"PROCESS FOR PREPARING POLYMORPHIC FORMS A AND C OF SERTACONAZOLE MONONITRATE"

FIELD OF THE INVENTION

The present invention relates to process for preparing Polymorphic forms A and C of sertaconazole mono nitrate. More particularly, the present invention relates to a stable Polymorph form-C of sertaconazole mononitrate.

BACKGROUND OF THE INVENTION

Sertaconazole mono nitrate (Ertaczo, Dermofix) is an antifungal medication of the imidazole class. It is available as a cream to treat skin infections such as athlete's foot. Sertaconazole refers to 1- [2- (7- chlorobenzo [b] thiophene-3-yl-methoxy) -2- (2,4-dichloro- phenyl) ethyl] -1H-imidazole. Commonly sertaconazole is used as mononitrate salt (I). EP 151477B1 discloses the preparation of sertaconazole mononitrate (I) by reacting l-(2,4-dichlorophenyl) -2- (lH-imidazol-1-yl) -ethanol with sodium hydride and 3-bromomethyl-7-chlorobenzo[b]thiophene in hexamethylphosphoramide (HMPA) and treating the resulting free base with nitric acid to give sertaconazole mono nitrate having melting point 156-157°C(polymorph-A). Sertaconazole mononitrate exhibits two polymorphs B and C, which have a melting point in the range of 163-164°C and 164.5-165.5°C respectively and these forms are disclosed in Arz.Forsch. 42,695-8, 1992 EP0748806B1 discloses a process for the preparation of polymorph B and polymorph C. In EP'806B1 have found out in the course of different crystallization assays that when polymorph A is recrystallized from absolute ethanol to get polymorph B and when polymorph A is recrystallized from chloroform to get polymorph C; the physical properties of polymorphs B and C of sertaconazole mononitrate are also disclosed.

CN1358719C discloses the synthesis of sertaconazole mononitrate (I) by etherifying 3-bromomethyl-7-chlorobenzo [b] thiophene with 1- (2,4 dichlorophenyl) -2- (lH-imidazol-1-yl) -ethanol at a molar ratio of 1:1 in toluene water (3:1, v/v) in the presence of sodium hydroxide and 50% tetrabutyl ammonium chloride (IV, Z = CI) solution at 80°C for 4 hours, extracting with ethyl ether to obtain free base of sertaconazole, traeting with nitric acid and recrystallizing in presence of ethanol. There is consequently a need for an alternative method for the preparation of sertaconazole mononitrate form-C. Also there is a constant need to have the cost effective and industrial friendly process for the preparation of the solid state form in substantially pure sertaconazole mononitrate having stable Form-C.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of polymorphic form A and C of sertaconazole mononitrate. The invention also provides a cost effective process for large scale production of polymorphic form-C of sertaconazole mononitrate. In one aspect of the present invention is to provide a process for the preparation of polymorphic form-C of sertaconazole mononitrate (I) comprising the steps of;

a) reacting 1- (2,4-dichlorophenyl) -2- (1H- imidazol-1-yl) -ethanol of formula(III) with 3-bromomethyl-7- chlorobenzo [b]thiophene in presence of tetrabutyl ammonium bromide and base to give a compound of formula(II).

b) optionally, the compound of formula(II) is purified in presence of ethyl acetate, nitrating the compound of formula(II) in presence of nitric acid and ethyl acetate as a solvent, and

c) isolating form-C of sertaconazole mononitrate (I) The above synthetic process is illustrated as per the following Scheme-I

Another aspect of the present invention provides a process for preparing polymorphic form-A of sertaconazole mononitrate.

a) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 0-5°C, and

b) isolating form-A of sertaconazole mononitrate (I)
In another aspect of the present invention provides a process for preparing polymorphic form-C of sertaconazole mononitrate.

a) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 60-65°C, and

b) isolating form-C of sertaconazole mononitrate (I) In yet another aspect of the present invention provides a stable Polymorphic form-C of sertaconazole mononitrate.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1: X-ray powder diffraction (PXRD) of Sertaconazole mononitrate form-A Fig 2: X-ray powder diffraction (PXRD) of Sertaconazole mononitrate form-C Fig 3: Differential scanning calorimetry (DSC) of Sertaconazole mononitrate form-A Fig 4: Differential scanning calorimetry (DSC) of Sertaconazole mononitrate form-C

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing Polymorphic forms A and C of sertaconazole mono nitrate. More particularly, the present invention relates to a stable Polymorphic form-C of sertaconazole mononitrate. In one embodiment of the present invention is to provide a process for the preparation of polymorphic form-C of sertaconazole mononitrate (I) comprising the steps of;

a) reacting 1- (2,4-dichlorophenyl) -2- (1H- imidazol-1-yl) -ethanol of formula(III) with 3-bromomethyl-7- chlorobenzo [b]thiophene in presence of tetrabutyl ammonium bromide and base to give a compound of formula(II).

b) optionally, the compound of formula(II) is purified in presence of ethyl acetate, nitrating the compound of formula(II) in presence of nitric acid and ethyl acetate as a solvent, and

c) isolating form-C of sertaconazole mononitrate (I)

According to the embodiment, the compound of formula (III) was added sodium hydroxide in toluene at 25-30°C, followed by the addition of water. The reaction mixture was raised to reflux at 115-120°C for 4 -5 hrs by using dean stark apparatus, remove the water completely from reaction mixture, cooling the reaction mixture temperature to 25-30°C. Which is further treated with 3 bromomethyl-7- chlorobenzo [b]thiophene in the presence of tetrabutyl ammonium bromide in toluene at 25-30°C and the reaction mixture is allow to stirred at 111-115°C for 1-2 hrs. After completion of reaction, the reaction mass was allow to cooled at 25-30°C, filter the solid, wash the solid and dried under vacuum. The crude sertaconazole was added to ethyl acetate, followed by addition of water and allow to heated the reaction mixture at 75-80°C to get clear solution. The organic layer was separated and cooled to 0-5°C, filtered the solid, washed with ethyl acetate and dried under vacuum to get pure sertaconazole of formula (II).

The sertaconazole is treated with nitric acid in presence of ethyl acetate and the reaction mixture was allowed to stirred, heated to 60-75° C to get clear solution. The reaction mixture was allow to cooled at 25-30°C, resultant solid was filtered, washed with ethyl acetate and dried under vacuum to get polymorphic form-C of sertaconazole mononitrate (I) Another embodiment of the present invention provides a process for preparing polymorphic form-A of sertaconazole mononitrate.

c) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 0-5°C, and

d) isolating form-A of sertaconazole mononitrate (I) According to the embodiment of present invention, the sertaconazole base is treated with nitric acid and acetate as a solvent at 0-5°C over a period of 1-3 hrs, most preferably 1-2 hrs at same temperature. The resultant solid was filtered, washed with ethyl acetate and dried under vacuum at 65-70°C to get Sertaconazole mononitrate Polymorphic form-A Another embodiment of the present invention is Polymorphic form-A of sertaconazole mononitrate characterized by a d90 particle size is having range between 50 um to 120 um. More preferably dgo particle size is 71 um.

In another embodiment of the present invention provides a process for preparing polymorphic form-C of sertaconazole mononitrate.

a) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 60-65°C,and

b) isolating form-C of sertaconazole mononitrate (I) According to the embodiment of present invention, Sertaconazole base was suspended in ethyl acetate and heated to 60-65°C to get clear solution; followed by addition of fuming nitric acid over a period of 1-2 hrs at 60-65°C, most preferably 30-60 min at same temperature. The obtained slurry was stirred at 60-65°C for 1-2 hrs; further it was cooled to 25-30°C. The resultant solid was filtered, washed with ethyl acetate and dried under vacuum at 65-70°C to get sertaconazole mononitrate Polymorphic form-C
According to the embodiment of present invention, acetate solvent is selected from ethyl acetate, propyl acetate, and isopropyl acetate.

