FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
POLYMORPHS OF S-(-)-9-FLUORO-6,7-DIHYDRO-8-(4-HYDROXYPIPERIDIN-l-YL)-5-METHYL-l-OXO-lH,5H-BENZO[i,jlQUINOLlZlNE-2-CARBOXYLIC ACID LYSINE SALT
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D-4, MI DC, Chikalthana,
Aurangabad (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to novel polymorphs S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-1 H,5H-benzo[i,j]quinolizine-2-carboxylie acid lysine salt.
The following specification particularly describes the invention and the manner in which it is to be performed.


Field of the Invention
The present invention relates to novel polymorphs and processes for the preparation of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1 H,5H-benzo[i,j]quino lizine-2-carboxylic acid lysine salt (1)
O O

NH2 (1)
Background of the Invention
The fluoroquinolone class of compounds forms an important armamentarium as an antibacterial agent due to their broad spectrum and excellent pharmacokinetics. Several compounds from this class of antibacterials are in clinical use, for example nalidixic acid, norfloxacin, ofloxacin, ciprofloxacin and moxilloxaein. The fluoroquinolone, 9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-
1 H,5H-benzo[i,j]quinolixine-2-carboxylie acid referred as S-naditloxacin henceforth, is reported in the US 4.399,134. The Japanese patents .IP 63J92.753A and JP 05,339,238 A; disclose racemic nadifloxacin and S-(-)-nadifloxacin. Salts of the S-(-)-nadifloxacin are reported in the following patents and applications :-
PCT application WO 00/68229, PCT application WO 01/85095, WO 03/099815A1. WO 05/023805A1. L-lysine salt of S-(-)-nadifloxacin is reported in WO 00/68229. The present invention provides novel polymorphs of L-lysine salt of S-(-)-nadifloxaein. The occurrence of different crystal polymoiphs is a property of some molecules and molecular complexes. A single molecule, or its salt may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum. The differences in the physical properties of polymoiphs result from the orientation and intemiolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymoiphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other tonus in the polymorph family. One of the most important physical properties of
pharmaceutical polymorphs is their stability under various conditions of temperature and humidity. It is important from the large-scale manufacturability that the active drug substance is stable to handling and storage conditions.
Description of the Drawings
FIG. 1 is Powder X-Ray Diffractogram pattern of crystalline S-(-)-9-Fluoro-6,7-dihydro-8-(4-
hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH.5H-bcnzo[ij]quinolizine-2-carboxylic acid lysine
salt.
FIG. 2 is Infra-Red spectrum of crystalline S-(-)-9-fluoro-6.7-dihydro-8-(4-hydroxypiperidin-
l-yl)-5-methyl-l-oxo-l H,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
FIG. 3 is Powder X-Ray Diffractogram pattern of amorphous S-(-)-9-fluoro-6,7-dihydro-8-
(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-l H,5H-benzo[i,j]quinolizine-2-carboxylic acid
lysine salt.
FIG. 4 is Infra-Red spectrum of amorphous S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy
piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quino!izine-2-carboxylic acid lysine salt.
Summary of the Invention
The present invention provides novel polymorphs of S-(-)-9-fluoro-6.7-dihydro-8-(4-
hydroxypiperidin-l-yl)-5-methyl-l-oxo-l H,5H-benzo[i,j]quinolizine-2-earboxylic acid lysine
salt (1). The invention also relates to novel processes for the preparation of the polymorphs.
The invention further provides pharmaceutical compositions comprising the compounds of
the present invention. In yet another aspect, the invention provides a method of treating
bacterial infections using a phamiaceutical composition comprising the polymorph of the
invention. A further aspect of the invention describes the characterization of the polymorphs
of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-I H,5H-
benzo[i,j]quinolizine -2-carboxylic acid lysine salt (1).





