This application claims priority to Indian patent application number 3941/CHE/2011 filed on Nov 17,2011.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Nitrofurantoin Macrocrystals.

BACKGROUND OF THE INVENTION:

Nitrofurantoin, having chemical name l-[(5-nitro-2-furyl) methylideneamino] Imidazolidine-2, 4-dione, is an antibacterial agent specific for urinary tract infections and it is a higly effective chemotherapeutic agent and has proved outstandingly effective in all infectious diseases of the urinary tract. This effective property is due to its great resistance to metabolic destruction & rapid absorption in the gastrointestinal tract. It is approved by USFDA under the brand name "Macrodantin" and is available in three dosage forms at 25 mg, 50mg and 100 mg.

US Patent No. 2610181 discloses Nitrofurantoin as a product having following structure of formula (I) and also discloses process for the preparation of chemotherapeutically effective Nitrofurantoin by combining 1-amino hydantoin or its derivatives with 5-Nitro-2-furfural derivatives.

US 3,317,521 disclosed a process for the preparation of nitrofurantoin, which comprises reacting 5-nitrofurfural-hydrazone with chloroacetyl isocyanate in dioxane the precipitate is filtered off & washed with dioxane. The product (5-nitrofurfural-chloroacetyl semicarbazone) dissolved in dimethyl formamide, triethyl amine warmed to 40°C for an hour. Then reaction mixture acidified with hydrochloric acid and carefully evaporated to dryness in a vacuum. Product triturated & washed with water. Product is recrystallised by acetic acid & water with addition of charcoal.

GB 954,841 describes a process for preparing the nitrofurantoin monohydrate which comprises the reaction of 1-amino-hydantoin in acidic medium with 5-nitro-2-furfuraldehyde in ethanol at 85°C for half an hour. After cooling crystals of nitrofurantoin were precipitated. The obtained crystals were dried at 55-70°C for 3-5 hours.

GB 991,644 describes a process for preparing N-(5-nitro-2-furfurylidene)-1-amino-hydantoin which comprises the coupling of 5-nitro-2-furfural diacetate and 1-amino hydantoin hydrochloride in methanol, nitric acid & water refluxed for 45 minutes and then cooled. After filtering crystals of N-(5-nitro-2-furfurylidene)- 1-amino-hydantoin were obtained.

The present invention provides industrially scalable process for the preparation of Nitrofurantoin Macrocrystals.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide an improved process for the preparation of Nitrofurantoin Macrocrystals.

One aspects of the present invention provides, an improved process for the preparation of Nitrofuantoin Macrocrystals comprising the steps of:

a) suspending Nitrofurantoin in Dimethylformamide,
b) optionally heating the reaction mixture,
c) adding water or a mixture of water and water miscible organic solvent, and
d) isolating Nitrofurantoin Macrocrystals.

BRIEF DESCRIPTION OF THE DRAWINGS:

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :

Figure 1: illustrates the powder X-ray diffraction pattern of Nitrofurantoin Macrocrystals.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Nitrofurantoin Macrocrystals.
The main aspect of the present invention is to provide an improved process for the preparation of Nitrofurantoin Macrocrystals comprising the steps of:

a) suspending Nitrofurantoin in polar solvent,
b) optionally heating the reaction mixture,
c) adding water or a mixture of water and water miscible organic solvent, and
d) isolating Nitrofurantoin Macrocrystals.

According to one embodiment of the present invention, polar solvent such as Dimethylformamide, Dimethylacetamide, Dimethylsulfoxide or mixture thereof is used in step-a.

In one more embodiment, the reaction mass is heated at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 80-85 °C.

In another embodiment, water is added in the ratio of 8:2 to 2:8 with respect to polar solvent, preferably 6:4 to 4:6. More preferably 1:1 ratio of water and polar solvent is used for the preparation of stable Nitrofurantoin Macrocrystals.

In one more embodiment, water miscible organic solvent is selected from acetic acid or formic acid.

In one more embodiment, a mixture of water and water miscible organic solvent is added in the ratio of 8:2 to 2:8 with respect to polar solvent, preferably 6:4 to 4:6, more preferably 1:1.

In one more embodiment, water or a mixture of water and water miscible organic solvent, is added at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 75-80 °C.

Another aspect of the present invention is to provide an improved process for the preparation of Nitrofurantoin Macrocrystals comprising the steps of:

a) suspending Nitrofurantoin in Dimethylformamide,
b) optionally heating the reaction mixture,
c) adding water or a mixture of water and water miscible organic solvent, and
d) isolating Nitrofurantoin Macrocrystals.

In one embodiment, the reaction mass is heated at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 80-85 °C.

