FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -: Improved methods for the quantitative determination of
rivaroxaban and its known impurities.
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which is to be performed.:

Field of the invention:
The present invention relates to an improved reversed-phase liquid chromatographic (RP-LC) method (Method-!) for the quantitative determination of rivaroxaban and its known impurities (Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G) and (Method-II) for the quantitative determination of known impurities of rivaroxaban namely impurity-B and impurity-H. The present invention farther provides a stability indicating analytical method using the samples generated from forced degradation studies.
Background of the invention:
Rivaroxaban is chemically known as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)phenyl]-1,3-oxazolidin-5-y1}methyl)-2-thiophene-carboxamide.
Rivaroxaban is an oral anticoagulant. It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effect lasts 8-12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.
Structure of Rivaroxaban:

The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the rivaroxaban contained in the product mixture into an active pharmaceutical ingredient ("API"), the rivaroxaban must be analyzed for purity, typically by UPLC, HPLC or GC analysis, to determine if it is suitable for continued processing or ultimately for use in a pharmaceutical product.
The U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER) has promulgated guidelines recommending that drug applicants identify organic impurities of 0.1% or greater in the active ingredient. "Guideline on Impurities in New Drug Substances," 61 Fed. Reg. 371 (1996); "Guidance for Industry ANDAs: Impurities in Drug Substances," 64 Fed. Reg. 67917 (1999). Unless an impurity has been tested for safety, is in a composition proven to be safe in clinical trials, or

is a human metabolite, the CDER further recommends that the drug applicant reduce the amount of the impurity in the active ingredient to below 0.1%. In order to obtain marketing approval for a new drug product, manufacturers must submit to the regulatory authority evidence that the product is acceptable for administration to humans. Such a submission must include, among other things, analytical data showing the impurity profile of the product to demonstrate that the impurities are either absent, or present in a negligible amount. Therefore, there is a need for analytical methods to detect impurities to identify and assay those impurities.
Generally, impurities (side products, byproducts, and adjunct reagents) are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("Rt"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRt") to identify impurities.
Summary of the invention:
In one aspect, the present invention provides a reversed-phase liquid chromatographic (RP-LC) method for the quantitative determination of rivaroxaban
In another aspect, the present invention provides a reversed-phase liquid chromatographic (RP-LC) method for the quantitative determination of impurity-B and impurity-H.
In another aspect, the present invention provides an HPLC method for rivaroxaban containing less than about 5% area by HPLC, preferably less than about 3% area by HPLC, more preferably less than 1% area by HPLC, of total impurities.
In another aspect, the present invention provides an HPLC method for rivaroxaban containing less than about 5% area by HPLC, preferably less than about 3% area by HPLC, more preferably less than 1% area by HPLC, of impurity-B and impurity-H.
In another aspect, the present invention further provides a stability indicating analytical method using the samples generated from forced degradation studies.

In another aspect, the present invention provides a simple, accurate and well-defined stability indicating and High performance liquid chromatography (HPLC) method for the determination of impurity-B and impurity-H in the presence of degradation products.
In another aspect, the present invention provides a simple, accurate and well-defined stability indicating a High performance liquid chromatography (HPLC) method for the determination of rivaroxaban in the presence of degradation products.
In another aspect, the HPLC method described in the present invention has the following advantages
when compared with prior art methods for determining rivaroxaban and its related impurities:
i) Gradient profile to elute all related impurities and organic phase is 70% which ensure the elution
and detection of non polar impurities forming during the process or stress study; ii) The present method mobile phase pH is about 4.0 which is more stable in all C18 HPLC columns; iii) Consistency in specificity, precision & reproducibility with good peak shape; and iv) The degradation impurities from stress studies are well separated from the known impurities.
In another aspect, the HPLC method described in the present invention has the following advantages
for determining impurity-B and impurity-H:
i) Gradient profile to elute all related impurities and organic phase is up to 40% which ensure the
elution and detection of non polar impurities forming during the process or stress study; iv) The present method mobile phase pH is about 4.0 which is more stable in all C18 HPLC columns; v) Consistency in specificity, precision & reproducibility with good peak shape; and iv) The degradation impurities from stress studies are well separated from the known impurities
Brief description of drawings:
Fig. 1 illustrates the HPLC chromatogram of spiked (lmpurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G spiked in rivaroxaban) sample.
Fig. 2 illustrates the HPLC chromatogram of spiked (Impurity-B and impurity-H spiked in rivaroxaban) sample.
Detailed description of the invention:
As used herein, "limit of detection (LOD)" refers to the lowest concentration of analyte that can be clearly detected above the base line signal, is estimated is three times the signal to noise ratio.
As used herein, "limit of quantization (LOQ)" refers to the lowest concentration of analyte that can be quantified with suitable precision and accuracy, is estimated as ten times the signal to noise ratio.