Detailed Description of the invention
The present invention provides novel polymorphs of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-1-oxo-l H,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt (1). One embodiment of the present invention provides a crystalline polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1 H,5H-benzo[ i,j jquino lizine-2-carboxylic acid lysine salt (1). Another embodiment of the present invention provides an amorphous polymorph of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-earboxylie acid lysine salt (1).
The invention also relates to the novel processes for the preparation of the polymorphs. The present invention further provides a process for preparing crystalline polymorph of S-(-)-9-nuoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-l-oxo-1 H,5H-benzo[i,j]quinolizine -2-carboxylic acid lysine salt, comprising following steps;
(a) treating S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-1-oxo-l H.5H-
benzo[i,j]quinolizine-2-carboxylic acid with L-lysine in solvent mixture of organic solvent
and water;
(b) heating the reaction mixture at a temperature in the range of 65 to 85 "C;
(c) cooling the suspension to effect precipitation;
(d) isolating crystalline polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-
yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid lysine salt.
The organic solvent in step (a) is water miscible solvent selected from acetone or acetonitrile. The organic solvent: water mixture used in the step (a) is in the range of 3:1 to 6:1 parts by volume.
Furthermore the present invention provides a process for preparing amorphous polymorph of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl- 1-oxo-l H,5H-benzo[i,j] quinolizine-2-earboxylic acid lysine salt, comprising following steps;
(a) treating S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-IH,5H-
benzo[i.j]quinolizine-2-carboxylic acid with L-lysine in solvent mixture of organic solvent
and water;
(b) heating the reaction mixture at a temperature in the range of 65 to 85 °C;


(c) isolating the crude S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-
oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylie acid lysine salt;
(d) stirring the above product in an organic solvent;
(e) isolating amorphous form of S-(-)-9-fluora-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-
methyl-l-oxo-1 H,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
The organic solvent in step (a) is water miscible solvent selected from acetone or acetonitrile or methanol. The organic solvent: water mixture used in the step (a) is in the range of 2:1 to 15:1 parts by volume. The organic solvent in step (d) is preferably ethers such as diethyl ether, dioxane, hexane, heptane, pentane.
Another embodiment of the present invention is identification and characterization of the polymorphs of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt by X-Ray Powder Diffractogram (XRPD), Differential Scanning Colorimetry thermogram (DSC) and Infra-red spectrum (1R). The crystalline polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-mcthyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt is characterized by X-ray powder diffraction pattern with peaks at (20 values) 9.70 ± 0.2, 14.10 ± 0.2, 15.40 ± 0.2, 19.58 ± 0.2. 23.04 ± 0.2 and 28.28 ± 0.2 as shown in FIG. 1. The DSC exhibits a significant endotherm peak at 158.0 °C and exothermic peaks at 125.33 °C and 231.50 CC. The characteristic 1R values at (KBr, cm-1) 3431, 2962, 1620, 1599, 1576 as shown FIG. 2.
The amorphous polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzofi,j]quinolizine-2-carboxylic acid lysine salt is characterized by X-ray powder diffraction pattern depicted in FIG. 3. The characteristic IR values at (KBr, cm" ') 2940, 1618, 1580. 1490, 1449, 1395, 1358, 1258, I 177, 1 134. 1065, 1031, 985, 822. 659 as shown FIG. 4.
The polymorphs of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid L-lysine salt of this invention are useful for preparation of pharmaceutical composition. The antibacterial polymorphic compound of the invention is useful in the treatment of humans and animals in need of prophylaxis and/or therapy for systemic or topical bacterial infections especially resistant gram-positive organism infections, gram-negative organism infections, mycobacterial infections and


