Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Novel polymorphs of Dorzolamide and process for preparation
thereof."
2. APPLICANT
l.NAME: USV LIMITED
2.NATIONALITY: Indian Company incorporated under the
Companies Act 1956
3.ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to novel polymorphs of trans (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide also known as Dorzolamide, formula (I) and process for their preparation.


3-i

0
II
S—NH.
II 0
NH
v_

Formula (I) Background of the invention:
US4797413 discloses trans (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, also known as Dorzolamide as a Carbonic anhydrase inhibitor. 2% ophthalmic solution of hydrochloride salt of Dorzolamide is approved for the treatment of elevated intraocular pressure, in patients with ocular hypertension or open angle glaucoma.
Orally administrated carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients but includes number of intolerable side effects associated with extraocular inhibition of the enzyme. Hence topically effective reagents can be advantageous over orally administrated agents.
Amongst topically effective carbonic anhydrase, Dorzolamide HC1 is the first agent with a good solubility.
The process to prepare Dorzolamide.HCl and its derivatives is disclosed in US5688968. Two polymorphic forms, Form I and Form II of Dorzolamide HC1 are listed in Analytical profiles of Drug Substances and Excipients, volume 26, p-283-317. International Patent Application No. WO 2004/016620 reports two polymorphic forms of Dorzolamide HC1, Form A and Form B. Patent application US 2004/0198805 reports Dorzolamide.HCl polymorph, Form III.
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US4797413 discloses a process to prepare Dorzolamide and its use as ocular antihypertensive agent for open angle glaucoma. The process to prepare Dorzolamide and its derivatives is disclosed in US 5688968. US 7109353 discloses an improved process for preparation of Dorzolamide.HCl.
US4797413 discloses a process to prepare Dorzolamide, which involves conversion of tartarate salt of Dorzoalmide to a free Dorzolamide with NaHC03. The base is extracted in ethyl acetate followed by evaporation to dryness to isolate the solid. However, there are no reports on existence of Dorzolamide base in different polymorphic forms.
Polymorphism is the ability of the compound to exhibit more than one orientation or conformation of molecule within the crystal lattice. Many organic compounds including active pharmaceutical ingredients (API's) exhibits polymorphisms.
Drug substance existing in various polymorphic forms, differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties, thus affecting dissolution, bioavailability and handling characteristics of the substance. Knowledge of existence of different crystal phases and their overall physical and chemical behaviour is required for selection of polymorphic form to be used in the preparation of final dosage form. Towards this end, investigation of crystal polymorphisms is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form.
The discovery of new polymorphs with same or better pharmaceutical equivalence and bioequivalence as that of the existing polymorphs provides an opportunity to improve the performance characteristic of the pharmaceutical product.
Polymorphs differ in their solubility and hence in the bioavailability. The existence of polymorph of Dorzolamide base would provide an opportunity to develop a more effective formulation. Hence the present invention provides novel crystalline polymorphs of Dorzolamide and process for their preparation.
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Summary of the invention:
The present invention discloses novel crystalline forms of Dorzolamide base namely, Form II and Form III. The invention also discloses the process for preparation of. novel crystalline forms of Dorzolamide.
According to the preset invention a process for preparation of Form I of Dorzolamide is also provided.
The invention further discloses pharmaceutical composition containing novel crystalline forms of Dorzolamide used for the treatment of elevated intraocular pressure in patients with ocular hypertension.
Brief description of the figures:
Fig. 1 illustrates X Ray Powder diffraction pattern of crystalline Dorzolamide Form I Fig. 2 illustrates X Ray Powder diffraction pattern of crystalline Dorzolamide Form II Fig. 3 illustrates X Ray Powder diffraction pattern of crystalline Dorzolamide Form III
Description of the invention:
The present invention provides two novel crystalline forms viz; Form II and Form III of Dorzolamide and process of their preparation. The present invention also provides process for preparation of Form I of Dorzolamide.
Dorzolamide is an effective agent against ocular hypertension. However no polymorphism is reported for Dorzolamide. The solid of Dorzolamide obtained by process disclosed in US4797413 is designated herein, as Form I.
In one embodiment the present invention there is provided polymorphic Form I of Dorzolamide base and process for preparation thereof which comprises the steps of:
a)dissolving crude Dorzolamide in a solublizing solvent at ambient temperature or at
an elevated temperature to form a solution;
b)cooling the solution obtained and
c)isolating the crystallized product by filtration to get Form I
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The solublizing solvent is selected from a group consisting of alcohols, CrC4 ketones, C1-C4 esters, aliphatic ethers, aromatic hydrocarbons and mixtures thereof.
