FIELD OF THE INVENTION
The present invention relates to an economic and industrially advantageous process for preparation of nitrofurantoin monohydrate and nitrofurantoin macrocrystals.
BACKGROUND OF THE INVENTION
Nitrofurantoin is an antibacterial agent specific for urinary tract infections. The Macrobid® brand of nitrofurantoin is a hard gelatin capsule shell containing the equivalent of 100 mg of nitrofurantoin in the form of 25 mg of nitrofurantoin macrocrystals and 75 mg of nitrofurantoin monohydrate.
In Macrobid, twenty-five percent is macrocrystalline nitrofurantoin, which has slower dissolution and absorption than nitrofurantoin monohydrate. The remaining 75% is nitrofurantoin monohydrate contained in a powder blend which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time.
Indian patent application number IN 3941/CHE/2011 discloses process for the preparation of macrocrystals of nitrofurantoin by dissolving nitrofurantoin in dimethylformamide and heating at 80°C. This patent also discloses another process for the preparation of macrocrystals of nitrofurantoin by dissolving nitrofurantoin in dimethylformamide followed by addition of aqueous acetic acid.
The major drawback of the processes known in the literature for the preparation of nitrofurantoin macrocrystals, is that these processes requires tedious and time consuming steps to remove the solvents such as dimethylformamide. Moreover, as per the prior art processes, the reaction is required to be carried out at elevated temperatures of 80°C that' results into formation of undesired side products ultimately results into multistep purification process which is uneconomical at large scale production

Further, Indian patent application number IN 820/CHE/2008 discloses process for .
preparation of nitrofurantoin monohydrate by dissolving nitrofurantoin in
dimethylformamide and heating the mixture so obtained at higher temperature of
80-85°C. . ' ■ '
The major drawback of the above said process is the involvement of elevated temperature conditions in preparation of nitrofurantoin monohydrate resulting into formation of impurities which ultimately involve multistep purification processes making process lengthy, tedious and'hence uneconomical.
Therefore, there is a need to develop an improved process for the preparation of nitrofurantoin monohydrate as well as nitrofurantoin macrocrystals which is simple, reproducible and well suited on commercial scale. Based on the aforesaid drawbacks of prior art processes, the instant application is focussed on development of novel and simple process for preparation of highly pure nitrofurantoin monohydrate and macrocrystals.
OBJECT OF THE INVENTION
The main object of the present invention is to prepare nitrofurantoin monohydrate in a simple and economical way.
Another object of the present invention is to develop a novel process for preparation of nitrofurantoin macrocrystals.
Another object of the present invention is to prepare highly pure nitrofurantoin monohydrate and macrocrystals.

SUMMARY OF THE INVENTION
The present invention relates to a new process for the preparation of Nitrofurantoin monohydrate. The present invention further relates to a new process for the preparation of nitrofurantoin macrocrystals.
0
Accordingly, the main aspect of the present invention provides a process of preparation of nitrofurantoin macrocrystals, wherein said process comprises the steps of:
* i) suspending nitrofurantoin in an acid, optionally in presence of alcohol to obtain a mixture; ii) heating the mixture to get a clear solution; iii) adding water to the clear solution to obtain crystals; and iv) isolating the crystals and drying to get pure nitrofurantion macrocrytals.
The present invention further relates to a new process for preparation of nitrofurantoin monohydrate, wherein said process comprises the steps of:
i) suspending nitrofurantoin either in an organic solvent or an aqueous acid to ' obtain a mixture;
ii) heating the mixture to get a clear solution; and
iii) adding water to the clear solution to get pure nitrofurantion monohydrate.
In a further aspect, the present invention also provides a manufacturing process of nitrofurantoin crude compound.
DESCRIPTION OF THE INVENTION
While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications,

equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to
understanding the embodiments of the present invention and so as not to obscure
i
the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
The present invention relates to a new and an advantageous process for preparation of nitrofurantoin monohydrate and macrocrystals.
Accordingly, in one embodiment the present invention relates to a process of preparation of nitrofurantoin macrocrystals, wherein said process comprises the steps of:
i) suspending nitrofurantoin in an acid, optionally in presence of alcohol to obtain a mixture;
ii) heating the mixture to get a clear solution;
iii) adding water to the clear solution to obtain crystals; and
iv) isolating the crystals and drying to get pure nitrofurantoin macrocrystals.
In another embodiment, the Nitrofurantoin used for preparation of nitrofurantoin macrocrystals is in any of the crude/wet/pure/monohydrate form which are prepared either by the process of the present invention or by any of the conventional methods known in the literature.