As used herein, "gradient elution" refers to the change in the composition of the gradient eluent over a fixed period of time, stepwise or at a constant rate of change, as the percentage of the first eluent is decreased while the percentage of the second eluent is increased.
As used herein, "gradient eluent" refers to an eluent composed of varying concentrations of first and second eluents.
The main known impurities of rivaroxaban are:
(i)2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Impurity-A) which has the following structure:

The impurity-A is detected and resolved from rivaroxaban by HPLC with a relative retention time (hereafter referred as RRT) of 0.89.
(ii) 5-chlorothiophene-2-carboxylic acid (Impurity-C). which has the following structure:

The Impuriry-C is detected and resolved from rivaroxaban by HPLC with an RRT of 0.33.
(iii)N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyi)-2-thiophenecarboxamide(Impurity-D), which has the following structure:

The impurity-D is detected and resolved from rivaroxaban by HPLC with an RRT of 0.57.
(iv) 5-chloro-N-methylthiophene-2-carboxamide (Impurity-E), which has the following structure:

The impurity-E is detected and resolved from rivaroxaban by HPLC with an RRT of 0,63. (v) N-Methyl phthalimide (Impurity-F), which has the following structure:

The impurity-F is detected and resolved from rivaroxaban by HPLC with an RRT of 0.68. (vi) 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl] amino}propyl] thiophene-2-carboxamide (Impurity-G) which has the following structure:

The Impurity-G is detected and resolved from rivaroxaban by HPLC with an RRT of 0.84.
(vii)2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino) propyl]-lR- isoindole-l,3(2H)-dione. Hydrochloride (Impurity-B) which has the following structure:

The impurity-B is detected and resolved from rivaroxaban by HPLC with a relative retention time (hereafter referred as RRT) of 0.18.
(viii)N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl) acetamide (Impurity-H), which has the following structure:

Impurity-H is detected and resolved from rivaroxaban by HPLC with an RRT of 0.32,

According to one aspect of the present invention, there is provided a reversed-phase liquid chromatographic (RP-LC) method for quantifying, by area percent, the amounts of impurity-B and impurity-H present in a sample of rivaroxaban.
According to another aspect of the present invention, there is provided a reversed-phase liquid chromatographic (RP-LC) method for quantifying, by area percent, the amounts of rivaroxaban and all impurities, preferably, Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G present in a sample of rivaroxaban.
According to another aspect of the present invention, there is provided a stability indicating analytical method using the samples generated from forced degradation studies.
According to another aspect of the present invention, there is provided an accurate and well-defined stability indicating HPLC method for the determination of rivaroxaban in the presence of degradation products.
Preferably, the method for determining the amount of impurities in a rivaroxaban sample comprises the steps of:
a) combining a Rivaroxaban sample with water and acetonitrile in the ratio of 20:80 (v/v) to obtain a solution;
b) injecting the sample solution into a 250mm x4.6 mm column with 3.0 um Unison UK-C18 column;
c) Gradient eluting the sample with a mixture of A Eluent and B Eluent in the ratio of 80:20 (v/v) initial.
d) Preparing Eluent A by dissolving 2.76 g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted orthophosphoric acid and filter through 0.45 micron filter paper.
e) Measuring of the amounts of rivaroxaban and each impurity at 240 nm wavelength with a UV detector (having an appropriate recording device).
Preferably, the initial ratio of eluent A and eluent B in step-(c) may be continued at the same ratio for 5 minutes then changed linearly to 60:40 (v/v). Again changed the ratio linearly to 30:70 (v/v) followed by same ratio for 5 minutes. After 2 minutes the initial gradient of 80:20 is for 8 minutes to be conditioned for every analysis. The column temperature may be maintained at about 35°C.
The LOD /LOQ values of rivaroxaban and its related impurities, Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G are summarized in Table 1.
Table 1

