WO2013114397A2

WO2013114397A2 - Pharmaceutically acceptable salt of brinzolamide and composition thereof

Info

Publication number: WO2013114397A2
Application number: PCT/IN2013/000027
Authority: WO
Inventors: Kiran Kumar Kothakonda; Srinivas Pullela Venkata; Shanmughasamy Rajmahendra; Sandeep Madhukar MHETRE; Arun CHANDAVARKAR
Original assignee: Biocon Limited
Priority date: 2012-01-16
Filing date: 2013-01-16
Publication date: 2013-08-08
Also published as: WO2013114397A3

Abstract

The present invention discloses the pharmaceutically acceptable salt of Brinzolamide as Brinzolamide maleate, process for the preparation of the Brinzolamide maleate, its polymorph and composition thereof.

Description

PHARMACEUTICALLY ACCEPTABLE SALT OF BRINZOLAMIDE AND COMPOSITION THEREOF

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. Further, the present invention relates to the ophthalmic solution composition comprising brinzolamide maleate and its combinations thereof, for the treatment of disease associated with high intra-ocular pressure.

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]-l,2-thiazine-6-sulfonamide-l,l-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.

US patent 5,344,929 discloses process for the preparation carbonic anhydrase inhibitors having the general formula

where in Brinzolamide is Rl = H, R₂ = Et, R₃ = 3-Methoxypropyl. Depicted process resulted Brinzolamide with only 17% overall yield.

US 2010/0009977 Al 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.

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.

Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to allow normal eye function, significantly elevated intra-ocular pressure of aqueous humour. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. Glaucoma may eventually lead to blindness, if it is not treated.

U.S. Patent Nos. 4,797,413, 4,847,289 and 4,731 ,368 disclose topically administered thiophene sulfonamides which lower IOP by inhibiting carbonic anhydrase.

Brinzolamide is a white powder, which is insoluble in water as described in FDA approved label dated March 08, 2011 for the product AZOPT® (Brinzolamide ophthalmic suspension). Marketed available formulation of Brinzolmaide ophthalmic suspension is not a clear solution. US patent no. 5,473,067 disclosed the process for synthesizing carbonic anhydrase inhibitors, brinzolamide. Further, US patent no. 5,585,377, discloses methods for controlling intraocular pressure through administration of the compositions containing brinzolamide.

Polyethoxylated derivatives of castor oil preferably, Polyoxyl 35 Castor oil (also known as Cremophore EL) is used to formulate topical ophthalmic formulations of Brinzolamide as disclosed in US patent no. 5,620,970. Polyoxyl 35 Castor oil is a non-ionic solubilizer helps in making a stable ophthalmic formulation of Brinzolamide.

US 6071904 disclosed the formulation of sterile ophthalmic suspensions containing brinzolamide. It further discloses formulation of sterile ophthalmic suspensions containing brinzolamide and a beta-blocker such as timolol maleate or betaxolol hydrochloride. US patent nos. 6,242,442 and 6,316,441 discloses the compositions for treating ocular conditions in compromised ocular blood flow with ophthalmic suspension composition comprising brinzolamide and brimonidine tartrate. The aqueous solution composition of brinzolamide and a polycarboxyjic acid or its pharmaceutically acceptable salt, an acid saccharide is disclosed in Japanese Patent application no. JP2010037327.

Sterilization by gamma irradiation or ethylene oxide of brinzolamide and methods of manufacturing pharmaceutical suspensions comprising brinzolamide sterilized by gamma irradiation or ethylene oxide is disclosed in European patent application EP2394637.

The suspension form; apart from being difficult to formulate/manufacture; has its own disadvantages;

1. Slower rate of absorption (compared to solutions)

2. It may develop residue in the eyelashes (after dose administration)

3. Feeling of foreign body in eye, blurred vision and swift humour secretion resulting quick wash out of drug even before it acts (suboptimal dose administration)

4. Physical stability, sedimentation and compaction

5. Uniform and accurate dose cannot be achieved unless suspensions are packed in unit dosage form.

There are few restrictions with marketed product Brinzolamide to form it as suspension form only such as:

a) Studies are done by various research institutes that formulations which are at physiological pH prove to be more comfortable & acceptable by patients and results in greater patient compliance.

b) Brinzolamide has pH dependent solubility and has very limited solubility at physiological pH c) Due to limited solubility of Brinzolamide between pH 6.0 to 7.5, the therapeutic dose of Brinzolamide studied in clinical trials (which is lOmg/ml) cannot be made in solution form and results in suspension form.