•^

In one another embodiment, the temperature maintained during the process is in the range of 25-85°C, preferably in the range of 40-70°C and more preferably in the range of 40-60°C,
In further embodiment, the acid used for preparation of nitrofurantoin macrocrystals is selected from the group comprising of acetic acid, 30-70% aqueous sulphuric, orthophosphoric acid or mixture thereof.
In furthermore embodiment, the above said alcohol is selected from the group comprising of methanol, ethanol, propanol and isopropanol.
In another embodiment, present invention further relates to a new process for preparation of nitrofurantoin monohydrate, wherein said process comprises the steps of:
i) suspending nitrofurantoin either in an organic solvent or an aqueous acid to obtain a mixture;
ii) heating the mixture to get a clear solution; and
iii) adding water to the clear solution to get pure nitrofurantion monohydrate.
In further embodiment, the organic solvent is selected from dimethyl formamide, dimethyl sulfoxide and N-methyl pyrrolidinone.
In furthermore embodiment, the aqueous acid is selected from 30-70% aqueous sulphuric acid, aqueous acetic acid and the like.
In furthermore embodiment, the process of preparing nitrofurantoin monohydrate is carried out at a low temperature which is in .the range of 40 to 120°C and preferably in the range of 50 to 110°C and more preferably in the range of 50-70°C.

In one another embodiment, the nitrofurantoin compound that can be used for the preparation of macrocrystals and monohydrate is prepared by the process comprising the steps of:
i) condensation of 1-aminohydantoin hydrochloride of Formula III with
. acetone semicarbazone of Formula II in presence of organic solvent to give nitrofurantoin of Formula I as represented in the scheme below:
H I °VNV 0- VN\H
*Yv^ — )>0 —_ ,^J>o
o H2N HC| j^jr
Formula II Formula III Formula I
ii) optionally purifying crude nitrofurantoin to get pure nitrofurantoin of Formula I.
In another embodiment, the process of preparing nitrofurantoin crude is carried out in an alcoholic solvent like methanol in presence of base such as sodium methoxide solution.
In fixrther embodiment, the process of preparing nitrofurantoin crude is carried out a temperature below 70°C.
i
In accordance with one embodiment of the present invention, the nitrofurantoin
monohydrate as well as macrocrystals is isolated with high purity of 99.0% or
above. v
In a preferred embodiment, the nitrofurantoin monohydrate as well as macrocrystals is isolated with high purity of 99.5% or above.
In another embodiment, the present invention provides nitrofurantoin monohydrate characterized by particle size distribution wherein dgo is 0.I to 200\im.

In a preferred embodiment, the present invention provides nitrofurantoin monohydrate characterized by particle size distribution wherein dgo is 2.0 to 150^im.
In another embodiment, the present invention provides nitrofurantoin macrocrystals characterized by particle size distribution wherein dgo is 0.1 to 200^im.
In a preferred embodiment, the present invention . provides nitrofurantoin macrocrystals characterized by particle size distribution wherein d9o is 2.0 to 150jam.
Further, the present invention provides a composition comprising nitrofurantoin monohydrate or nitrofurantoin macrocrystals or both, along with atleast one pharmaceutical acceptable excipient, wherein said Nitrofurantoin monohydrate and nitrofurantoin macrocrystals are prepared as per the process of the present invention.
Further, the present invention is illustrated in detail by way of the following examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES;
Example 1. Preparation of Nitrofurantoin Crude:
283.2g of Acetone semicarbazone was added to the sodium methoxide solution (30.0%) 1549.0g at 25-30°C. Heated the reaction mass at 50-60°C followed by addition of ethyl chloro acetate (406.9g in methanol) at 50-60°C. After Addition, stirred the reaction mass at 50-60°C. After completion of reaction, distilled out methanol from the reaction mass and added DM water at 25°C to get clear solution of reaction mass. Reaction mass was then quenched in diluted HC1 solution at 10-20°C followed by addition of 5-nitro-furfuraldiacetate (400.0g) at room

temperature and heated the reaction mass at 68-72°C for 1.0 h. Filtered the reaction mass at 30-35°C to get the final compound (460.0 g, wet weight).
Example 2. Preparation of Nitrofurantoin Monohydrate:
460.0 g of nitrofurantoin crude was dissolved in dimethylformamide (4.0V). Heated the reaction mass at 65-70°C to clear reaction mass. Charged Activated Carbon 20.Og and stirred for 30.0min 65-70°C. Filtered the reaction mass through celite bed followed by addition of DM water (8V) at 35-40°C, Filtered and washed with Methanol (5V), further Stir reaction mass in DM water (6V). Filtered and wash with D. M. water to get the nitrofurantoin monohydrate. Dried the compound at 60-65°C for 10-16 hrs to get 320.0 g of final compound. HPLC purity=NLT 99.0%, Loss on Drying: 6.5%-7.5%
Example 3. Preparation of Nitrofurantoin Monohydrate:
460.Og of nitrofurantoin crude was dissolved in N-methyl pyrolidine (6.5V). Heated the reaction mass at 45-50°C to clear reaction mass. Charged Activated Carbon 20.0 g and stirred the reaction mass at 45-50°C for 30.0min. Filtered the reaction mass through celite bed followed by addition of DM water at 35-40°C, Filtered and washed with Methanol, further Stir reaction mass in DM water (6V). Filtered and wash with DM Water to get the nitrofurantoin monohydrate. Dried the compound at 60-65°C for 10-16 hrs to get 300.0 g of final compound. HPLC purity=NLT 99.0%, Loss on Drying: 6.5%-7.5%
Example 4. Preparation of Nitrofurantoin Monohydrate:
460.0 g of nitrofurantoin crude was added in aqueous sulfuric acid (50.0%) and heated the reaction mass at 60-65°C. Charged activated carbon 20.0 g and stirred the reaction mass at 60-65°Cfor 30.0 min. Filtered the reaction mass through celite bed followed by addition of DM water at 25-35°C. Filtered and washed with Acetone, further washed with DM water to get the nitrofurantoin monohydrate. Dried the compound at 60-65°C under vacuum for 10-16 hrs to get 290.0 g of final compound.

