Claims:1. Crystalline form I of Camostat mesilate.

2. A crystalline form I of Camostat mesilate as claimed in claim 1, characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflection at about 3.4, 7.8, 11.9, 14.7, 15.5, 16.0, 16.8, 17.3, 18.4, 22.0, 23.1, 24.6, 24.8, 25.6 and 27.5 ±0.2 degrees 2θ.

3. A crystalline form I of Camostat mesilate as claimed in claim 2 and 3, further characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflections at about 3.4, 6.9, 7.8, 9.5, 11.9, 13.9, 14.7, 15.5, 16.0, 16.8, 17.3, 18.4, 19.1, 20.5, 21.3, 22.0, 23.1, 24.6, 24.8, 25.6, 26.7, 27.5, 28.2, 29.8, 30.6, 31.1, 32.5, 33.5, 34.8, 35.5, 36.8, 37.4 and 38.8 ±0.2 degrees 2θ.

4. A crystalline form I of Camostat mesilate as claimed in claim 2, having a powder X-ray powder diffraction pattern substantially in accordance with Figure-1.

5. A crystalline form I of Camostat mesilate as claimed in claim 1, having a differential scanning calorimetry (DSC) onset at 162.94ºC as depicted in Figure 2.

6. A crystalline form I of Camostat mesilate as claimed in claim 1, Infra-red (IR) spectrum having peak reflections at about 3388, 3180, 3018, 1749, 1728, 1696, 1650, 1630, 1613, 1514, 1463, 1422, 1406, 1358, 1332, 1279, 1240, 1215, 1184, 1166, 1149, 1089, 1059, 1048, 1040, 1021, 925, 866, 850, 784, 757, 729, 700, 676, 635, 604, 562, 526, 519, 498, 409 as depicted in Figure 3.

7. A purification process for preparing Camostat mesilate comprising:

a. Crude Camostat mesilate was dissolved in organic solvent,
b. heating the obtained suspension at suitable temperature
c. cooling the obtained solution in step b), and
d. isolating the pure Camostat mesilate.

8. The process as claimed in claim 6 step b), wherein the heating reaction is carried out at suitable temperature 40-45º C for 30 mins.

9. The process as claimed in claim 6, wherein the organic solvent is selected from group consisting of ethyl acetate, methyl isobutyl ketone (MIBK), acetone, methanol, ethanol, isopropanol, isopropyl ether, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetonitrile and water or mixture thereof.

10. The crystalline form I of Camostat mesilate as claimed in claim 1, having particle size distribution D90 10 to 250 μm.
, Description:CRYSTALINE FORM I OF CAMOSTAT MESILATE

FIELD OF THE INVENTION

The present invention relates to crystalline form I of Camostat mesilate. The present invention also relates to a purification process for preparing Camostat mesilate.

BACKGROUND OF THE INVENTION

Camostat mesilate (Foipan ®) is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so Camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. The manufacturer is Ono Pharmaceutical. The drug is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.

It is an inhibitor of the enzyme transmembrane protease, serine 2 (TMPRSS2). Inhibition of TMPRSS2 partially blocked infection by SARS-CoV and Human coronavirus NL63 in HeLa cell cultures. Another in vitro study showed that Camostat significantly reduces the infection of Calu-3 lung cells by SARS-CoV-2, the virus responsible for COVID-19. It is currently in Phase 1 and Phase 2 clinical trials. For chronic pancreatitis camostat's typical dose is 600 mg daily, for postoperative reflux esophagitis 300 mg are taken. The daily dose is split in 3 doses and taken after each meal.

Camostat mesilate is chemically known as 4-[[4-[(Aminoiminomethyl) amino]benzoyl] oxy] benzene acetic acid 2-(dimethylamino)-2-oxoethyl ester Methanesulfonate of formula (I) has the following structure.

US 4021472 (Ono Pharmaceutical.,) discloses Camostat mesilate and it’s process for preparation. Camostat mesilate is obtained in ‘472 patent by recrystallization / purification with diethyl ether to get Camostat mesilate melting at 150-155°C.