In another embodiment, water is added in the ratio of 8:2 to 2:8 with respect to Dimethylformamide, preferably 6:4 to 4:6. More preferably 1:1 ratio of water and Dimethylformamide is used for the preparation of stable Nitrofurantoin Macrocrystals.

In one more embodiment, water miscible organic solvent is selected from acetic acid or formic acid.

In one more embodiment, a mixture of water and water miscible organic solvent is added in the ratio of 8:2 to 2:8 with respect to Dimethylformamide, preferably 6:4 to 4:6, more preferably 1:1.

In one more embodiment, water or a mixture of water and water miscible organic solvent, is added at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 75-80 °C.

As per the present invention, mixture of Dimethylformamide and Nitrofurantoin is taken in a RB flask. The reaction mixture is heated at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 80-85 °C and reaction mass was optionally filtered through micron filter to separate insoluble particles . The filtrate was taken into another flask and purified water or mixture of water and water miscible organic solvents such as aqueous acetic acid or aqueous formic acid is added at a temperature of 60-95 °C, preferably 70-90 °C, more preferably 75-80 °C. 80°C. The reaction mass is cooled to room temperature, obtained solid is filtered and washed with methanol.

The solvents used in the prior art for the preparation of Nitrofurantoin Macrocrystals does not give good colour consistently. The present inventors surprisingly found that the usage of solvents Dimethylformamide and water or mixture of water and water miscible organic solvent is giving yellow colour consistently and yield also increased when compared with the prior art solvents.

The Nitrofurantoin Macrocrystals obtained by the present invention is characterized by the Powder X-ray diffraction as depicted in Figure 1.

Instrumentation
Powder X-rav Diffraction (PXRD)
The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/9 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Experimental procedure:
Example -1: Preparation of Nitrofurantoin crude
A mixture of 5-Nitrofurfural diacetate (176.5 g) and DM water (1200 ml) was taken in a RB flask. To this Cone. HC1 solution (32.4 ml) was added. To this resultant mixture 1-Amino hydantoin HC1 (100 g) was added and refluxed at 95-105 °C. The reaction mixture was cooled to 25-35 °C. This was filtered and washed with DM water. The compound was dried and methanol was added. The material was filtered and dried to get Nitrofurantoin.

Example-2: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. The filtrate was taken into another flask and purified water (400 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

Example-3: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. To the filtrate 80 % aqueous acetic acid (400 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

Example - 4: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. To the filtrate 70 % aqueous acetic acid (400 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

Example - 5: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. To the filtrate 60 % aqueous acetic acid (400 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

Example - 6: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. To the filtrate formic acid (300 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

Example - 7: Preparation of Nitrofurantoin Macrocrystals
A mixture of Dimethylformamide (400 ml) and Nitrofurantoin (100 g) was taken in a RB flask. The reaction mixture was heated to 80°C and reaction mass was filtered through micron filter. To the filtrate 10 % aqueous formic acid (300 ml) was added at 80°C. The reaction mass was cooled to room temperature and washed with methanol. The compound was dried under vacuum and passed through mesh to obtain the Nitrofurantoin Macrocrystals.

We claim:

1. An improved process for the preparation of Nitrofurantoin Macrocrystals comprising the steps of:

a) suspending Nitrofurantoin in Polar solvent,
b) optionally heating the reaction mixture,
c) adding water or a mixture of water and water miscible organic solvent, and
d) isolating Nitrofurantoin Macrocrystals.

2. The process according to claim 1, wherein polar solvent is selected from Dimethylformamide, Dimethylacetamide, Dimethylsulfoxide or mixture thereof.

3. An improved process for the preparation of Nitrofurantoin Macrocrystals comprising the steps of:

a) suspending Nitrofurantoin in Dimethylformamide,
b) optionally heating the reaction mixture,
c) adding water or a mixture of water and water miscible organic solvent, and
d) isolating Nitrofurantoin Macrocrystals.

4. The process according to claim 1 and 3, wherein the reaction mass is heated at a temperature of 60-95 °C.

5. The process according to claim 4, wherein the reaction mass is heated at a temperature of 80-85 °C.

6. The process according to claim 1 and 3, wherein water is added in the ratio of 8:2 to 2:8 with respect to the solvent used in step-a.

7. The process according to claim 1 and 3, wherein water is added in the ratio of 1:1 (v/v) with respect to the solvent used in step-a.

8. The process according to claim 1 and 3, wherein water miscible organic solvent is selected from acetic acid or formic acid.

9. The process according to claim 1 and 3, wherein mixture of water and water miscible organic solvent is added in the ratio of 8:2 to 2:8 with respect to the solvent used in step-a.

10. The process according to claim 1 and 3, wherein mixture of water and water miscible organic solvent is added in the ratio of 1:1 with respect to the solvent used in step-a.