According to the embodiment of present invention, the stress stability study of Sertaconazole Mononitrate Polymorph -C prepared at 75°C for 15 days and recorded the XRD and HPLC of purity initial samples and after stress stability.
Stability data of Sertaconazole Mononitrate Polymorph –C In yet another embodiment of the present invention provides a stable Polymorph form-C of sertaconazole mononitrate. XRD data of Sertaconazole Mononitrate Polymorph -C (Stability condition)


According to the embodiment of present invention, the above XRD data is concluded that Sertaconazole Mononitrate Polymorph -C is stable form at 75°C.
Another embodiment of the present invention is Polymorphic form-C of sertaconazole mononitrate characterized by a dg0 particle size is having range between 90 to 150 um. More preferably d% particle size at 105 urn The present invention will now be described in more detail with reference to the following examples. The technical scope of the present invention is not limited to these examples.

EXAMPLES

Example -1: Preparation of [2-(7-Chloro-benzo[b]thiophen-3-yl methoxide)- 2-(2,4-dichloro-phenyl) ethyl]-lH imidazole Mixture of toluene (250 ml ),l-(2,4-dichlorophenyl-2-(lH-imidazole -l-yl)-ethanol (50 g 0.195 moles) and 50% aqueous sodium hydroxide solution ( 50 g) was heated to 115-120°C; water was separated by Dean stark apparatus. The reaction mixture was cooled to 25-30°C, followed by addition of tetra butyl ammonium bromide (5g) and toluene (250 ml) solution of 3-bromomethyl-7-chlorobenzo[b]-thiophene ( 50 g 0.193 moles) at 30°C, stirred the mixture in 60-90 min and allow to heated at 111-115°C for 60 -90 min .After completion of reaction, the mixture was cooled to 0-5°C and stirred for 60 min at same temperature. The resultant solid was filtered and washed with Toluene ( 10 ml); obtained solid was added in Ethyl acetate ( 700 ml) and heated to 40-45 °C to get a clear solution, later the ethyl acetate solution was washed with the purified water (150 ml). The obtain ethyl acetate layer was distilled under vacuum till 210 ml, further it was cooled to 0-5°C. The resultant solid was filtered and dried at 65-70°C to get pure title compound.

Example -2: Preparation of [2-(7-Chloro-benzo[b]thiophen-3-yl methoxide)- 2-(2,4-dichloro-phenyl ) ethyl]-lH imidazole Mixture of toluene (250 ml ),l-(2,4-dichlorophenyl-2-(lH-imidazole -l-yl)-ethanol (50 g 0.195 moles) and 50% aqueous sodium hydroxide solution ( 50 g) was heated to 115-120°C; water was separated by Dean stark apparatus. The reaction mixture was cooled to 25-30°C, followed by addition of tetra butyl ammonium bromide (5g) and toluene (250 ml) solution of 3-bromomethyl-7-chlorobenzo[b]-thiophene ( 50 g 0.193 moles) at 30°C, stirred the mixture in 60-90 min and allow to heated at 111-115°C for 60 -90 min .After completion of reaction, the mixture was cooled to 0-5°C and stirred for 60 min at same temperature. The resultant solid was filtered and washed with Toluene (10 ml). The obtained solid was added in purified water (800 ml), heated to 40-45°C and maintained for 30 min , the obtained solid was filtered and washed with the purified water ( 200 ml) . The resultant solid was crystallized with Methanol (1500 ml), obtained solid was filtered at 0-5°C and dried at 65-70°C to get pure title compound

Example 3-: Preparation of Sertaconazole mononitrate Polymorphic form-A
Sertaconazole base (100 g) was added to a mixture of ethyl acetate (1000 ml) and 70% nitric acid (40 g) at 0-5°C over a period of 60-75 min, which is further stirred for 60 min at same temperature. The resultant solid was filtered, washed with ethyl acetate (100 ml) and dried under vacuum at 65-70°C to get Sertaconazole mononitrate Polymorphic form-A