JP 4545911B2 of Sumika Fine Chemicals discloses purification process of Camostat mesilate, nitrogen atmosphere, wet crystals of Camostat in DMF was added, and heated to about 70°C. The mixture was stirred at 65-75°C for 30 minutes and cooled to 60°C. Then acetone was added dropwise at 55 to 65°C., seed crystal was added, and the mixture was stirred at 55 to 65°C for 1 hour. It was cooled to 5°C and aged at 0 to 5°C for 6 hours or more. After filtration, the mixture was washed with acetone to obtain wet crystals of Camostat mesilate (purity 99.7% by HPLC).

WO2006108643 of Novartis A.G., discloses solution of 1,45 g phosphoric acid in water is added dropwise to a suspension of Camostat base in water at 50°C. The resulting clear solution is allowed to cool. Crystallization takes rapidly place after seeding at 40°C. The very thick suspension is diluted with water and stirred over night at r. t. After filtration the solid is washed first with water and then with acetone. The crystals are dried at 60°C and ca. 10 mbar for 20 h.

According to patents and literature reports on other crystal forms, only the instructions for tablets on the market in Japan describe the melting point of the active ingredient at 194-198°C.

CN 111349021 A of Nanjing Changao Pharmaceutical discloses Crystalline form A of Camostat mesilate and it’s process for preparation, which comprises add Camostat mesilate to methanol, heat to reflux (60~70℃), stir the solids to dissolve completely, add acetonitrile, naturally cool down and crystallize, down to 10℃, continue crystallization after 4 hours, suction filtration, and drying at 50°C to obtain Camostat mesilate crystal form A. According to the ‘021 patent, the crystalline form A of Camostat Mesilate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 4.9, 9.0, 9.8, 12.5, 13.8, 14.4, 16.2, 17.0, 17.9, 19.3, 19.9, 21.4, 21.9, 22.5, 24.4, 24.9, 27.2, 28.1, 30.0, 31.3 and 36.6. and melting point at 188~189℃.

We have found a crystalline form I of Camostat mesilate. The crystalline form has been found to be stable over the time and reproducible. Hence it is suitable for pharmaceutical preparations.

The object of the present invention to purification process of Camostat mesilate, which it enhances in pharmaceutical composition.

In view of the foregoing, the present inventors have provided purification process of Camostat mesilate and Crystalline Form I of Camostat mesilate with commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical and eco-friendly.

SUMMARY OF THE INVENTION

The present invention relates invention relates to crystalline form I of Camostat mesilate. The present invention also relates to a purification process for preparing Camostat mesilate.

In one aspect of the present invention, it provides a crystalline form I of Camostat mesilate characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.4, 7.8, 11.9, 14.7, 15.5, 16.0, 16.8, 17.3, 18.4, 22.0, 23.1, 24.6, 24.8, 25.6 and 27.5 ±0.2 degrees 2θ.

In another aspect of the present invention, it provides a purification process for the preparation of Camostat mesilate, comprising:

a. Crude Camostat mesilate was dissolved in organic solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b), and
d. isolating the pure Camostat mesilate.

In yet another aspect of the present invention, A pharmaceutical composition comprising a therapeutically effective amount of crystalline form I of Camostat mesilate e having particle size distribution D90 less than about 250 μm.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline form I of Camostat mesilate.

Figure 2: Differential scanning calorimetry (DSC) crystalline form I of Camostat mesilate.

Figure 3: Infra-red (IR) spectra crystalline form I of Camostat mesilate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates invention relates to crystalline form I of Camostat mesilate. The present invention also relates to a purification process for preparing Camostat mesilate.

In one embodiment of the present invention, the crystalline form I of Camostat mesilate is characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

In an embodiment of the present invention provides the crystalline form I of Camostat mesilate characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.4, 7.8, 11.9, 14.7, 15.5, 16.0, 16.8, 17.3, 18.4, 22.0, 23.1, 24.6, 24.8, 25.6 and 27.5 ±0.2 degrees 2θ.

