PHARMACEUTIALLY ACCEPTABLE SALT OF BRINZOLAMIDE

FIELD OF THE INVENTION

The present invention relates to process for the preparation of Brinzolamide of Formula-1. Also the present invention relates to preparation of highly pure Brinzolamide base and crystalline and amorphous form of the Brinzolamide maleate.

BACKGROUND OF THE INVENTION:

Brinzolamide of Formula-1 is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

BRINZOLAMIDE

(Formula -1)

Brinzolamide is described chemically as (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-3 4-dihydro-2H-thieno [3 2-e]-1 2-thiazine-6-sulfonamide-1 1-dioxide which has an empirical formula C12H21N3O5S3 with molecular weight 383.5 and melting point of about 131°C. It is a white powder which is insoluble in water and soluble in methanol as well as ethanol.

Brinzolamide is developed and marked by Alcon laboratories inc. under the trade name Azopt®. AZOPT 1% is supplied as a sterile aqueous suspension of Brinzolamide which has been formulated to be readily suspended and slow settling following shaking. It has a pH of approximately 7.5. US patents US 5 153 192; US 5 240 923; US 5 378 703 discloses use of thiophene sulfonamides and pharmaceutical compositions containing the compounds in controlling intraocular hypertension.

US patent 5 344 929 discloses process for the preparation carbonic anhydrase inhibitors having the general formula where in Brinzolamide is R1 = H R2 = Et R3 = 3-Methoxypropyl. Depicted process resulted Brinzolamide with only 17% overall yield.

US 2010/0009977 A1 teaches about the process preparation of Brinzolamide involving novel intermediates.

Though few process for the preparation of Brinzolamide are known in the prior art involving harsh reaction conditions tedious work-up procedures with low overall recovery; still there is a need for a robust process for the preparation of substantially pure Brinzolamide with industrially feasible techniques and operations during the bulk production.

SUMMARY OF THE INVENSION:

It is an object of the present invention to prepare pure Brinzolamide base.

It is another object of the present invention to prepare Brinzolamide base in a solid form.

It is yet another object of the present invention to prepare crystalline Brinzolamide maleate.

It is yet another object of the present invention to prepare amorphous Brinzolamide maleate.

The present invention (Scheme-1) provides a process for preparation of substantially pure Brinzolamide comprising:

i. Conversion of the Brinzolamide hydrochloride salt to Brinzolamide free base

ii. Conversion of the Brinzolamide free base to Brinzolamide maleic acid salt

iii. Optionally isolation of Brinzolamide maleic acid salt as chromatographically pure salt

iv. Conversion of substantially pure Brinzolamide maleic acid salt to substantially pure Brinzolamide free base.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the PXRD pattern of crystalline Brinzolamide maleate salt.

Figure 2 represent the PXRD pattern of substantially crystalline Brinzolamide maleate salt.

DETAILED DESCRIPTION OF THE INVENSION

The present invention discloses process for the preparation of pure Brinzolamide base of Formula-1. Also the present invention discloses preparation of highly pure Brinzolamide base and crystalline and amorphous form of the Brinzolamide maleate.

The Brinzolamide Hydrochloride salt was converted to Brinzolamide free base using triethylamine as counter base to react with hydrochloric acid under suitable conditions.

In the second step the Brinzolamide free base was treated with maleic acid to prepare Brinzolamide maleate salt. The maleate salt thus obtained was subsequently treated to obtain chromatographically pure Brinzolamide base.

In the first embodiment of the present invention Brinzolamide hydrochloride salt was converted to Brinzolamide free base using triethylamine as counter base to react with hydrochloric acid under suitable conditions.

In the second embodiment of the present invention Brinzolamide free base was treated with organic acid to prepare Brinzolamide novel organic acid salt to obtain chromatographically pure salt.

Preferably the organic acid is containing 1-3 carboxylic acid groups more preferably di-carboxylic acid most preferably maleic acid.

where the organic acid is maleic acid formula of Brinzolamide maleic acid salt is:

Formula-2

In another embodiment of the present invention substantially pure Brinzolamide was prepared as free base from Brinzolamide organic acid salt.

The present invention (Scheme-1) provides a process for preparation of substantially pure Brinzolamide comprising:

i. Conversion of the Brinzolamide hydrochloride salt to Brinzolamide free base

ii. Conversion of the Brinzolamide free base to Brinzolamide maleic acid salt

iii. Optionally isolation of Brinzolamide maleic acid salt as chromatographically pure salt

iv. Conversion of substantially pure Brinzolamide maleic acid salt to substantially pure Brinzolamide free base.