Example 4-: Preparation of of Sertaconazole mononitrate Polymorphic form-A
Sertaconazole base (100 g) was added to a mixture of propyl acetate (1000 ml) and 70% nitric acid (40 g) at 0-5°C over a period of 60-75 min, which is further stirred for 60 min at same temperature.The resultant solid was filtered, washed with propyl acetate (100 ml) and dried under vacuum at 65-70°C to get Sertaconazole mononitrate Polymorphic form-A

Example 5-: Preparation of Sertaconazole mononitrate Polymorphic form-C
Sertaconazole base (100 g) was suspended in a ethyl acetate (1000 ml) and heated to 60-65°C to get clear solution; followed by addition of fuming nitric acid ( 34 g) over a period of 30-40 min at 60-65°C. The obtained slurry was stirred at 60-65°C for 30 min; further it was cooled to 25-30°C. The resultant solid was filtered, washed with ethyl acetate (100 ml) and dried under vacuum at 65-70°C to get sertaconazole mononitrate Polymorphic form-C

Example 6-: Preparation of Sertaconazole mononitrate Polymorphic form-C
To the mixture of ethyl acetate (1000 ml) and Sertaconazole base (100 g) was added fuming nitric acid ( 34 g) at 25-30 over a period of 30-40 min at 25-30°C .The resultant slurry was heated to 60-65°C and maintained for 60 min and cool the slurry to 25-30°C The obtain solid was filtered, washed with ethyl acetate (100 ml) and dried under vacuum at 65-70°C to get Sertaconazole mononitrate Polymorphic form-C

Example 7-: Preparation of Sertaconazole mononitrate Polymorphic form-C
Mixture of ethyl acetate (1000 ml) and Sertaconazole mononitrate Polymorph form-A (100 g) was heated to 75-80°C and maintained for 120 min and cool the slurry to 25-30°C . The obtain solid was filtered, washed with ethyl acetate (100 ml) and dried under vacuum at 65-70°C to get (90-95 g) Sertaconazole mononitrate Polymorphic""' form-C

We claim:

1. A process for the preparation of polymorphic form-C of sertaconazole mononitrate (I) comprising the steps of

a) reacting 1- (2,4-dichlorophenyl) -2- (1H- imidazol-1-yl) -ethanol of formula(III) with 3-bromomethyl-7- chlorobenzo [b]thiophene in presence of tetrabutyl ammonium bromide and base to give a compound of formula(II).

b) optionally, the compound of formula(II) is purified in presence of ethyl acetate, nitrating the compound of formula(II) in presence of nitric acid and ethyl acetate as a solvent, and

c) isolating form-C of sertaconazole mononitrate (I)

2. Process for the preparation of polymorphic form-A of sertaconazole mononitrate comprising the steps;

a) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 0-5°C, and

b) isolating form-A of sertaconazole mononitrate (I)

3. Process for the preparation of polymorphic form-C of sertaconazole mononitrate comprising the steps;

a) nitrating Sertaconazole base in presence of nitric acid and acetate as a solvent at 60-65°C, and

b) isolating form-C of sertaconazole mononitrate (I)

4. According to claim 1 and 3, the present invention provides a stable Polymorph form-C of sertaconazole mononitrate

5. According to claim 2 and 3, the acetate solvent is selected from ethyl acetate, propyl acetate and isopropyl acetate.

6. According to any preceding claims, the crystalline form-A of sertaconazole mononitrate having a particle size D90 in the range of 50 um to 120 um. Most preferable Dgoparticle size is 71 um.

7. The process according to claim 8, wherein the particle size D90 is 71 um.

8. According to any preceding claims, the crystalline form-C of sertaconazole mononitrate having a particle size D90 in the range of 90 to 150 um. Most preferable Dgoparticle size is 105 um