S.No Components LOD (%) LOQ (%)
1 Impurity-A 0.0030 0.0091
2 Impurity-C 0.0054 0.0162
3 Impurity-D 0.0039 0.0118
4 Impurity-E 0.0049 0.0149
5 Impurity-F 0.0033 0.0099
6 Impurity-G 0.0048 0.0147
7 Rivaroxaban 0.0043 0.0129
Specificity is the ability of the method to measure the analyte response in the presence of its potential impurities and degradation products. The specificity of the LC method for rivaroxaban. Intentional degradation was attempted to stress conditions of acid hydrolysis (using 1 .0M HC1), base hydrolysis (using 1.0M NaOH), and oxidative degradation (using 3.0% H202), thermal and photo degradation to evaluate the ability of the proposed method to separate rivaroxaban from its degradation products. To check and ensure the homogeneity and purity of rivaroxaban peak in the stressed sample solutions, PDA-UV detector was employed.
Preferably, the limit of detection (LOD) and limit of quantification (LOQ) were estimated by signal to noise ratio method, by injecting a diluted solution with known concentration.
The accuracy of the related substances method with the spiked impurities was evaluated at 0.15 % concentration level,
According to another aspect of the present invention, there is provided a chromatographic method to get the separation of all impurities and stress studies degradants from analyte peak. Satisfactory chromatographic separation was achieved using the mobile phase consists of buffer (2.76 g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted orthophosphoric acid) In the optimized conditions the rivaroxaban, Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G were well separated and the typical retention times (RT) of rivaroxaban, Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G were about 30.57, 27.17, 9.58, 17.27, 19.13, 20.80 and 25.65 minutes respectively, and typically shown in Figure 1. The system suitability results and the developed LC method was found to be specific for rivaroxaban and its six impurities, namely Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G.

The system suitability values and mass numbers of rivaroxaban and its impurities were summarized in Table 2.
Table 2

Compound (n=l) Rt Rs N T (m/z)
Impurity-A 27.17 3.57 70I7I 0.94 421.4
Impurity-C 9.58 10646 0.99 162.6
Impurity-D 17.27 19.80 30185 0.97 401.4
Impurity-E 19.13 4.44 30509 0.95 175.6
Impurity-F 20.80 3.60 30238 0.94 161.2
Impurity-G 25.65 11.07 69578 1.13 409.9
Rivaroxaban 30.57 8.16 84647 0.88 435.9
*n=l: determination, Rt: retention time, Rs: USP resolution, N: number of theoretical plates (USP tangent method), T: USP tailing factor, m/z: mass number.
Degradation in test solution was observed using 1M Sodium hydroxide at room temperature for 1 hour, 1 M HC1 at 60°C for 1 hour and 3% H202 at 60°C for 6 hours in extreme oxidative degradation condition. Impurities observed in stress condition using PDA detector, Major degradants was impurity-G .Other unknown were also specific in this method The peak test results obtained from PDA & IX-MS/MS confirm that the rivaroxaban peak is homogeneous and pure in alt analyzed stress samples.
The percentage recovery of rivaroxaban of its impurities in bulk drug samples was done at 0.15 %. The percentage recovery of Impurity-A, impurity-C, impurity-D, impurity-E, impurity-F and impurity-G in bulk drugs samples was ranged from 90.00 to 110.00.
According to another aspect of the present invention, there is provided an accurate and well-defined stability indicating HPLC method for the determination of impurity-B and impurity-H in the presence of degradation products.
Preferably, the method for determining the amount of impurities in a rivaroxaban sample comprises the steps of:
a) combining a Rivaroxaban sample with water and acetonitrile in the ratio of 70:30 (v/v) to obtain a solution;
b) injecting the sample solution into a 250mm x 4.6 mm column with 5.0 urn Enable C18-G column;