Hence, there is unmet need for improved dosage form over the already existing suspension form. After extensive experimentation, the inventors of present invention come up with improved dosage form with better solubility and better patient compliance, which is more cost effective and easy to manufacture. 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.

As one of the embodiment of the present invention is to provide an ophthalmic solution composition comprising brinzolamide, preferably comprising brinzolamide maleate.

Another embodiment of the present invention is to provide an ophthalmic solution composition comprising brinzolamide maleate in combination with atleast one more active moiety selected among Prostaglandin analogs, Topical beta-adrenergic receptor antagonists, a2-adrenergic agonists, Miotic agents, Carbonic anhydrase inhibitors for the treatment of disease associated with high intra-ocular pressure.

One of the important embodiments of the present invention is to provide an ophthalmic solution comprising brinzolamide maleate in combination with topical beta-adrenergic receptor antagonists selected from timolol maleate, betaxolol hydrochloride or metipranolol, along with other pharmaceutically acceptable ingredients

Another embodiment of the present invention is to provide an ophthalmic solution comprising brinzolamide maleate optionally in combination with topical beta-adrenergic receptor antagonists selected from timolol maleate, betaxolol hydrochloride or metoprolol, along with other pharmaceutically acceptable ingredients selected from the group of surfactants, cosolvents, complex forming agent or combination thereof. 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.

Figure 3 represent the solubility profile of Brinzolamide base and brinzolamide maleate at different pH. Figure 4 represent the Co-solvent & HP CD mixed approach Formulation Optimization for Brinzolamide maleate

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.

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

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

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 2θ values: 7.39, 7.91 , 9.33, 10.24, 10.59, 10.97, 1 1.43, 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 Ή NMR and ¹ C NMR.

Ή NMR (DMSO): δ 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 1 H), 6.07 (s 2H) 7.80 (s 1 H), 8.15 (s 2H).

¹³C NMR: δ 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- 1 spectrometer, 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 1 volume 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:

lOOg 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 Brinzoiamide 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 Brinzoiamide maleate salt.

Example 5: Preparation of substantially pure Brinzoiamide free base:

Brinzoiamide 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 1 volume of water. Dried the wet cake at 40°C under vacuum to obtain Brinzoiamide free base (45 g, HPLC purity: 99.5%).

Example 6: Purification of Brinzoiamide free base:

Brinzoiamide 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 Brinzoiamide free base (HPLC purity: 99.6%). Example 7: Solubility Studies for Brinzoiamide and its salts:

In a pharmaceutical liquid formulation solubility of a drug plays an important role. Solubility of drug is directly affecting the amount of drug contact with absorption site. Solubility studies were carried out between Brinzoiamide base (API of marketed formulation) and Brinzoiamide maleate (Table 1 ). Brinzoiamide maleate salt shows remarkably higher solubility than brinzoiamide base alone.

Table 1

^♦Solubility studies were carried out in presence of solubilising agent. As one of the embodiment of the present invention is to provide an ophthalmic solution composition comprising brinzolamide, preferably comprising brinzolamide maleate. Brinzolamide maleate presents in the range from about 0.01% (w/V) to about 5% (w/v); preferably, in the range from about 0.1 % (w/v) to about 2% (w/v).

The ophthalmic solution composition of present invention can additionally comprise of atleast one excipient. The excipient can be one or more selected from the group consisting of preservatives, co-solvents, viscosity enhancing agents, solubilizing agents, chelating agent, isotonicity agent, pH adjuster, suspension vehicle and the like.

The term "preservative" as used herein, refers to an agent or mixture of agents that is used to protect a composition against microbial (e.g., yeast, mold, bacteria) activity. Preservatives include, but are not limited to paraoxybenzoates, benzalkonium chloride, benzethonium chloride, benzyl alcohol, sorbic acid or a salt thereof, chlorhexidine gluconate, sodium dehydroacetate, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, chlorobutanol, polyhexamide hydrochloride and the like. The preferred preservative of the present invention is benzalkonium chloride.

The isotonicity agent in respect to present invention is selected from sorbitol, mannitol, glycerol, propylene glycol, sodium chloride and alike.

As the solubilizing agent, for example, polyvinylpyrrolidone, polyethylene glycol, propylene glycol, poly oxy ethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxy 40 stearate, polysorbate 80, Carbomer, polyoxyethylene-polyoxypropylene block copolymers and alike can be used. The solubilizing agent increase solubility of brinzolamide maleate (Table 2).