Scheme-1

As depicted in the scheme-1 Brinzolamide hydrochloride salt was converted to Brinzolamide free base by treating with base in water under suitable conditions. The base is selected from the group of alkyl amines and aromatic amine wherein aromatic amine is selected from triethylamine diisopropylethylamine diethylamine di-isopropylamine pyridine and lutidine. The pH is adjusted between 7 and 9 further stirred and precipitated at temperature between -10 to 50 ?C. The stirring time is between 10 minutes to 48hr. The precipitated solid is isolated and dried under high vacuum.

Optionally the isolated crude solid is purified by re-crystallization in C1-C4 lower chain alcohol under appropriate conditions to obtain semi-pure Brinzolamide free base. The C1-C4 lower chain alcohol is selected from the group methanol ethanol propanol isopropanol n-butanol 2-butanol t-butanol and mixture thereof. The temperature of the re-crystallization is between -10 to 60 ?C with 1 to 25 volumes of solvents. The pure solid is isolated and optionally washed with the minimum volumes of solvent. The wet cake is dried under vacuum to obtain the substantially pure Brinzolamide free base with chromatographic purity more than 99%.

Maleic acid is added to Brinzolamide free base in a suitable solvent and stirred for complete salt formation and precipitation. The precipitated salt is isolated and optionally washed with minimum solvent. The isolated wet cake is dried under vacuum to obtain the dried pure Brinzolamide maleate salt. The solvent used for the preparation of Brinzolamide maleate salt is selected from polar organic solvent such as DMF DMSO THF acetonitrile propionitrile acetone NMP and mixture thereof. The volumes are between 2-20 volumes and the temperature range is between -15 to 85 ?C. optionally the solution is concentrated to minimum volumes and stirred for precipitation. More optionally small amount of Brinzolamide maleate is seeded and stirred for precipitation. The precipitated solid is isolated optionally washed with solvent and dried under vacuum to obtain pure dried Brinzolamide maleate salt. The isolated Brinzolamide maleate salt is crystalline and the crystallinity is characterized by well-established techniques like XRD DSC and FTIR. Observed the peaks in the PXRD of crystalline Brinzolamide maleate salt at 2? values: 7.39 7.91 9.33 10.24 10.59 10.97 11.43 12.20 12.88 13.76 14.11 15.23 15.90 17.94 18.42 19.39 19.8 20.67 21.99 24.19 24.48 ± 0.2. Brinzolamide maleate salt is further characterised by 1H NMR and 13C NMR.

1H NMR (DMSO): d 1.16 (t 3H) 1.80 (m 2H) 3.00 (t 2H) 3.24 (m 4H) 3.38 (m 3H) 4.08 (m 2H) 4.74 (s 1H) 6.07 (s 2H) 7.80 (s 1H) 8.15 (s 2H).

13C NMR: d 12.68 28.98 40.74 46.05 48.37 48.72 58.42 69.19 129.89 135.23 138.80 149.68 167.69.

In another yet embodiment of the present invention amorphous Brinzolamide maleate salt is prepared by dissolving the material in suitable solvent and drying under suitable conditions.

The solvents selected from polar solvents water acetonitrile DMF DMSO methanol isopropanol and mixture thereof.

Brinzolamide maleate is dissolved in solvent treated with base under suitable conditions to precipitate out as free base isolated the precipitated substantially pure solid and optionally dried under vacuum to obtain substantially pure Brinzolamide. The solvent is selected from suitable polar solvent such as water C1-C4 lower chain alcohol acetone acetonitrile and mixture thereof. The base used is selected from the list of inorganic bases such as sodium bicarbonate sodium carbonate potassium carbonate lithium hydroxide sodium hydroxide potassium hydroxide mixture thereof. Base is also selected from the list of low boiling organic bases such as triethyl amine diethylamine di-isopropylamine diisopropylethylamine pyridine and mixture thereof. Temperature range is between -15 to 65 ?C and the stirring time is between 10 minutes to 48 h. the purity of isolated material is more than 99.5% with any single max impurity not more than 0.2%.

The invention is further illustrated by the following examples which should not be construed to limit the scope of the invention in anyway.

Characterization
Brinzolamide maleate salt of the present invention is characterized by X-Ray powder Diffraction (XRD) DSC analysis and FTIR spectroscopy.

XRD: XRD Diffractograms were collected on Bruker AXS D-8 advance X- Ray powder diffract meter Scintillation detector. Scanning Parameters: ScanType - Locked Coupled Scan Mode -Continuous Range (2 theta) - 3.0°- 60.0° Rate - 3.6°/min.