c) gradient eluting the sample with a mixture of A Eluentand B Eluent in the ratio of 82:} 8 (v/v) initial.
d) Preparing Eluent A by dissolving 2.76 g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted orthophosphoric acid and filter through 0.45 micron filter paper.
e) Measuring of the amounts of impurity-B and impurity-H at 250 nm wavelength with a UV detector (having an appropriate recording device).
Preferably, the initial ratio of eluent A and eluent B in step-(c) may be change linearly to 60:40 (v/v), followed by same ratio for 5 minutes. After 3 minutes the initial gradient of 80:20 is for 7 minutes to be conditioned for every analysis.
The LOD /LOQ values of impurity-B and impurity-H are summarized in Table 3.
Table 3

S.No Components LOD (%) LOQ (%)
1 Impurity-B 0.0054 0.0162
2 Impurity-H 0.0046 0.0138
Specificity is the ability of the method to measure the analyte response in the presence of its potential impurities and degradation products. The specificity of the LC method for rivaroxaban. Intentional degradation was attempted to stress conditions of acid hydrolysis (using 1.0M HC1), base hydrolysis (using 1.0M NaOH), and oxidative degradation (using 3.0% H2O2), thermal and photo degradation to evaluate the ability of the proposed method to separate impurity-B and impurity-H from the degradation products. To check and ensure the homogeneity and purity of rivaroxaban peak in the stressed sample solutions, PDA-UV detector was employed.
Preferably, the limit of detection (LOD) and limit of quantification (LOQ) were estimated by signal to
noise ratio method, by injecting a diluted solution with known concentration.
The accuracy of the related substances method with the spiked impurities was evaluated at 0.15 % of
concentration levels,
According to another aspect of the present invention, there is provided a chromatographic method to
get the separation of impurity-B and impurity-H and stress studies degradants from analyte peak.
Satisfactory chromatographic separation was achieved using the mobile phase consists of buffer (2.76
g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted
orthophosphoric acid.) In the optimized conditions the rivaroxaban, Impurity-B and impurity-H were
well separated and the typical retention times (RT) of rivaroxaban, Impurity-B and impurity-H were

about 18.85, 3.42 and 6.08 minutes respectively, and typically shown in Figure 2. The system
suitability results and the developed LC method was found to be specific for impurity-B and
impurity-H.
The system suitability values and mass numbers of impurity-B and impurity-H were summarized in
Table 4.
Table 4

