60 21.42 21.78 28.97 . and a melting point, determined by DTA, of from 249°C to 252°C. 3. 8-Cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxlyic acid (CCDC) of the crystal modification A, obtainable by dissolving CCDC of unknown modification" or amorphous CCDC in water or a water/alcohol mixture, followed by hot precipitation after the addition of alcohol. Dated this 14th day of February, 2004. (JAYANTA PAL) OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"CRYSTAL MODIFICATION OF A 8-CAYNO-l-CYCLOPROPYL-7-(IS,6S-2,8-DIAZABICYCLO[4.3.0]NONAN-8-YL)-6-FLUORO-l,4-DIHYDRO-4-OXO-3-QUINOLINECARBOXLYIC ACID"
BAYER AKTIENGESELLSCHAFT, a company of Germany, D-51368, Leverkusen, Germany,
GRANTED
The following specification particularly describes the invention and the manner in which it is to be performed:

15-5-2006

ORIGINAL 134/MUMNP/2005

The present invention relates to a defined crystal modification of 8-cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yI)-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-1 -cyclopropyl-7-( 1 S,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-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS,6S)-2,8-diaza-bicyclo[4.3.0jnonane 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 unambiguously which of its crystal modifications is used for preparing the agent.
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 and its behaviour towards water, is easy to handle in
pharmaceutical formulations.
This object is achieved according to the invention by a novel crystalline form of CCDC which is referred to as modification A hereinbelow.
The invention accordingly provides the crystalline modification A of CCDC which is
characterized by an X-ray powder diffractogram having the reflection signals (2 theta) of high and medium intensity (> 30% relative intensity) listed in Table 1 below. '

Le A 33 269-Foreign Countries
Table 1:
X-ray powder diffractogram of CCDC of the modification A
2 0 (2 theta)
6.70
8.92
12.44
13.66
15.96
17.60
21.42
21.78
28.97
A characteristic X-ray powder diffractogram of the modification A is also shown in Figure 1 Moreover, the CCDC modification A according to the invention differs from other 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 A according to the invention.
The CCDC of the modification A is, inter alia, characterized by a melting point, determined with the aid of differential thermoanalysis (DTA), of from 249 to 252°C. A characteristic differential thermodiagram is shown in Figure 2.
CCDC of the modification A is also characterized in that it has an infrared spectrum, measured in KBr, as shown in Figure 3.
CCDC of the modification A is furthermore characterized in that it is obtainable by

Le A 33 269-Foreign Countries
the preparation process given below. The crystal modification A of CCDC is obtained by dissolving CCDC of unknown modification or amorphous CCDC in hot water or a hot alcohol/water mixture, subsequently adding an alcohol and, after cooling to room temperature, isolating the precipitated solid.
In a preferred embodiment, the alcohol used is ethanol or isopropanol.
CCDC of the crystal modification A is surprisingly stable and does not change into
another crystal modification or the amorphous form, even on prolonged storage. In
addition, compared with amorphous CCDC, the modification A tends to absorb much
less water from the atmosphere. 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 A, it is
therefore possible to prepare, in a defined and targeted manner, stable solid
preparations of CCDC.
CCDC of the crystal modification A is highly active against pathogenic bacteria in the field 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 A 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 A was heated exposed to the atmosphere in an aluminium crucible at 10 K/min.

The KBr ER spectrum was obtained using the FTS 60A unit from Biorad.
The examples below illustrate the invention without limiting it. The solvent/base systems used in the examples below are particularly preferred.

Le A 33 269-Foreign Countries
Comparative Example
A mixture of 3.07 g of 7-chIoro-8-cyano-l-cycIcpropyI-6-fluoro-I,4-dihydro-4-oxo-
3-quinolinecarboxylic acid, 1.39g 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 of 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.
At a relative atmospheric humidity of 95% (established using a saturated solution of Na2HP04 x 12 H20 with sediment in water), the solid obtained according to this procedure absorbs approximately 17 % by weight of water within one day.
Example 1
617 g of CCDC of any modification are dissolved in 6170 ml of chloroform. 100 g of
sodium sulphate are added, ihe mixture is stirred for 5 minutes and then filtered
through 50 g of kieselguhr, which is then washed with 100 ml of chloroform. The
solvent is distilled off on a rotary evaporator up to a residual pressure of 10mbar, resulting in a glass-like residue. 740 ml of water and 740 ml of ethanol are added to this residue, and the mixture is heated at 60°C until the entire residue has been dissolved. This solution is then added to 17 litres of boiling ethanol. This mixture is boiled for a further 5 minutes and then cooled to 35°C over a period of one hour. The precipitated crystals are filtered off with suction and dried at 20°C for.approximately

Le A 33 269-Foreign Countries
16 hours and then at 30°C under reduced pressure until the weight remains constant.
This gives 530 g of a solid which has the X-ray powder diffractogram shown in Figure 1, the differential thermodiagram shown in Figure 2 and the DR spectrum shown in Figure 3.
At a relative atmospheric humidity of 95% (established using a saturated solution of Na2HP04 x 12 H20 with sediment in water), the solid obtained according to this procedure absorbs approximately 3% by weight of water within one day.
Example 2
2 g of CCDC of unknown modification are dissolved in 4 ml of water. 4 ml of isopropanol are added, the reaction mixture is slowly heated with stirring and a further 32 ml oi' isopropanol are then added. The resulting clear solution is brought to the boil. The solution becomes turbid, and within a short period of time, crystals precipitate out. After 3 minutes at reflux, the heating is removed and the mixture is allowed to stand without stirring for 3 to 4 hours. The solid is then Filtered off with suction, washed with isopropanol and dried in the atmosphere until the weight remains constant. This gives 1.54 g of a solid which has an X-ray powder diffractogram identical to that shown in Figure 1, a differential thermodiagram identical to that shown in Figure 2 and an [R spectrum identical to that shown in Figure 3.

WE CLAIM:
1. 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 (CCDC) of the crystal modification A, characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity
20 (2 theta)
6.70
8.92
12.44 13.66 15.96 17.60 21.42 21.78 28.97
2. 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 (CCDC) of the crystal modification A,v characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity

2 6 (2 theta)
6.70
8.92 .
12.44
13.66
15.96
17.60
21.42
21.78
28.97
. and a melting point, determined by DTA, of from 249°C to 252°C.
3. 8-Cyano-l-cyclopropyl-7-(lS,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxlyic acid (CCDC) of the crystal modification A, obtainable by dissolving CCDC of unknown modification" or amorphous CCDC in water or a water/alcohol mixture, followed by hot precipitation after the addition of alcohol.
Dated this 14th day of February, 2004.
(JAYANTA PAL)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

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Patent Number

207886

Indian Patent Application Number

134/MUMNP/2005

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

29-Jun-2007

Date of Filing

15-Feb-2005

Name of Patentee

BAYER AKTIENGESELLSCHAFT

Applicant Address

GERMANY, D-51368, LEVERKUSEN,

Inventors:

#	Inventor's Name	Inventor's Address
1	THOMAS HIMMLER	SCHONE AUSSICHT 1B, D-51519 ODENTHAL,
2	WERNER HALLENBACH	LICHTENBERGEER STRASSE 68, D-40789 MONHEIM,
3	HUBERT RAST	AUF DEM BRUCH 77A, D-51381, LEVERKUSEN,

PCT International Classification Number

C07D

PCT International Application Number

PCT/EP99/08775

PCT International Filing date

1999-11-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	19854356.5	1998-11-25	Germany