According to the embodiment of the crystalline form I of Camostat mesilate is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.4, 6.9, 7.8, 9.5, 11.9, 13.9, 14.7, 15.5, 16.0, 16.8, 17.3, 18.4, 19.1, 20.5, 21.3, 22.0, 23.1, 24.6, 24.8, 25.6, 26.7, 27.5, 28.2, 29.8, 30.6, 31.1, 32.5, 33.5, 34.8, 35.5, 36.8, 37.4 and 38.8 ±0.2 degrees 2θ.

According to the embodiment of the present invention, the crystalline form I of Camostat mesilate differential scanning calorimetry (DSC) onset at 162.94ºC as depicted in Figure 2.

According to the embodiment of the present invention, the crystalline form I of Camostat mesilate Infra-red (IR) spectrum having peak reflections at about 3388, 3180, 3018, 1749, 1728, 1696, 1650, 1630, 1613, 1514, 1463, 1422, 1406, 1358, 1332, 1279, 1240, 1215, 1184, 1166, 1149, 1089, 1059, 1048, 1040, 1021, 925, 866, 850, 784, 757, 729, 700, 676, 635, 604, 562, 526, 519, 498, 409 as depicted in Figure 3.
Another embodiment of the present invention provides a purification for the preparation of Camostat mesilate, comprising:

a. Crude Camostat mesilate was dissolved in organic solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b), and
d. isolating the pure Camostat mesilate.

According to the embodiment of the present invention, Crude Camostat mesilate was dissolved in water and acetone at 25-30ºC and the mixture was heated to 40-45º C for 30 min. The obtained reaction mixture was cooled to 10-15°C and it was filtered at the same temperature. The obtained residue was diluted with methanol and stirred for 1 hr at 20-30ºC. The resultant solid was filtered and dried at 60-65°C for 6 hrs to obtained pure Camostat mesilate.

According to the embodiment of the present invention, the organic solvent is selected from group consisting of ethyl acetate, methyl isobutyl ketone (MIBK), acetone, methanol, ethanol, isopropanol, isopropyl ether, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetonitrile and water or mixture thereof.

Another embodiment of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of Camostat mesilate crystalline form I in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient or pharmaceutically acceptable carrier may preferably be formulated into cream, tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

In yet another embodiment of the present invention provides, A pharmaceutical composition comprising a therapeutically effective amount of crystalline form I of Camostat mesilate having particle size distribution D90 10 to 250 μm.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLES

Example-1:

Purification of Camostat mesilate:

100 g (0.202 moles) of Camostat mesilate crude material, water (60 ml) and acetone (400 ml) were taken at 25-30°C. The reaction mass temperature was raised to 45-50°C and the reaction mass was maintained for 30 min at 45-50°C. After that, undissolved material was removed by filtration at 45-50°C. The obtained filtrate was cooled to 10-15°C and the precipitated solid was filtered at 10-15°C. The wet material was dried at 60-65°C for 6hr to obtain pure Camostat mesilate.

HPLC purity: 99.5%.

Yield: 65 g.

Example-2:

Purification of Camostat mesilate:

100 g (0.202 moles) of Camostat mesilate crude material and water (150 ml) were taken at 25-30°C. The reaction mass temperature was raised to 45-50°C and the reaction mass was maintained for 30 min at 45-50°C. After that, undissolved material was removed by filtration at 45-50°C. The obtained filtrate was cooled to 10-15°C and maintained reaction mass at 10-15°C for 3-4 hr. The precipitated solid was filtered at 10-15°C. The wet material was dried at 60-65°C for 6hr to obtain pure Camostat mesilate.

HPLC purity: 99.4%

Yield: 40 g.

Example-3:

Purification of Camostat mesilate:

100g (0.202 moles) of Camostat mesilate crude material, water (60 ml) and acetone (400 ml) were taken at 25-30°C. The reaction mass temperature was raised to 45-50°C and the reaction mass was maintained for 30 min at 45-50°C. After that, undissolved material was removed by filtration at same temperature and the filtrate was distilled under vacuum at below 50°C. The obtained residue was diluted with methanol (200 ml) and stirred for 1hr at 20-30°C. The precipitated solid was filtered at 20-30°C. The wet material was dried at 60-65°C for 6hr to obtain pure Camostat mesilate

HPLC purity: 99.7%

Yield: 70 g