Table 2

Present invention optionally employs cosolvents to improve solubility of Brinzolamide Maleate. The cosolvents were chosen to water miscible compounds selected from Alcohols, Propylene Glycol (PEG), Polyethylene Glycol, Glycerine, Hypromellose or any combination thereof. The effect of cosolvent like PEG in different ratios on solubility of brinzolamide is described in Table 3.

Table 3

The solubility of brinzolamide maleate enhances with increase in the concentration of PEG in water.

The complex forming agents with reference to present invention is selected among disodium edentate, ascorbic acid, cyclodextrins, citric acid, maleic acid. The preffered stabilizer agents in present invention are maleic acid, cyclodextrins. More preferably, Beta( )-cyclodextrin, and Hydroxypropyl-beta(HP-P)-cyclodextrin improve the solubility of Brinzolamide across the pH from 4.5 to 7.5 (Table 4).

Table 4

The combination of changed salt form, cosolvents and complex forming agent can be used to improve the solubility of brinzolamide (table 5). Table 5

The term "viscosity enhancer," as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby keeping the active ingredient suspended to allow accurate dosing. Viscosity enhancers include, but are not limited to Polyoxyethylene- Polyoxypropylene block copolymer (like Poloxamer 407), Cellulose Acetophthalate, a polysaccharide (low-acetyl gellan gum), methylcellulose, hydroxyethylcellutose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like. The viscosity enhancers are also known as thickening agents or thickeners also. In concern to present invention, the viscosity enhancers are optionally required, as the instant invention is a clear solution formulation.

The pH adjuster(s) are selected from sodium hydroxide, potassium hydroxide, boric acid hydrochloric acid, citric acid and the like.

The compositions of the invention can be seen by the following, non-limiting examples:

Example 8: Brinzolamide Maleate Ophthalmic Solution

Ingredients Concentration (w V %)

Brinzolamide maleate 1.33

Poloxamer 407 0.2

Edetate disodium 0.3

Benzalkonium chloride 0.1

Sodium chloride 1.0

Maleic Acid 2.0

Polyethylene Glycol 400 4.0

Sodium hydroxide/Hydrochloric acid to adjust pH

Water for Injection q.s. to 100%

Procedure:

1. A solution of poloxamer 407 and Polyethylene glycol 400 in purified water was prepared.

2. Another solution of brinzolamide maleate, maleic acid in purified water was prepared.

3. Third solution of excipients such as Benzalkonium chloride, Edetate sodium, Sodium chloride was prepared.

4. Solutions of step 1 and step 3 were mixed.

5. Mixed the solution of step 2 and step 4 and pH was adjusted with Sodium hydroxide/Hydrochloric Acid (pH approximately 7.5) and osmolality was adjusted with Sodium chloride to 300 mOsm/kg and sterilized the whole solution.

Example 9 & 10: Brinzolamide Maleate Ophthalmic Solution

Ingredients Concentration (w/V %)

Example 09 10

Brinzolamide maleate 1.33 1.33

Timolol maleate 5.00 5.00

Beta cyclodextrin 10.00

Hydroxypropyl beta cyclodextrin — 10.00

Edetate disodium 0.01 0.01

Benzalkonium chloride 0.10 0.10

Sodium chloride 1.00 1.00

Maleic Acid 2.32 2.32

Polyethylene Glycol 400 4.00 4.00

Hydroxyethyl cellulose 0.10 0.10

Sodium hydroxide/Hydrochloric acid to adjust pH to adjust pH

Water for Injection q.s. to 100% q.s. to 100% Procedure:

1 . A solution of poloxamer 407 and Polyethylene glycol 400 in purified water was prepared.

2. Another solution of brinzolamide maleate, timolol maleate, maleic acid, Hydroxypropyl beta cyclodextrin/ beta cyclodextrin in purified water was prepared.

3. Third solution of excipeints such as Benzalkonium chloride, Edetate sodium, Sodium chloride was prepared.

4. Solutions of step 1 and step 3 were mixed.

5. Mixed the solution of step 2 and step 4 and pH was adjusted with Sodium hydroxide/Hydrochloric Acid (pH approximately 7.5) and osmolality was adjusted with

Sodium chloride to 300 mOsm/kg and sterilized the whole solution.