FTIR Spectroscopy: FTIR Spectrum was recorded on Perkin-Elmer spectrum-1spectrometer Diffuse Reflectance Technique. The sample was finely ground with Potassium Bromide and the spectrum was recorded using Potassium Bromide background in a Diffused reflectance accessory.

Thermal analysis: Differential Scanning Calorimetry (DSC) was performed on Perkin Elmer Diamond. The Crucible was Crimped and punched prior to analysis.

Experimental conditions: sample Weight: 2.0–3.0 mg Heating Rate: 10°C/min.

Examples

Example 1: Preparation of Brinzolamide free base from hydrochloride salt:
Brinzolamide Hydrochloride (750 g) was dissolved in 5 volume water and filtered through celite bed to remove insoluble particles. Further the solution was adjusted the pH to 7-8.5 with Triethylamine under stirring. Stirring was continued for additional 2 hours at 25 to 30°C followed by chilling the reaction mass at 0 to 5°C and stirred for 1 hour. The solids were filtered and washed with 1volume of water. Wet cake was dried at 40°C under vacuum to yield Brinzolamide free base (500 g HPLC purity: 98.5%).

Example 2: Preparation of Crystalline Brinzolamide maleate salt:
100g of Brinzolamide free base was taken in acetonitrile 500 ml followed by the addition of 33g of maleic acid under inert atmosphere at ambient temperature further stirred for 3 h. The solid precipitated was filtered washed with di-isopropyl ether and the wet cake was dried under vacuum at 45-50°C to get of crystalline Brinzolamide maleate salt (110 g HPLC purity > 99.3%).

Example 3: Preparation of Amorphous Brinzolamide maleate salt:

Brinzolamide maleate salt (100 g) was dissolved in acetone (400 ml) and stirred for 30 min. The reaction mass was then concentrated and dried under vacuum for 12h at 45-50°C to obtain amorphous Brinzolamide maleate salt (97 g).

Example 4: Preparation of Amorphous Brinzolamide maleate salt
Brinzolamide base (0.026mol) is taken in acetone (50 ml) added maleic acid (0.026 mol) under inert atmosphere at the ambient temperature and stirred for 3h. The reaction mass was concentrated and dried under vacuum for 12h at 45-50°C to get of amorphous Brinzolamide maleate salt.

Example 5: Preparation of substantially pure Brinzolamide free base:
Brinzolamide maleate salt (75 g) was dissolved in 5 volume water filtered through celite bed to remove insoluble particles then adjusted the pH to 7-8.5 with triethylamine under stirring. Continued the stirring for additional 2 hours at 25 to 30°C Then chilled the reaction mass at 0 to 5°C and then stirred for 1 hour. Filter the precipitated solid and washed with 1volume of water. Dried the wet cake at 40°C under vacuum to obtain Brinzolamide free base (45 g HPLC purity: 99.5%).

Example 6: Purification of Brinzolamide free base:
Brinzolamide was taken in 10 volume of methanol dissolved at 40 to 45° for 30 minutes and concentrated the solution to minimum volumes (2 vol) and stirred for 2 hours at 25 to 30°C filtered the precipitated solid and dried the wet cake under vacuum to obtain pure Brinzolamide free base (HPLC purity: 99.6%).

We claim:

1. A process for the preparation of substantially pure Brinzolamide comprises;
i. Converting the Brinzolamide free base to Brinzolamide maleate salt and isolated as solid
ii. Converting the Brinzolamide maleate salt from step (i) to Brinzolamide free base
iii. Optionally re-purifying the Brinzolamide free base.

2. The process as claimed in claim 1 wherein the Brinzolamide free base of step (i) is obtained from Brinzolamide hydrochloride salt which is treated with organic base in water.

3. The process as claimed in claim 2 wherein the organic base is selected from triethylamine dimethylamine di-isopropylamine di-isopropylethylamine pyridine and mixtures thereof.

4. The process as claimed in claim 2 wherein the preparation of Brinzolamide free base comprises:
a) Brinzolamide hydrochloride is dissolving in suitable solvent
b) Adjusting the pH with the organic base
c) Optionally concentrating to minimum volumes
d) Stirring the reaction mass to precipitate
e) Isolating the solid and optionally drying to obtain Brinzolamide free base.