The alcohol is selected from C1-C4 alcohol preferably methanol, ethanol, 1-propanol, 2-propanol (IP A).
The C1-C4 ketones is selected from acetone, 2-butanone, diethyl ketone , preferably acetone.
The CrC4 esters is selected from methyl acetate, ethyl acetate, preferably ethyl acetate.
An aliphatic ethers is selected from diethyl ether (DEE), diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE) or a mixture thereof, preferably DIPE
An aromatic hydrocarbon is selected from toluene, xylene, preferably toluene.
Preferably, dissolving Dorzolamide in a solubilising solvent at an ambient temperature or elevated temperature of 65° C to 80° C . Further the solution is cooled at a temperature of between 0 to 30 ° C and the product isolated by filtration and dried at a temperature of 30 to 90 ° C.
In another embodiment the present invention polymorphic Form I of Dorzolamide is prepared by the process comprising the steps of:
a) dissolving crude Dorzolamide in solublizing solvent
b) precipitating the Dorzolamide by adding an anti-solvent;
c. stirring the suspension with or without cooling;
d. isolating the precipitated solid to get polymorphic Form I.
Solublizing solvent is selected is selected from a group consisting of polar aprotic solvents, esters, ketones, nitriles, alcohols or a mixtures thereof.
The ester is selected from methyl acetate, ethyl acetate, butyl acetate , preferably ethyl acetate.
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Alcohol is selected from CrC4 alcohols preferably methanol, ethanol and isopropyl alcohol.
The ketone is selected from Ci-C4 ketones preferably acetone, 2-butanone, diethyl ketone, preferably acetone. The nitrile is preferably acetonitile.
The polar aprotic solvents is selected from dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N, N-dimethyl acetamide (DMA), preferably dimethyl formamide.
The anti-solvents is selected from a group consisting of either aliphatic ethers, aliphatic hydrocarbons, water or a mixtures thereof.
Aliphatic ethers is selected from DEE, DIPE, MTBE, THF, 1,4-Dioxane or a mixture thereof, preferably DIPE.
Aliphatic hydrocarbons may be selected from pentane, hexane, heptane or a mixture thereof, preferably Hexane.
Preferably, Dorzolamide is dissolved in solublizing solvent at temperature 30°C to 35°C and precipitated by the addition of an anti-solvent, further the suspension is stirred for 1 to 8 hours and cooled to a temperature of 20°C to 30°C.The precipitated solid is filtered and dried at a temperature of 30 to 90° C to get Form I of Dorzolamide.
Dorzolamide Form I is characterized by the following XRPD peaks:

Pos. Rel. Int. [%]
[°2Th.l
9.9371 4.02
12.4213 100.00
14.9389 8.50
15.9706 16.19
16.5688 46.57
17.9460 22.17
19.4279 15.05
20.5761 89.78
21.1398 37.77
22.1950 16.47
24.5703 41.82
24.9294 10.26
25.7474 29.58
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25.7474 29.58
26.5904 8.78
26.9608 26.62
27.5317 8.26
28.2982 12.14
29.7584 7.72
30.2664 36.02
30.9088 20.43
31.2041 24.83
31.7218 8.51
32.1909 3.39
33.0156 14.33
33.6123 17.04
35.1426 3.60
36.0541 10.00
36.4457 10.21
36.8161 5.65
37.1944 6.90
38.6980 8.70
39.4194 2.99
40.0055 8.57
41.6693 9.80
42.4139 8.54
43.1314 4.95
45.0130 5.72
45.7973 3.26
46.8301 9.42
47.8575 4.88
48.4803 6.77
49.4185 3.35
In a further embodiment the present invention provides polymorphic Form II of Dorzolamide base prepared by the process comprising the steps of,
c) dissolving Dorzolamide Form I in solublizing solvent containing water;
d) concentrating the solution under vacuum;
e) isolating the solid and drying the product to get Form II of Dorzolamide.
Solublizing solvent is selected from a group consisting of water miscible solvents such as alcohols, CrC4 ketones and nitriles or mixture thereof.
The alcohols is selected from C1-C4 alocohol selected from methanol, ethanol, 2-propanol, preferably IP A or ethanol.
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The C1-C4 Ketones is selected from acetone, 2-butanone, diethyl ketone preferably acetone. Nitrile selected is acetonitrile. The content of water in the solublizing solvent may vary from 2-8% preferably 3%.