HPLC purity=NLT 99.0%, Loss on Drying: 6.5%-7.5%
Example 5. Preparation of Nitrofurantoin Monohydrate:
200.0 g of nitrofurantoin crude was added in 20 V of aqueous acetic acid and heated the reaction mass at 110-115°C to get the clear solution. Distilled the acetic acid and charged 2L of DM water at 40-5 0°C. Stirred and filtered the reaction mass through celite bed at 40-50°C. Further, stirred the reaction mass in 5V of DM water at 40-50°C and filtered to get 160.0 g of nitrofurantoin monohydrate. HPLC purity=NLT 99.0%, Loss on Drying: 6.5%-7.5%
Example 6, Preparation of Nitrofurantoin Macrocrystals:
Added 460.Og of nitrofurantoin crude to acetic acid (10.0V), followed by addition of aqueous sulfuric acid (50.0%) (24 V) at 60-65°C to get the clear solution followed by addition of DM water (10 V) at 60-65°C. Cooled the reaction mass to 25-30°C. Filtered the reaction mass after 10-24 hrs and wash with DM water to get the macrocrystals of nitrofurantoin. Dried the compound at 70-75°C under vacuum for 10-16 hrs to get 200.Og of final compound. HPLC purity=NLT 99.0%, Loss on Drying: NMT 1.0%
Example 7, Preparation of Nitrofurantoin Macrocrystals:
Suspended 460.Og of nitrofurantoin crude in methanol (10 V) and added aqueous sulfuric acid (50%) (24 V). Heated the reaction mass at 60-65°C to get the clear solution followed by addition of DM water (10 V) at 60-65 °C Filtered the reaction mass after 10-24hrs and washed with DM water to get the macrocrystals of nitrofurantoin. Dried the compound at 70-75°C under vacuum for 10-16 hrs to get 200.0 g of final compound. HPLC purity=NLT 99.0%, Loss on Drying: NMT 1.0%
Example 8. Preparation of Nitrofurantoin Macrocrystals:
Added 460.0g of nitrofurantoin crude to Orthophosphoric acid (10 V) and aqueous sulfuric acid (50.0%) (24 V) at 60-65°C to get the clear solution and added DM

water (10 V) at 60-65°C. Filtered the reaction mass after 10-24 hrs and washed with DM water to get the macrocrystals of nitrofurantoin. Dried the compound at 70-75°C under vacuum for 10-16 hrs to get 190.0 g of final compound. HPLC purity=NLT 99.0%, Loss on.Drying: NMT 1.0%

WE CLAIM
1. A process for preparation of nitrofurantoin macrocrystals, wherein said process
comprises the steps of:
i) suspending nitrofurantoin in an acid, optionally in presence of alcohol to
obtain a mixture; ii) heating the mixture to get a clear solution; iii) adding water to the clear solution to obtain crystals; and iv) isolating the crystals and drying to get pure nitrofurantion macrocrytals.
2. The process as claimed in claim 1, wherein said acid used in step i) is selected from the group comprising of acetic acid, 30-70% aqueous sulphuric acid, orthophosphoric acid or mixture thereof.
3. The process as claimed in claim 1, wherein said alcohol used in step i) is selected from the group of methanol, ethanol, propanol and isopropanol
/
4. The process as claimed in claim 1, wherein said heating in step ii) is carried out
at temperature in the range of 40-70°C.
5. A process for preparation of nitrofurantoin monohydrate, wherein said process
comprises the steps of:
i) suspending nitrofurantoin either in an organic solvent or an aqueous acid to
obtain a mixture; ii) heating the mixture to get a clear solution; and iii) adding water to the clear solution to get pure nitrofurantion monohydrate.
6. The process as claimed in claim 5, wherein said organic solvent used in step i) is
selected from dimethyl formamide, dimethyl sulfoxide and N-methyl
pyrrolidinone.

7. The process as claimed in claim 5, wherein said aqueous acid used in step i) is selected from 30-70% aqueous sulphuric.acid and aqueous acetic acid.
8. The process as claimed in claim 5, wherein the heating in step ii) is carried out at a temperature in the range of 40-120°C.
9. A composition comprising nitrofurantoin macrocrystals obtained as per the
process claimed in claim 1, along with atleast one pharmaceutical acceptable
<
excipient
10. A composition comprising nitrofurantoin monohydrate obtained as per the
process claimed in claim 5, along with atleast one pharmaceutical acceptable
excipient.