Compound (n=l) Rt Rs N T (m/z)
impurity-B 3.42 8301 1.23 327.7
Impurity-H 6.08 16.50 22171 1.12 333.3
Rivaroxaban 18.85 67.13 127981 1.01 435.9
*n=l: determination, Rt: retention time, Rs: USP resolution, N: number of theoretical plates (USP tangent method), T: USP tailing factor, m/z: mass number.
Degradation was not observed using extreme oxidative, basic and acidic condition. Other unknown were also specific in this method. The peak test results obtained from PDA & LC-MS/MS confirm that the rivaroxaban peak is homogeneous and pure in all analyzed stress samples.
The percentage recovery of rivaroxaban of its impurities in bulk drug samples was done at 0.15 %.
The percentage recovery of Impurity-B and impurity-H in bulk drugs samples was ranged from 90.00
to 110.00.
In deliberate varied chromatographic conditions (pH and column), the robustness of the method is
confirmed.
Experimental-1
The LC system, used for method development and forced degradation studies and method validation was Waters-Alliance (manufactured by Waters India Ltd) LC system with a photo diode detector. The out put signal was monitored and processed using Empower software system (designed by Waters India) on IBM computer (Digital Equipment Co).
The chromatographic column used was a Unison UK-C18, 250mm x 4.6mm,_coIumn with 3.0 u.m particles. The mobile phase consists buffer (2.76 g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted orthophosphoric acid), and solvent is acetonitrile. The flow rate of the mobile phase was kept at 1.0 ml/min. Beginning with the gradient ratio of mobile phase buffer and solvent 80:20(v/v), system was continued at the same ratio for 5 minutes. The ratio was changed linearly 60:40(v/v) in 35 minutes, again the ratio was changed linearly 30:70(v/v) in 5 minutes and again system was continued at the same ratio for 5 minutes. After 2 minutes the initial gradient of 80:20 is for 8 minutes to be conditioned for every analysis. The column temperature was

maintained at 35°C and the wavelength was monitored at a wavelength of 240 nm. The injection volume was 10 μL for related substances determination. Water: Acetonitrile :: 20:80 (v/v) was used as diluent during the standard and test samples preparation.
Preparation of reference solution-l (Impurity Stock solution).
7.5 mg each of Impurity-A, Impurity-C, Impurity- D, Impurity-E, Impurity-F and lmpurity-G standard were accurately weighed and transferred to the l00mL volumetric flask(BOROSIL-Class-A), 20 mL of diluent was added in to the flask and shaken for five
minutes in an ultrasonic bath and made up to mark with diluent.
Preparation of reference solution-2 (Standard stock preparation);
Weigh and transfer about 50 mg of Rivaroxaban standard into a 50mL volumetric flask, add about 30 mL diluent and sonicate to dissolve it. Make up the volume with diluent and mix well. Dilute 1.0 mL of this solution to 100 mL with diluent.
Reference solution (a) preparation.
Add 1.0 mL impurity stock solution and 5 mL of standard stock preparation into 50 mL volumetric flask and make up the volume with diluent and mix well.
Reference solution (b) preparation:
Dilute 5 mL of Standard stock preparation into 50 mL volumetric flask and make up the volume with
diluent.
Experimental-2
The LC system, used for method development and forced degradation studies and method validation was Waters-Alliance (manufactured by Waters India Ltd) LC system with a photo diode detector. The out put signal was monitored and processed using Empower software system (designed by Waters India) on IBM computer (Digital Equipment Co).
The chromatographic column used was Eable-C18 G, 250mm x 4.6mm, column with 5.0 u,m particles. The mobile phase consists of buffer (2.76 g of sodium dihydrogen phosphate monohydrate in 1000 mL of water. Adjust the pH 4.0 with diluted orthophosphoric acid), and solvent is acetonitrile. The flow rate of the mobile phase was kept at 1.0 ml/min. Beginning with the gradient ratio of mobile phase buffer and solvent 82:18(v/v, the ratio was changed linearly 60:40(v/v) in 15 minutes, and system was continued at the same ratio for 5 minutes. After 3 minutes the initial gradient of 82:18 is for 7 minutes to be conditioned for every analysis, and the wavelength was monitored at a wavelength of 250 nm. The injection volume was 10 μL for related substances determination. Water: Acetonitrile :: 70:30 (v/v) was used as diluent during the standard and test samples preparation.

Blank preparation:
Transfer 5 mL DMSO into 50 mL volumetric flask and makeup the volume with diluent and mix well.
Reference stock solution preparation (Impurities @ 75 ppm and rivarpxaban 50ppm):
Weigh and transfer about 5.0 mg of Rivaroxaban and 7.5 mg of each impurity B and impurity H
standard into 100 mL volumetric flask. Add about 10 mL DMSO and sonicate to dissolve. Make up the
volume with diluent and mix well.
Reference solution preparation (Imps. @ 0,15 and API @ 0.10%)
Transfer 5 mL DMSO into 50 mL volumetric flask and add 1.0 mL reference stock solution. Make up
the volume with diluent and mix well.