nosocomial pathogen infections, which composition comprises an amount of the compound of the invention substantially sufficient to eradicate said infection, but not to cause any undue side effects. The eompound and compositions of this invention can be administered to for prevention of bacterial infections to humans and animals who are at risk of being infected, for example a compound or composition of this invention can be administered to a patient prior to and/or after surgery, health care workers or others who are at risk of being infected. These findings have an important implication from the point of view of the systemic use of the eompound of the invention in view of its superior potency, superior bactericidal activity, expanded biospeetrum, better bioavailability and improved tolerability which are now enabled to be administered systemically in therapeutically effective doses. Utilizing the compound of the invention, whether in systemic or topical dosage form, results in clearer dose-related definitions of efficacy, diminished toxic effects and accordingly an improved therapeutic index.
The bacterial infections which can be treated by using the compound and composition comprising the eompound of invention are infections such as impetigo, pneumonia, bronchitis, skin and soft tissue infections, respiratory tract infections, pharyngitis, endocarditis, urinary tract infections, gastro-intestinal infections and bacteremias caused by Staphylococcus aureus, coagulase negative staphylococci, methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase negative staphylococci, enterococci. beta-haemolytic streptococci, viridans group of streptococci, mycobacterial infections due to multi-drug resistant M. tuberculosis and other atypical mycobacteria such as M. intracellulare and M. avium, as well as newly emerging Gram-negative pathogens such as Chryscobacterium meuingosepticum, Chryseohacteriuin inc/ologense and other Gram-negative pathogens such as E. coli. Klebsiella, Proteus, Serratia. Citrobacter. and Pseudomonas.
The present invention encompasses of administering the compound of present invention to a human or other animal subject. The compound and compositions to be used in the invention must, accordingly, be phamiaeeutically acceptable. As used herein, sueh a "pharmaeeutieally acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.


The phannaceutical compositions are prepared according to conventional procedures used by persons skilled in the art to make stable and effective compositions. Such methods include combining the polymorph of this invention with a suitable carrier, diluent, solvent or excipient. In the solid, liquid, parenteral and topical dosage forms, an effective amount of the active compound or the active ingredient is used which produces the desired results. The polymorphs of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-lH,5H-benzo[i,j]-quinolizine-2-carboxylie acid L-lysine salt can be used to prepare aqueous dosage forms. It can also be used to prepare tablets by wet and dry granulation.
The pharmaceutical compositions of the compounds of invention could be oral solid dosage forms. The dosage forms can be prepared by any conventional techniques recognized in the art, but would preferably be formulated by mixing the polymorph of the invention with the other ingredients. The other ingredients utilized to formulate solid oral dosage forms would include conventional inert ingredients such as microcrystalline cellulose, methyl cellulose and the like, suitable sweetening and/or flavouring agents, and preservatives thereof if required. Such solid oral dosage forms or dry formulations suitable for the preparation of suspensions would be formulated such that they would contain an effective dose of the compound of the invention. In general, solid dosage forms containing 100 mg-2000 mg of the compound of the invention are contemplated. Preparations suitable for oral suspension would contain a similar dosage. Pharmaceutical formulations can be formulated together with auxiliaries and additives usually employed in pharmacy, such as tablet binders, fillers, preservatives, tablet disintegrating agents, flow regulating, agents, plasticizers. wetting agents, dispersing agents, emulsiliers, solvents, pH altering additives, flavourings and the like.
A second preferred method is parenteral route, for intramuscular, intravenous or subcutaneous administration. When the pharmaceutical composition is formulated into an injectable preparation, in formulating the pharmaceutical composition into the form of a solution or suspension, all diluents customarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent. It is preferred that the concentration of active ingredient in the injectable preparation be in the range of 0.1 mg/ml to 100 mg/ml.


A third preferred route of administration is topically, for which creams, ointments, sprays, shampoos, lotions, gels, dusting powders and the like are well suited. Generally, an effective amount of the compound according to the present invention in a topical form 0.1% composition is to about 10% by weight of the total composition. Preferably, the effective amount is 1% of the total composition.
For topical application, there are used as non-sprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water. Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are. if desired, sterilized or mixed with auxiliary agents, e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc. For topical application, also suitable are sprayable aerosol preparations wherein the active ingredient preferably in combination with a solid or liquid inert carrier material. In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536.809; 3,598,123 and 4,008,719; the disclosures of which are hereby incorporated by reference. The total daily dose range is generally from about 200 mg to about 1 500 mg of the Lysine salt form. However, the dose may be higher or lower depending on the needs and conditions of the patient.
The following detailed examples serve to more fully illustrate the invention without limiting its scope. It is understood that various other embodiments and modifications in the practice of the invention will be apparent to, and can be readily made by, those or ordinary skill in the art without departing from the scope and spirit of the invention as described above. The invention is further described with reference to the following experimental work.