Preferably, Dorzolamide Form I is dissolved in solublizing solvent containing water at an ambient temperature or at an elevated temperature of 50°C to 70°C . Further the solution is concentrated under vacuum at 50°C to 75°C preferably 65°C to isolate Dorzolamide Form II and dried at a temperature of 30°C to 90° C.
The XRPD of Form II is given in Fig. 2. Form II is characterized by the following XRPD peaks,

Pos. [°2Th.] Rel. Int. [%]
10.2462 21.74
11.5757 10.13
12.4446 16.61
12.7779 35.74
16.6651 8.99
17.8136 16.14
19.5215 16.02
20.0010 18.68
20.3807 29.00
20.7218 100.00
21.0207 44.31
22.1343 2.88
23.1334 9.36
24.6374 12.33
25.5526 14.49
26.4792 4.73
27.0133 10.31
28.0946 13.69
28.3288 31.88
29.1426 15.53
30.0626 13.38
30.7440 9.47
31.2655 8.78
32.1260 3.63
33.0508 4.96
33.6796 3.77
34.4311 4.02
34.9185 3.80
35.6124 5.63
36.0652 4.87
36.5298 5.22
37.8597 2.48
38.6711 3.24
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39.4672 6.21
41.2751 7.29
42.7474 1.33
44.9199 2.39
46.1142 3.18
46.6667 2.88
48.5401 1.45
In a further embodiment the invention provides polymorphic Form III of Dorzolamide and process for preparation thereof comprising the steps of,
a) dissolving Dorzolamide Form I in solublizing solvent;
b) precipitating the solid by adding an anti-solvent;
c) stirring the suspension with or without cooling and
d) isolating the precipitated solid and drying the product.
The solublizing solvent of the present invention for dissolution is selected from a group consisting of aliphatic cyclic ethers, preferably tetrahydrofuran (THF), 1,4-Dioxane or mixtures thereof.
The anti-solvents is selected from a group consisting of aliphatic ethers. The aliphatic ethers may be selected from diethylether (DEE),diisopropyl ether (DIPE), methyl tertiary butyl ether (MTBE) , preferably DIPE.
Preferably, the Dorzolamide Form I is dissolved in solublizing solvent at an ambient temperature or at an elevated temperature of 25°C to 35°C and precipitated by the addition of an anti-solvent, further the suspension is stirred for 1 to 2 hours and cooled to a temperature of 20°C to 30°C.The product is dried at a temperature of between 30°C to 90°C to obtain Form III of Dorzolamide base.
The XRPD of Form III is given in Fig. 3. Form III is characterized by following characteristic XRPD peaks:
Pos. [°2Th.1 Rel. Int. \%]
10.9063 9.34
11.3668 3.26
13.5137 40.28
14.7064 34.75
17.3604 88.58
18.7247 81.39
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19.0542 31.76
19.9564 66.65
20.7014 23.16
21.9419 100.00
22.6383 57.16
23.5203 32.61
24.5573 83.90
25.8813 7.50
27.4495 18.93
27.7072 14.67
28.0283 14.37
28.5551 13.68
28.8695 6.58
29.2888 5.23
29.7899 26.56
30.2864 23.72
30.5940 20.11
31.1140 8.36
31.8031 13.96
32.1041 24.56
33.6776 7.24
34.5850 21.15
35.6974 5.87
36.9938 2.28
38.0538 8.36
38.7248 24.64
39.8133 7.14
40.8548 13.16
41.9093 5.85
43.2317 6.29
44.5397 5.26
45.0848 3.98
46.1768 2.53
48.0137 3.65
The crystallization process hitherto described to prepare the novel polymorphs consists of dissolving Dorzolamide in the selected solvent either with or without heating, preferably with heating at or near boiling point of the solvent. Cooling the resultant solution to -5°C to 30°C for several hours to regenerate the solid. Isolating the precipitated solids and drying the isolated solids at about ambient to 65°C temperature.
The solvent and anti solvent combination process described to prepare the novel polymorphs consist of dissolving Dorzolamide in the selected solvent. The dissolution is carried out at room temperature or under reflux condition. Adding anti-solvent, to the resulting solution under warm condition to regenerate the Dorzolamide. The anti-solvent
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addition is carried out at room temperature or at 35-55°C. Isolating the precipitated solids and drying the isolated solids at about ambient to 65 °C temperature.
