FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A CRYSTALLINE POLYMORPH OF BROMFENAC SODIUM"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A CRYSTALLINE POLYMORPH OF BROMFENAC SODIUM
FIELD OF THE INVENTION:
The present invention is concerned with a novel polymorph of bromfenac sodium. This polymorph exhibits superior properties compared to the previously known form of bromfenac sodium and can be used as medicament for the treatment of postoperative inflammation in patients who have undergone cataract extraction.
BACKGROUND OF THE INVENTION:
Bromfenac sodium is designated chemically as sodium 2-amino-3-(4-bromobenzoyl) phenylacetate sesquihydrate, with an empirical formula of C15H11BrNNaO3.1½H2O.The bromfenac sodium is known from U.S. Patent No. 4,683,242 and the structural formula of bromfenac sodium is represented by a compound of formula I.

Bromfenac and its pharmaceutically acceptable salts are reported in U.S. Pat. No. 4,683,242 ("the '242 patent"). The '242 patent discloses a preparation of bromfenac sodium wherein bromfenac sodium is isolated after treatment of a sludge of bromfenac sodium with diisopropyl ether. However, the '242 patent reports only the melting point of the obtained solid bromfenac sodium (284-286°C), but does not disclose the polymorphic form. The present inventors have carried out the same experiment in ditto to knew the polymorphic form of bromfenac sodium obtained by a process described in '242 patent and the same will be hereinafter designated as Form I.

The bromfenac sodium crystalline Form I is thermodynamically unstable and having a poor solubility and dissolution rate and therefore it was still considered desirable to have a form of bromfenac sodium which is thermodynamically more stable and exhibits a better solubility and dissolution rate than Form I.
Polymorphism is defined as the ability of a substance to crystallize in more than one crystal lattice arrangement. Polymorphism can influence many aspects of solid state properties of a drug. Different crystal modifications of a substance may differ considerably from one another in many respects such as, for example, solubility, dissolution rate, and bioavailability. An exhaustive treatment of polymorphism in pharmaceutical and molecular crystals is given for example by Byrn (Byrn, S. R., Pfeiffer, R. R., Stowell, J. G., "Solid-state Chemistry of Drugs" 2nd edition, SSCI Inc., West Lafayette, Ind., 1999), by Brittain, H. G., "Polymorphism in Pharmaceutical Solids", Marcel Dekker, Inc., New York, Basel, 1999) or by Bernstein (Bernstein, J., "Polymorphism in Molecular Crystals", Oxford University Press, 2002), the disclosures of which are incorporated herein by reference.
Surprisingly, it has now been found that bromfenac sodium can exist in a second crystalline polymorphic form, designated as Form II, which is thermodynamically more stable and exhibits a better solubility in water and high dissolution rate than the known crystalline Form I.
Thus, the present invention provides a novel crystalline polymorph of bromfenac sodium which unexpectedly exhibit increased thermodynamically stability, Solubility and high dissolution rate with respect to Form I. The polymorph of the present invention will consequently have improved pharmacological properties when compared to the known Forrn I.
BRIEF DESCRIPTION OF THE DRAWINGS:
FIG. 1 illustrates the X-ray powder diffraction (XRD) of bromfenac sodium crystalline Form I. FIG. 2 illustrates the X-ray powder diffraction (XRD) of bromfenac sodium crystalline Form II.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8

Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha[A]: 1.54060
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
SUMMARY OF THE INVENTION:
The present invention provides thermodynamically stable bromfenac sodium crystalline Form II, processes thereof, and compositions comprising bromfenac solium crystalline Form II.
In one embodiment, the present invention provides thermodyhamically stable bromfenac sodium crystalline Form II having an X-ray diffraction pattern as described herein in Figure 2
Other embodiment of the invention provides a process for Preparing thermodynamically stable bromfenac sodium crystalline Form II comprises crystallizing bromfenac sodium in water.
Other embodiment of the invention provides a process of preparing thermodynamically stable bromfenac sodium crystalline Form II comprising the steps of