EXAMPLE-1
Preparation of crystalline S-(-)-c)-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid L-lysinc salt:
S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-1-oxo-l H,5H-benzo[i,j] quinolizine-2-carboxylic acid (30 g. 0.083 mol, chiral purity 96.94%) in acetone (600 ml): water (150 ml) mixture (4:1) was heated to 70 °C to obtain a clear solution. To the clear solution, L-lysine monohydrate (14.0 g, 0.85 mol) was added as a solid. The reaction mixture was stirred for 1 hour at 70 °C whereupon suspension was obtained. The suspension was cooled to 30 °C to 35 °C and was filtered under suction to provide a crystalline solid. The solid was dried at 50 °C to 55 °C under vacuum (50 mbar) to furnish title compound in 40 g quantity, m/z 361.1 (M+l), [a]D 2S -199.47° ( c 1, methanol), Chiral purity by HPLC: 99.60%. The polymorph was characterized by the following analytical data. Differential Scanning Colorimetry (DSC): endotherm peak at 158.0 °C and exothermic peaks at 125.33 °C and 231.50 °C.
XRPD analysis: (20 values): 9.70 ± 0.2, 10.58 ± 0.2, 12.20 ± 0.2, 13.54 ± 0.2, 14.10 ± 0.2, 14.42 ±0.2, 15.40 ±0.2, 16.26 ±0.2, 17.44 ±0.2, 18.94 + 0.2, 19.58 ± 0.2, 20.82 ± 0.2, 21.44 ± 0.2. 21.74 ± 0.2, 22.42 ± 0.2, 23.04 ± 0.2, 23.66 ± 0.2, 23.96 ± 0.2, 24.40 ± 0.2, 25.26 ± 0.2, 26.38 ± 0.2, 27.44 ± 0.2, 27.66 ± 0.2, 28.28 ± 0.2, 28.44 ± 0.2, 29.24 ± 0.2, 29.62 ± 0.2, 29.96 ± 0.2. 30.54 ± 0.2, 31.24 ± 0.2, 33.88 ± 0.2. 34.32 ± 0.2, 34.70 ± 0.2, 36.08 ± 0.2, 37.50 ± 0.2, 38.08 ± 0.2, 38.60 ± 0.2.
IR values (KBr. Cm-1): 3431, 2962, 1620, 1599, 1576, 1451, 1418, 1391, 1375, 1356, 1338. 1260, 1 185, 1060, 950, 891, 820, 663, 568, 507.
EXAMPLE-2
Preparation of amorphous S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylie acid L-lysine salt:
(S)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-1-oxo-l H,5H-benzo-[i,j]-quinolizine-2-carboxylic acid (1.0 gm; 2.77 mol) was dissolved in 40 ml of methanol. To this solution L-Lysine (0.456; 2.77 mol) and water (4 ml) was added and the reaction mixture was heated. The reaction mixture, which was turbid initially, was turned to a clear solution at 65-70 °C. The reaction mixture was stirred for 15 min at temperature between 65-70°C. The reaction mixture was cooled to room temperature. The solvent was evaporated under vacuum at temperature below 25 °C to provide oily residue. The oily residue was then stirred with