We Claim,
1. An improved RP-LC for the quantitative determination of Rivaroxaban having the below structural formula

2. Rivaroxaban as represented in claim 1 has purity greater than about 98.0 area% to about 99.0 area % as measured by improved RP-LC. The retention time of Rivaroxaban is 30.57 with the detection limit of 0.0043 and quantification limit of 0.0129 in an improved RP-LC method.
3. Rivaroxaban as represented in claim 2 having individual impurities lower than about 0.15 area %, and total impurities lower than about 0.5 area % by HPLC.
4. Rivaroxaban as represented in claim 3 having the compound 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Impurity-A) represented by the structure

5. The compound 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-1,3(2H)-dione (Impurity-A)represented in claim 4 in an amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
6. The compound 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Impurity-A)represented in claim 5 is detected and resolved from rivaroxaban by HPLC with retention time of 27.17 and relative retention time (hereafter referred as RRT) of 0.89.
7. The compound 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Impurity-A)represented in claim 6 has the limit of detection 0.0030 and limit of quantification 0.0091 in an improved RP-LC method.

8. Rivaroxaban as represented in claim 3 having the compound 5-chlorothiophene-2-carboxylic acid (Impurity-C), represented by the structure

9. The compound 5-chlorothiophene-2-carboxylic acid (Impurity-C) represented in claim 8 in an
amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
10. The compound 5-chlorothiophene-2-carboxylic acid (Impurity-C) represented in claim 9 is detected and resolved from rivaroxaban by HPLC with retention time of 9.58 and relative retention time (hereafter referred as RRT) of 0.33.
11. The compound 5-chlorothiophene-2-carboxylic acid (Impurity-C) represented in claim 10 has the limit of detection 0.0054 and limit of quantification 0.0162 in an improved RP-LC method.
12. Rivaroxaban as represented in claim 3 having the compound N-({(5S)-2-oxo-3-[4-(3-oxo-4-
morpholinyl)phenyl]-],3-oxazo]idin-5-yl}methyl)-2-thiophenecarboxamide(Impurity-D), represented
by the structure

13. The compound N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide(Impurity-D) represented in claim 12 in an amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
14. The compound N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide(Impurity-D) represented in claim 13 is detected and resolved from rivaroxaban by HPLC with a retention time of 17.27 and relative retention time (hereafter referred as RRT) of 0.57.

15. The compound N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-I,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide(Impurity-D) represented in claim 14 has the limit of detection 0.0039 and limit of quantification 0.0118 in an improved RP-LC method.
16. Rivaroxaban as represented in claim 3 having the compound 5-chloro-N-methylthiophene-2-carboxamide (Impurity-E), represented by the structure

17. The compound 5-chloro-N-methylthiophene-2-carboxamide (Impurity-E) represented in claim 16 in an amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
18. The compound 5-chloro-N-methylthiophene-2-carboxamide (Impurity-E) represented in claim 17 is detected and resolved from rivaroxaban by HPLC with a retention time of 19.13 and relative retention time (hereafter referred as RRT) of 0.63.
19. The compound 5-chloro-N-methylthiophene-2-carboxamide (Impurity-E) represented in claim 14 has the limit of detection 0.0049 and limit of quantification 0.0149 in an improved RP-LC method.
20. Rivaroxaban as represented in claim 3 having the compound N-Methyl phthalimide (Impurity-F), represented by the structure

21. The compound N-Methyl phthalimide (Impurity-F) represented in claim 20 in an amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
22. The compound N-Methyl phthalimide (Impurity-F) represented in claim 21 is detected and resolved from rivaroxaban by HPLC with a retention time of 20.80 and relative retention time (hereafter referred as RRT) of 0.68.
23. The compound N-Methyl phthalimide (Impurity-F) represented in claim 22 has the limit of detection 0.0033 and limit of quantification 0.0099 in an improved RP-LC method.