a. dissolving bromfenac sodium in water at a temperature in the range of 80°C to 100°C,
b. gradual cooling of resulting bromfenac sodium solution obtained from step a and
c. isolating thermodynamically stable bromfenac sodium crystalline Form II.
Other embodiment of the present invention provides pharmaceutical compositions comprising thermodynamically stable bromfenac sodium crystalline Form II.
Other embodiment of the present invention provides the use of thermodynamically stable bromfenac sodium crystalline Form II in the treatment of postoperative inflammation and pharmaceutical formulations containing them.
DETAIL DESCRIPTION OF THE INVENTION:
Bromfenac sodium used for the preparation of thermodynamically stable bromfenac sodium crystalline Form II may be obtained by processes reported in literature such as U.S. Pat. No. 4,683,242.
Bromfenac sodium used for the preparation of thermodynamically stable bromfenac sodium crystalline Form II may be bromfenac sodium crystalline Form I.
Thermodynamically stable bromfenac sodium crystalline Form II shows X-ray powder diffraction pattern having characteristic peaks at a reflection angle 20 of about 15.5 ± 0.2, 17.3 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, 23.9± 0.2, 25.2 ± 0.2, 26.1 ± 0.2, 27.5 ± 0.2, 28.9 ± 0.2, 32.1 ± 0.2, 33.3 ± 0.2, 33.9 ± 0.2, 34.8 ± 0.2, 36.2 ± 0.2 and 38.3° ± 0.2.
Thermodynamically stable bromfenac sodium crystalline Form II may be further characterized by X-ray powder diffraction peaks at 17.3 ± 0.2, 19.8 ± 0.2, 25.2 ± 0.2, 26.1 ± 0.2, 27.5 ± 0.2, 28.9 ± 0.2, 32.1 ± 0.2, and 36.2 ± 0.2° 20.

Thermodynamically stable bromfenac sodium crystalline Form II may be further characterized by X-ray powder diffraction peaks at 17.3 ± 0.2, 19.8 ± 0.2, 26.1 ± 0.2, 28.9 ± 0.2 and 32.1± 0.2 °20.
Thermodynamically stable bromfenac sodium crystalline Form II may be further characterized by following X-ray powder diffraction peaks:

Sr.No Pos. [°2Th] d-spacing [A] Rel.Int.[%]
1. 15.5840 5.68163 6.66
2. 17.3313 5.11256 40.91
3. 18.4886 4.79507 19.41
4. 19.8736 4.46389 55.69
5. 23.9169 3.71762 10.95
6. 25.2046 3.53053 49.93
7. 26.1830 3.40078 76.42
8. 27.5045 3.24030 27.78
9. 28.9023 3.08670 57.88
10. 32.1159 2.784 100.00
11. 33.3179 2.68702 11.48
12. 33.9045 2.64186 7.46
13. 34.8430 2.57282 21.50
14. 36.2446 2.47648 34.47
15. 38.3519 2.34511 17.59
Thermodynamically stable bromfenac sodium crystalline Form II may be further characterized by X-ray powder diffraction peaks at 17.3 ± 0.2, 28.9 ± 0.2 and 32.1± 0.2 ° 20.
Thermodynamically stable bromfenac sodium crystalline Form II may be further characterized by having a pH in the range of 8.2 to 9.2.

Thermodynamically stable bromfenac sodium crystalline Form II shows greater solubility in water and high dissolution rate than the bromfenac sodium crystalline Form I.
Thermodynamically stable bromfenac sodium crystalline Form II may be prepared by crystallizing bromfenac sodium in water.
The crystallization of bromfenac sodium in water may be carried out by first dissolving bromfenac sodium in water at a temperature in the range of 80°C to 100°C followed by the filtering to removed undissolved particles and then gradual cooling up to the temperature in the range of-5°C to 5°C.
The cooling of bromfenac sodium solution may be carried out in a period of 2 hours to 6 hours.
The water used for the crystallization of bromfenac sodium may be 2 volumes / weight to 8 volumes / weight of bromfenac sodium compound of structural formula I.
The crystallization of bromfenac sodium may be carried out at a temperature in the range of-5°C to 5°C for a period of 30 minutes to 5 hours.
Thermodynamically stable bromfenac sodium crystalline Form II may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
Thermodynamically stable bromfenac sodium crystalline Form II may be washed with cold water having a temperature in the range of 0°C to 5°C.
The water used for the washing of thermodynamically stable bromfenac sodium crystalline Form II may be 0.25 volume / weight to 2 volumes / weight of bromfenac sodium compound of structural formula I.
Thermodynamically stable bromfenac sodium crystalline Form II may be dried at a temperature in the range of 50°C to 80°C for 2 hours to 12 hours under reduced pressure.

