POLYMORPHS OF BROMFENAC SODIUM AND METHODS FOR PREPARING BROMFENAC SODIUM POLYMORPHS

• US 20140011880A1
• Filed: 09/13/2013
• Published: 01/09/2014
• Est. Priority Date: 10/15/2009
• Status: Active Grant

• Current Assignee: Macfarlan Smith (Hong Kong) Ltd. (Johnson Matthey PLC)
• Original Assignee: Johnson Matthey PLC
• Inventors: Matharu, Saroop Singh, Reddy, Gurijala Venu, Mencel, James J., Sun, Xiaoyong
• Granted Patent: US 9,061,968 B2
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 221/00 Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 225/22 having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 227/22 from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
• CPC Class Codes: C07C 227/42 Crystallisation
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains

Abstract

Different polymorphs of bromfenac sodium may be prepared and interconverted using crystallization/recrystallization, drying and/or hydration techniques.

Claims

1. Bromfenac sodium, characterized by a powder x-ray diffraction pattern having a main peak expressed as 2-theta at about 20.7 degrees.

2. Bromfenac sodium in accordance with claim 1, characterized by a powder x-ray diffraction pattern having additional main peaks expressed as 2-theta at about 18.5, 34.1, and 16.5.

3. Bromfenac sodium in accordance with claim 1, characterized by a powder x-ray diffraction pattern having additional main peaks expressed as 2-theta at about 11.3, 14.4, 17.3, 19.4, 21.0, 22.7, 29.0, 31.8, and 36.1.

4. Bromfenac sodium in accordance with claim 1, characterized by a powder x-ray diffraction pattern exhibiting main peaks substantially in accordance with those shown in FIG. 6.

5. Bromfenac sodium in accordance with claim 1, characterized by an XRPD d-spacing/% intensity pattern substantially in accordance with that shown in Table D.

10. A pharmaceutical formulation comprising a formulated crystalline form of bromfenac sodium according to claim 1 and at least one excipient.

11. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is a liquid.

12. The pharmaceutical formulation of claim 11, wherein the liquid is a solution.

13. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is a suspension.

14. The pharmaceutical formulation of claim 12, wherein the formulated crystalline form of bromfenac sodium is dissolved in the solution in an amount from about 0.01% to about 5% by weight.

15. The pharmaceutical formulation of claim 10, wherein the at least one excipient is selected from the group consisting of at least one of carriers, solvents, preservatives, stabilizers, surfactants, pH adjusting agents, diluents, and fillers.

16. The pharmaceutical formulation of claim 10, wherein the at least one excipient comprises a water soluble polymer.

17. The pharmaceutical formulation of claim 10, wherein the at least one excipient comprises a preservative, a chelating agent, a pH-adjusting agent, a water soluble polymer, a sulfite, a buffer system, and water.

18. The pharmaceutical formulation of claim 17, wherein the pH-adjusting agent comprises sodium hydroxide, the water soluble polymer comprises polyvinyl pyrrolidone, the sulfite comprises sodium sulfite, and the buffer system comprises boric acid and sodium borate.

19. The pharmaceutical formulation of claim 18, wherein the chelating agent comprises sodium edetate.

20. The pharmaceutical formulation of claim 10, wherein the crystalline form of bromfenac sodium is characterized by a powder x-ray diffraction pattern having additional main peaks expressed as 2-theta at about 18.5, 34.1, and 16.5.

21. The pharmaceutical formulation of claim 10, wherein the crystalline form of bromfenac sodium consists essentially of bromfenac sodium Form II.

22. The liquid pharmaceutical formulation of claim 10, wherein the pH of the formulation is about 7.5 to 8.5

23. A method for reducing inflammation comprising administering the pharmaceutical formulation of claim 10 to an eye of a human patient in need of such treatment, wherein the pharmaceutical formulation is an ophthalmic composition.

24. The method of claim 23, wherein the ophthalmic composition is in the form of an eye drop.

25. The method of claim 23, wherein the inflammation is a result of an operative procedure or surgery.

26. A method for reducing pain comprising administering the pharmaceutical formulation of claim 10 to an eye of a human patient in need of such treatment, wherein the pharmaceutical formulation is an ophthalmic composition.

27. The method of claim 26, wherein the ophthalmic composition is in the form of an eye drop.

28. The method of claim 26, wherein the inflammation is a result of an operative procedure or surgery.

29. The method of claim 28, wherein the operative procedure or surgery is cataract surgery.

6. A method for converting bromfenac sodium Form I into bromfenac sodium Form II, comprising drying bromfenac sodium Form I under vacuum.

7. A method for converting bromfenac sodium Form II into bromfenac sodium Form I, comprising hydrating the bromfenac sodium Form II.

8. The method of claim 7, where hydrating is accomplished either under vacuum with a wet nitrogen bleed or at atmospheric pressure using a moist atmosphere within an enclosure.

9. A method for converting bromfenac sodium Form III into bromfenac sodium Form II, comprising crystallizing or recrystallizing bromfenac sodium Form III from a solvent mixture comprised of water, at least one dialkoxyalkane, and at least one anti-solvent to obtain an intermediate product and drying the intermediate product under vacuum.