The novel polymorphs of Dorzolamide are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Koc (A, = 1.5406 A) radiation with scanning range between 4-50 0 at scanning speed of 2°/min.
The present invention further encompasses the pharmaceutical compositions comprising Dorzolamide Forms I or II or III or mixtures thereof and one or more pharmaceutically acceptable excipients. The polymorphic forms of Dorzolamide base, namely Form I or II or III are prepared by the processes as described in the present invention.
The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
EXAMPLES
Preparation of Form I of Dorzolamide base
Example 1
0.5g of Dorzolamide was dissolved in 10 ml methanol at reflux temperature. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 2
0.5g of Dorzolamide was dissolved in 10 ml ethanol at reflux temperature. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 3
0.5g of Dorzolamide was dissolved in 10 ml isopropyl alcohol at reflux temperature. The
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hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 4
0.5g of Dorzolamide was dissolved in 20 ml diisopropyl ether (DIPE) at reflux temperature. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 5
0.5g of Dorzolamide was dissolved in 10 ml water at reflux temperature. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 6
0.5g of Dorzolamide was dissolved in 10 ml acetone at reflux temperature. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 7
0.5g of Dorzolamide was dissolved in 50 ml toluene at reflux temperature for 30 minutes. The substance gets partly dissolved and the solution was filtered to remove undissolved substance. The hot solution was filtered. The hot solution was allowed to cool to room temperature. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 8
0.5g of Dorzolamide was dissolved in 10 ml ethyl acetate at room temperature. To this solution 50 ml DIPE was added. The solution was stirred at the same temperature for 24 hours. The solid obtained was filtered and dried at 65°C to get Form I.
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Example 9
0.5g of Dorzolamide was dissolved in 6 ml acetonitrile at room temperature. To this solution 50 ml DIPE was added. The solution was stirred at the same temperature for 24 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 10
0.5g of Dorzolamide was dissolved in 10 ml ethyl acetate at room temperature. To this solution 50 ml Hexane was added. The solution was stirred at the same temperature for 24 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 11
0.5g of Dorzolamide was dissolved in 10 ml isopropyl alcohol (IP A) at room temperature. To this solution 50 ml Hexane was added. The solution was stirred at the same temperature for 24 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 12
0.5g of Dorzolamide was dissolved in 3 ml dimethylformamide (DMF) at room temperature. To this clear solution 30 ml of water was added. The solution was stirred at 5-10°C for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 13
0.5g of Dorzolamide was dissolved in 3 ml dimethylformamide (DMF) at room temperature. To this clear solution 30 ml of DIPE was added. The solution was stirred at 5-10°C for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
Example 14
0.5g of Dorzolamide was dissolved in 2 ml N,N-Dimethyl acetamide at room temperature. To this clear solution 30 ml of water was added. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I.
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Example 15
0.5g of Dorzolamide was dissolved in 2 ml N,N-Dimethyl acetamide at room temperature. To this clear solution 30 ml of IPA was added. The solution was stirred at the same temperature for 3 hours. The solid obtained was filtered and dried at 65°C to get Form I. (Kf = 4.82%)
Preparation of Form II of Dorzolamide base
Example 16
0.5g of Dorzolamide was dissolved in 15 ml isopropyl alcohol containing 3-8% water at reflux temperature. The hot solution was concentrated under vacuum to obtain the solid. The solid obtained was filtered and dried at 65°C to get Form II.
Example 17
0.5g of Dorzolamide was dissolved in 10 ml acetonitrile containing 3-8% water at room temperature. The solution was concentrated under vacuum to obtain the solid. The solid obtained was filtered and dried at 65°C to get Form II.
Example 18
0.5g of Dorzolamide was dissolved in 15 ml acetone containing 3-8% water at reflux temperature. The hot solution was concentrated under vacuum to obtain the solid. The solid obtained was filtered and dried at 65°C to get Form II.
Preparation of Form III of Dorzolamide base
Example 19
0.5g of Dorzolamide was dissolved in 4 ml 1,4-Dioxane at room temperature. To this solution 30ml diisopropyl ether (DIPE) was added. The solid separated after DIPE addition was filtered immediately dried at 65°C to get Form III.
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Example 20
0.5g of Dorzolamide was dissolved in 4 ml tetrahydrofuran at room temperature. To this solution 30ml DIPE was added . The solid separated after DIPE addition was filtered immediately dried at 65°C to get Form III.
Dated this the 6,h day of July 2007
VDr. K.G. Rajendran USV Limited Applicant
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