Thermo dynamically stable bromfenac sodium crystalline Form II is substantially free from the bromfenac sodium crystalline Form I.
Thermodynamically stable bromfenac sodium crystalline Form II is having a chemical purity of 99.5 to 99.98% as determined by high performance liquid chromatographic technique.
Bromfenac sodium crystalline Form II is having a pH in the range of 8.2 to 9.2, which makes it thermodynamically more stable than bromfenac sodium crystalline Form I obtained by following example 74 of U.S.Patent No. 4,683,242.
The bromfenac sodium crystalline Form I obtained by following example 74 of U.S.Patent No. 4,683,242 is having a pH in the range of 9.3 to 10.0. which makes the bromfenac sodium crystalline Form I unstable and having poor solubility in water and low dissolution rate than bromfenac sodium crystalline Form II.
The thermodynamically stable bromfenac sodium crystalline Form II may be used as an ophthalmic solution of 0.09% strength.
The pharmaceutical composition of thermodynamically stable bromfenac sodium crystalline Form II comprises benzalkonium chloride (0.05 mg/ml), boric acid, disodium edentate (0.2 mg/ml), polysorbate 80 (1.5 mg/ml), povidone (20 mg/ml), anhydrous sodium sulfite (2 mg/ml), sodium borate (2 mg/ml) and water for injection, USP.
EXAMPLES:
The following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

EXAMPLE 1: PREPARATION OF THERMODYNAMICALLY STABLE BROMFENAC SODIUM CRYSTALLINE FORM II
Bromfenac sodium (100gm) was dissolved in water (300ml) at 90°C and agitated for 30 minutes.
The resulting hazy solution was filtered and allowed to cool gradually up to 0-5°C. The resulting
solids were filtered, washed with chilled water (30ml) and dried at 70°C under reduced pressure.
Yield: 75gm
Purity: 99.76% (By HPLC)
pH = 8.3
XRD: As depicted in Figure 2
EXAMPLE 2: PREPARATION OF THERMODYNAMICALLY STABLE BROMFENAC SODIUM CRYSTALLINE FORM II
Bromfenac sodium Form I (50gm) was dissolved in water (200ml) at 75°C and agitated for 60
minutes. The resulting hazy solution was filtered and allowed to cool gradually up to 5°C. The
resulting solids were filtered, washed with chilled water (20ml) and dried at 60°C under reduced
pressure.
Yield: 39gm
Purity: 99.86% (By HPLC)
pH = 8.9
XRD: As depicted in Figure 2

WE CLAIM:
1. A thermodynamically stable bromfenac sodium crystalline Form II characterized by X-ray powder diffraction pattern having characteristic peaks at a reflection angle 20 of about 15.5 ± 0.2, 17.3 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, 23.9± 0.2, 25.2 ± 0.2, 26.1 ± 0.2, 27.5 ± 0.2, 28.9 ± 0.2, 32.1 ± 0.2, 33.3 ± 0.2, 33.9 ± 0.2, 34.8 ± 0.2, 36.2 ± 0.2 and 3S3°± 0.2.
2. A thermodynamically stable bromfenac sodium crystalline Form II characterized by X-ray powder diffraction peaks at 17.3 ± 0.2, 19.8 ± 0.2, 26.1 ± 0.2, 28.9 ± 0.2 and 32.1± 0.2 ° 29.
3. A thermodynamically stable bromfenac sodium crystalline Form II characterized by having a pH in the range of 8.2 to 9.2.
4. A process of preparing thermodynamically stable bromfenac sodium crystalline Form II by crystallizing bromfenac sodium in water.
5. A process of preparing thermodynamically stable bromfenac sodium crystalline Form II comprising the steps of:
a. dissolving bromfenac sodium in water at a temperature in the range of 80°C to 100°C,
b. gradual cooling of resulting bromfenac sodium solution obtained from step a and
c. isolating thermodynamically stable bromfenac sodium crystalline Form II.
6. The process according to claim no. 5, wherein water is 2 volumes / weight to 8 volumes / weight of bromfenac sodium.
7. The process according to claim no. 5, wherein cooling of resulting bromfenac sodium solution is carried out up to the temperature in the range of-5°C to 5°C for a period of 2 hours to 6 hours.
8. The process according to claim no. 5, wherein isolation of thermodynamically stable
bromfenac sodium crystalline Form II is carried out by crystallization at a temperature in the

range of -5°C to 5°C for a period of 30 minutes to 5 hours followed by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
9. The thermodynamically stable bromfenac sodium crystalline Form II according to claim no. 1,
which is substantially free from the bromfenac sodium crystalline Form I and having a chemical
purity of 99.5 to 99.98% as determined by high performance liquid chromatographic technique.
10. A pharmaceutical composition comprising thermodynamically stable bromfenac sodium
crystalline Form II.