24. Rivaroxaban as represented in claim 3 having the compound 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl] amino}propyl] thiophene-2-carboxamide (Impurity-G), represented by the structure

25. The compound 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl] . thiophene-2-carboxamide (Impurity-G) represented in claim 24 in an amount less than or equal to 0.15 area present, as measured by new improved RP-LC method.
26. The compound 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl] amino} propyl] thiophene-2-carboxamide (Impurity-G) represented in claim 25 is detected and resolved from rivaroxaban by HPLC with a retention time of 25.65 and relative retention time (hereafter referred as RRT)of 0.84.
27. The compound 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl] thiophene-2-carboxamide (Impurity-G) represented in claim 26 has the limit of detection 0.0048 and limit of quantification 0.0147 in an improved RP-LC method.
28. Rivaroxaban as represented in claim 3 having the compound 2-[(2R)-2-hydroxy-3-{[4-(3-
oxomorpholin-4-yl)phenyl]amino} propyl]-lH- isoindole-l,3(2H)-dione. Hydrochloride (Impurity-B),
represented by the structure

29. The compound 2-[(2H)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-lH-
isoindole-l ,3(2H)-dione. Hydrochloride (Impurity-B), represented in claim 28 in an amount less than
or equal to 0.15 area present, as measured by new improved RP-LC method -II.
30. The compound 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-lH-
isoindole-l,3(2R)-dione. Hydrochloride (Impurity-B), represented in claim 29 is detected and resolved

from rivaroxaban by HPLC with a retention time of 3.42 and relative retention time (hereafter referred as RRT) of 0.18 in an improved RP-LC method -II. The Rivaroxaban eluted at the retention time of 18.85 in an improved RP-LC method-II.
31. The compound 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl]amino} propyl]-1H-isoindole-l,3(2H)-dione. Hydrochloride (Impurity-B), represented in claim 30 has the limit of detection 0.0054 and limit of quantification 0.0162 in an improved RP-LC method-II.
32. Rivaroxaban as represented in claim 3 having the compound N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI)phenyl]-l,3-oxazolidin-5-yl}methyl) acetamide (Impurity-H), represented by the structure

33. The compound N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl} methyl)
acetamide (Impurity-H), represented in claim 32 in an amount less than or equal to 0.15 area present, as
measured by new improved RP-LC method -II.
34. The compound N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl} methyl) acetamide (Impurity-H),represented in claim 33 is detected and resolved from rivaroxaban by HPLC with a retention time of 6.08 and relative retention time (hereafter referred as RRT) of 0.32 in an improved RP-LC method -II.
35. The compound N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl} methyl) acetamide (Impurity-H), represented in claim 34 has the limit of detection 0.0046 and limit of quantification 0.0138 in an improved RP-LC method-II.
36. The buffer used for the preparation of Eluent-A is 0.02M sodium dihydrogen phosphate monohydrate with pH of 4.0 by adjusting with orthophosphoric acid.
37. The RP-LC column used in method -I is Unison UK-C18, 250mm x 4.6mm,_coIumn with 3.0 μm particles.
38. The RP-LC column used in method-II is Enable-C18 G, 250mm x 4.6mm, column with 5.0 μm particles.

39. 10% DMSO is used as a solvent in the preparation of sample and standard in method -II.
40. The resolution between Impurity D and Impurity E is 4.44 in method-I
41. The resolution between Impurity E and Impurity F is 3.6 in method-I
42. In method-I, Gradient eluting the sample with a mixture of A Eluent and B Eluent in the ratio of 80:20 (v/v) initial.
43. In method -II, the initial ratio of eluent A and eluent B may be change linearly to 60:40 (v/v), followed by same ratio for 5 minutes. After 3 minutes the initial gradient of 80:20 is for 7 minutes to be conditioned for every analysis.