Example 11: Brinzolamide Maleate Ophthalmic Solution

Ingredients Concentration (w/V %)

Brinzolamide maleate 1.33

Mannitol 5.00

Hydroxyethyl Cellulose 0.50

Benzalkonium chloride 0.10

Disodium Edetate 0.10

Sodium chloride 6.30

Maleate Buffer 0.50 (mL)

Purified water q.s.

Procedure:

1. A solution of brinzolamide maleate in 0.05M maleate buffer was prepared.

2. Another solution of hydroxyethyl cellulose was prepared separately.

3. Solution of step 2 was mixed thoroughly with step 1.

4. A separate solution of Benzalkonium chloride, mannitol, disodium edetate, sodium chloride was prepared in small quantity purified water and later mixed with solution of step 3.

5. Purified water was used for makeup rest of the volume and final mix was filter through 0.45μπι nylon filters.

Claims

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.

1 1. 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 byΉ NMR and ¹³C NMR.

30. The process as claimed in claim 27, wherein the crystalline Brinzolamide maleate having 2Θ 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.

43. A pharmaceutical composition comprising brinzolamide maleate.

44. A pharmaceutical composition for topical administration comprising brinzolamide maleate.

45. The pharmaceutical composition according to claim 44, wherein the pharmaceutical composition of Brinzolamide maleate is suitable for ophthalmic use.

46. The ophthalmic composition according to claim 44, wherein the pharmaceutical composition of Brinzolamide maleate is in form of stable solution.

The ophthalmic composition according to claim 46, wherein the Brinzolamide maleate presents in the range from about 0.01% (w/V) to about 5% (w/v); preferably, in the range from about 0.1% (w/v) to about 2% (w/v).

48. The ophthalmic composition according to claim 46, wherein the pH of the ophthalmic composition is about from 4.5 to about 7.5.

49. The ophthalmic composition according to claim 46, wherein the ophthalmic composition further comprises pharmaceutically acceptable excipients.

50. The ophthalmic composition according to claim 49, wherein the pharmaceutically acceptable excipients selected from the group of co-solvents, complex forming agents, preservatives, viscosity enhancing agents, solubilizing agents, isotonicity agent, pH adjuster or mixture thereof.

51. The ophthalmic composition according to claim 50, wherein the co-solvents are water miscible compounds selected from Alcohols, Propylene Glycol (PEG), Polyethylene Glycol, Glycerine, Hypromellose or any combination thereof.

52. The ophthalmic composition according to claim 50, wherein the complex forming agents selected from group of disodium edentate, ascorbic acid, cyclodextrins, citric acid, maleic acid.

53. The ophthalmic composition according to claim 50, wherein the isotonicity of solution can be adjusted by any of the sorbitol, mannitol, glycerol, propylene glycol, sodium chloride or combination thereof.

54. The ophthalmic composition according to claim 50, wherein solubilizing agent chosen as one or more from the group consisting of polyvinylpyrrolidone, polyethylene glycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxy 40 stearate, polysorbate 80, Carbomer, polyoxyethylene-polyoxypropylene block copolymers and alike. The ophthalmic composition according to claim 50, wherein preservative selected from group comprises paraoxybenzoates, benzalkonium chloride, benzethonium chloride, benzyl alcohol, sorbic acid or a salt thereof, chlorhexidine gluconate, sodium dehydroacetate, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, chlorobutanol, polyhexamide hydrochloride and the like; preferably is benzalkonium chloride.

A process for the preparation ophthalmic composition claimed in claim 46, comprises steps of:

a) Preparing a sterilized first solution of co-solvent, solubilizing agent in purified water.

b) Preparing a sterilized second solution comprising Brinzolamide maleate, complex forming agent.

c) Preparing a sterilized third solution comprising preservative, isotonicity agent, complex forming agent.

d) Mixing the first and third solution aseptically to make solution fourth and adjust with Sodium hydroxide/ hydrochloric acid and tonicity with isotonicity agent aseptically.

e) Mix second and forth solution aseptically and sterilized again.

The ophthalmic composition according to claim 44, wherein ophthalmic composition comprising brinzolamide maleate in combination with atleast one more active moiety selected among Prostaglandin analogs, Topical beta-adrenergic receptor antagonists, a2- adrenergic agonists, Miotic agents, Carbonic anhydrase inhibitors for the treatment of disease associated with high intra-ocular pressure.

The ophthalmic composition according to claim 44, wherein the ophthalmic composition used for the treatment of disease associated with high intra-ocular pressure.