diethyl ether (20 ml) whereupon the solid was precipitated which was filtered and dried under vacuum at temperature between 25-30 °C to provide free flowing solid in quantitative yield, m/z 361.1 (M+l), [a]D25 =-194.40° ( c 1, methanol).
1R values (KBr, cm-1): 2940, 1618, 1580, 1490, 1449. 1395, 1358, 1258, 1177, 1134, 1065, 1031,985,822,659 cm-1.
TEST EXAMPLE-1
X-ray Powder Diffraction Analysis: 300 mg each of the teat sample prepared as above were thinly spread on a sample holder. X-ray powder diffraction analyses (4()kv x 40 mA Rigaku D/max 2200) were performed under the conditions listed below:
Scan speed 5/ min
Sampling time 7 min
Scan mode: continuous
20/0 reflection
Cu target (Ni filter) Results of the X-ray diffraction analysis of test compounds are depicted in FIG. 1 and FIG. 3.
TEST EXAMPLE-2
Thermal Analysis: For the Differential Scanning Calorimetry, PERK1N-ELMER system was used. 2.5 mg of the sample was weighed into the aluminum pan, which was then press sealed with an aluminum lid. After three tiny needle holes were made on the lid the sample was tested by heating from 30 °C to 300 °C at a rate of 10 °C/min.
TEST EXAMPLE-3
Infra-red speetrum analysis: Infra-red spectrum was obtained on BRUCKER VECTOR 22 system and by using KBr pellet. Results of the Infra-red speetrum analysis of the test compounds are depicted in FIG. 2 and FIG. 4.

CLAIMS:
1. Crystalline polymorph of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-
methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
2. The crystalline polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-earboxylic acid lysine salt according to claim 1, characterized by X-ray powder diffraction pattern with peaks (20) 9.70 ± 0.2, 14.10 ± 0.2, 15.40 ± 0.2, 23.04 ± 0.2 and 28.28 ± 0.2.
3. The crystalline polymorph of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylie acid lysine salt of claim 1, having characteristic differential scanning calorimctry thermogram, having endotherm peak at 158.0 °C.
4. The crystalline polymorph of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylie acid lysine salt of claim 1, having characteristic bands at 3431, 2962, 1620, 1599, 1576 cm-1 in Infra red spectrum.
5. Amorphous polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-
methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
6. The amorphous form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-1-oxo-l H,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt of claim 5, having characteristic bands at 1619, 1450, 1258, 1064 cm ' in Infra red spectrum.
7. The process for the preparation of crystalline polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt, comprising:
(a) treating S-(-)-9-tluoro-6,7-dihydro-8-(4-hydioxypipcridin-l-yl)-5-methyl-l-oxo-l H,5H-
benzo[i,j]quinolizine-2-carboxylic acid with L-lysine in solvent mixture of organic solvent
and water;
(b) heating the reaction mixture at a temperature in the range of 65 to 85 °C;
(c) cooling the suspension to effect precipitation;
(d) isolating crystalline polymorph of S-(-)-9-fiuoro-6,7-dihydro-8-(4-hydroxypiperidin-l-
yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
8. The process for the preparation of amorphous form of S-(-)-9-tluoro-6,7-dihydro-8-(4-
hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine
salt comprising:


(a) treating S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-1 H,5H-
benzo[i,j]quinolizine-2-carboxylic acid with L-lysine in solvent mixture of organic solvent
and water;
(b) heating the reaction mixture at a temperature in the range of 65 to 85 °C;
(c) isolating the crude S-(-)-9-tluoro-6.7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-
oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylie acid lysine salt;
(d) stirring the above product in an organic solvent;
(e) isolating amorphous form of S-(-)-9-tluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-
methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
9. A phamiaccutical composition comprising crystalline polymorph of S-(-)-9-fluoro-6,7-
dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-l H,5H-benzo[i,j]quinolizine-2-
carboxylic acid lysine salt and pharmaceutically acceptable carriers, excipients or diluents.
10. A phamiaccutical composition comprising amorphous polymorph of S-(-)-9-fluoro-6,7-
dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-1 H,5H-benzo[i,j]quinolizine-2-
carboxylic acid lysine salt and pharmaceutically acceptable carriers, excipients or diluents.

ABSTRACT
The present invention relates to novel polymorphs S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt. The invention also relates to the novel process for the preparation of the polymorphs. The invention further provides pharmaceutical compositions using the compounds of present invention.