The present invention relates to a novel crystalline form of dorzolamide hydrochloride, to processes for its preparation and a pharmaceutical composition containing it.
BACKGROUND OF THE INVENTION Dorzolamide hydrochloride, chemically (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride, which has the formula (1):

is a carbonic anhydrase inhibitor. Dorzolamide hydrochloride ophthalamic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension.
Analytical profiles of drug substnaces and excipients, volume 26, p-283-317 mentioned two crystalline forms of dorzolamide hydrochloride (form I, II).
It has now been found that dorzolamide hydrochloride can be prepared in a novel crystalline form (form III). The novel crystalline form is stable and is not spontaneously converted to the previously known forms. The novel form is found to be suitable for pharmaceutical preparations.
The object of the present invention is to provide a stable novel crystalline form of dorzolamide hydrochloride, a process for preparing it and a pharmaceutical composition containing it.
DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention, there is provided a novel crystalline form of dorzolamide hydrochloride, designated as form III, characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 5.7, 8.6, 15.5, 16.1, 16.8, 16.9, 17.2, 18.4, 19.0, 21.1, 22.5, 23.2, 25.1, 25.6, 27.3, 28.9 and 30.5 degrees. Figure 1 shows typical form III x-ray powder diffraction spectrum.

According to another aspect of the present invention, there is provided a process for preparation of the form III of dorzolamide hydrochloride. Thus, dorzolamide hydrochloride form III is precipitated from a solution comprising dorzoiamide hydrochloride and dimethylsulfoxide by adding an alcohol to the solution.
The volume of the alcohol required to precipitate dorzoiamide hydrochloride depends on the alcohol used, the volume of dimethylsulfoxide relative to the quantity of dorzoiamide and the temperature at which precipitation occurs. Thus, at least about 5 ml of isopropyl alcohol is required to precipitate dorzoiamide hydrochloride at 25°C from the solution containing 5.5 gm of dorzoiamide hydrochloride and 15 ml of dimethylsulfoxide.
According to another aspect of the present invention there is provided an another process for preparation of dorzoiamide hydrochloride form III. Thus, dorzoiamide free base is dissolved in dimethylsulfoxide, hydrochloric acid is added to the solution, the contents are maintained for 1 to 5 hours at 0°C to 20°C, an alcohol is added to the contents and the separated solid is collected by filtration or centrifugation.
The quantity of hydrochloric acid is not critical, but at least 1 mole of hydrochloric acid per mole of dorzoiamide is preferable.
The suitable alcohols are methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. A mixture of alcohols or an alcohol/s mixed with any other solvent may also be used. The preferable solvents are ethanol and isopropyl alcohol.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising dorzoiamide hydrochloride form III and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a x-ray powder diffraction spectrum of dorzoiamide hydrochloride form III.
x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Example 1 Dorzolamide free base (5.0 gm, obtained by the process described in example 24 of US 4,797,413) is dissolved in dimethyl sulfoxide (12 ml) and the pH of the solution is adjusted to 1.0 with conc, hydrochloric acid. The reaction mixture is maintained for 3 hours at 5°C to 10°C and then isopropyl alcohol (20 ml) is added. The contents are stirred for 1 hour at 15°C to 20°C and the solid is collected by filtration to give 4.0 gm dorzolamide hydrochloride form III.
Example 2 Dorzolamide hydrochloride (10 gm, obtained by the process described in example 24 of US 4,797,413) is mixed with dimethylsulfoxide (50 ml) and the contents are heated to 60°C. To the solution so obtained, isopropyl alcohol (60 ml) is added at 25°C. The precipitated crystals are filtered to give 9.1 gm dorzolamide hydrochloride form III.
Example 3 Example 2 is repeated substituting dorzolamide hydrochloride form I for dorzolamide hydrochloride to give dorzolamide hydrochloride form III.
Example 4 Example 2 is repeated substituting dorzolamide hydrochloride form II for dorzolamide hydrochloride to give dorzolamide hydrochloride form III.
Example 5 Dorzolamide free base (5.0 gm, obtained by the process described in example 24 of US 4,797,413) is dissolved in dimethyl sulfoxide (12 ml) and the pH of the solution is adjusted to 1.0 with cone, hydrochloric acid. The reaction mixture is maintained for 3 hours at 5°C to 10°C and then ethanol (30 ml) is added. The contents are stirred for 2 hour at 15°C to 20°C and the solid is collected by filtration to give 4.0 gm dorzolamide hydrochloride form III.

We claim:
1. A process for the preparation of the crystalline dorzolamide hydrochloride
form III, characterized by an x-ray powder diffraction pattern having peaks
expressed as 2θ at about 5.7, 8.6, 15.5, 16.1, 16.8, 16.9, 17.2, 18.4. 19.0,
21.1, 22.5, 23.2, 25.1, 25.6, 27.3, 28.9 and 30.5 degrees as shown in figure
1; as herein described comprising the steps of:
a) preparing a solution of dorzolamide hydrochloride either by adding hydrochloric acid to a solution of dorzolamide free base in dimethylsulfoxide; or by dissolving dorzolamide hydrochloride in dimethylsulfoxide;
b) maintaining for 1 to 5 hours at 0°C to 20°C;
c) adding an alcohol to the above solution; and
d) collecting the solid from the contents by filtration or centrifugation;
wherein the alcohol is selected from the group consisting of methanol,
ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
2. The process according to claim 1, wherein the alcohol is isopropyl alcohol.
3. The process according to claim 1, wherein the alcohol is ethanol.
4. The process according to claim 1, wherein the solid is collected at 15°C to 20°C.
5. The process according to claim 1, wherein the process comprising the step of precipitating dorzolamide hydrochloride form III from a solution comprising dorzolamide hydrochloride and dimethylsulfoxide by adding an alcohol to the solution; wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
6. The process according to claim 5, wherein the alcohol is isopropyl alcohol.
7. The process according to claim 5, wherein the alcohol is ethanol.
8. The process according to claim 1, wherein the process comprising the steps of:

a) dissolving dorzolamide free base in dimethylsulfoxide;
b) adding hydrochloric acid;
c) maintaining for 1 to 5 hours at 0°C to 20°C;
d) adding an alcohol to the above solution; and
e) collecting the solid from the contents by filtration or centrifugation;

wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
9. The process according to claim 8, wherein the alcohol is isopropyl alcohol.
10. The process according to claim 8, wherein the alcohol is ethanol