5. The process as claimed in claim 4(c) wherein the volumes are between 4 and 25 w/v.

6. The process as claimed in claim 5 wherein the volume is between 7-20 w/v.

7. The process as claimed in claim 5 wherein the volume is between 9 and 15 w/v.

8. The process as claimed in claim 4 wherein temperature is between -15 to 60 ?C.

9. The process as claimed in claim 4(b) wherein the pH is between 7 and 9.

10. The process as claimed in claim 9 wherein the preferred pH is 8.

11. The process as claimed in claim 4 wherein the purity of isolated material is not more than 99.3%.

12. The process as claimed in claim 1 wherein the process of the preparation of Brinzolamide maleate salt comprises;
a. addition of maleic acid to Brinzolamide free base in suitable solvent
b. optional concentration to minimum volumes
c. stirring for precipitation at appropriate conditions
d. isolation of the solid and
e. optionally drying.

13. The process of claim 12 wherein the suitable solvents are selected from the group of polar solvents such as DMF DMSO C1-C4 alcohols acetonitrile propionitrile acetone and mixture thereof.

14. The process as claimed in claim 13 wherein the C1-C4 lower chain alcohol is selected from the group of methanol ethanol propanol isopropanol n-butanol 2-butanol tert-butanol and mixtures thereof.

15. The process of claim 12 wherein the volumes are between 4 and 25 w/v.

16. The process as claimed in claim 15 wherein the volume is between 7-20 w/v.

17. The process as claimed in claim 15 wherein the volume is between 9 and 12 w/v.

18. The process as claimed in claim 12 wherein the Brinzolamide free base is suspended in solvent prior to the addition of maleic acid.

19. The process as claimed in claim 12 wherein optionally the precipitation is induced by seeding Brinzolamide maleate salt.

20. The process as claimed in claim 12 wherein the concentration of the solution to minimum volumes is preferably to half of the original volumes.

21. The process as claimed in claim 20 wherein the volume is more preferably less than 7 v/w.

22. The process as claimed in claim 20 wherein the temperature is between -15 to 60 ?C.

23. The process as claimed in claim 20 wherein Brinzolamide maleate salt precipitates as solid from solution.

24. The process as claimed in claim 20 wherein the Brinzolamide maleate salt is crystalline material.

25. The process as claimed in claim 20 wherein the Brinzolamide maleic acid salt as Brinzolamide maleate.

26. A process for the preparation of solid Brinzolamide maleate salt.

27. The process as claimed in claim 26 wherein the Brinzolamide maleate salt is crystalline.

28. The process as claimed in claim 26 wherein the Brinzolamide maleate salt is amorphous.

29. The process as claimed in claim 26 wherein the Brinzolamide maleate salt is characterized by 1H NMR and 13C NMR.

30. The process as claimed in claim 27 wherein the crystalline Brinzolamide maleate having 2? values at 7.39 7.91 9.33 10.24 10.59 10.97 11.43 12.20 12.88 13.76 14.11 15.23 15.90 17.94 18.42 19.39 19.8 20.67 21.99 24.19 24.48 ± 0.2.

31. A process for the preparation of amorphous Brinzolamide maleate comprises:
a. addition of maleic acid to Brinzolamide free base in a solvent and
b. evaporation to dryness to obtain Brinzolamide maleate salt.

32. The process as claimed in claim 31 wherein the solvent is selected from low boiling organic polar solvents such as acetone acetonitrile propionitrile C1-C4 alcohols and mixture thereof.

33. The process as claimed in claim 31 wherein Brinzolamide free base is prepared from Brinzolamide hydrochloride salt in suitable solvent with suitable base under appropriate conditions.

34. The process as claimed in claim 33 wherein the base is selected from inorganic base such as sodium bicarbonate sodium carbonate sodium hydroxide potassium hydroxide calcium hydroxide lithium hydroxide and mixtures thereof.

35. The process as claimed in claim 33 wherein the base is selected from low boiling organic base such as triethylamine dimethylamine di-isopropylamine di-isopropylethylamine pyridine and mixture thereof.

36. The process as claimed in claim 33 wherein the solvent is selected water acetone C1-C4 alcohols acetonitrile and mixture thereof.

37. The process as claimed in claim 33 wherein the isolated Brinzolamide free base is chromatographically substantially pure.

38. The process as claimed in claim 33 wherein Brinzolamide free base having the purity not less than 99.3% with single max impurity not more than 0.2%.

39. The process as claimed in claim 33 wherein optionally re-purifying the Brinzolamide free base to obtain in substantially pure from in suitable solvent under appropriate conditions.

40. The process as claimed in claim 39 wherein the solvent is selected from C1-C4 alcohol and mixture thereof.

41. The process as claimed in claim 33 wherein the purity of Brinzolamide free base not less than 99.5% with single max impurity not more than 0.15%.

42. A crystalline Brinzolamide free base having high content of amorphous form as depicted in figure 2.