FIELD OF THE INVENTION
The present invention relates to a method to obtain nitrofurantoin macrocrystal. The present invention further relates to a stable crystalline form of nitrofurantoin macrocrystal and composition comprising the said crystalline form.
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 macrocrystal 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.
The patent application number DE 2527584 Al discloses process for the preparation of a macrocrystalline 5-nitrofurantoin by dissolving nitrofurantoin in dimethylformamide and water and heating the solution so obtained in a water bath.
Indian patent application number IN 3941/CHE/2011 discloses process for the preparation of macrocrystal of nitrofurantoin by dissolving nitrofurantoin in dimethylformamide and heating at 80°C. This patent also discloses another process for the preparation of nitrofurantoin macrocrystal by dissolving nitrofurantoin in dimethylformamide followed by addition of aqueous acetic acid.
Although, there are several processes known in the literature to form nitrofurantoin macrocrystal, however there is always a need to develop a cost effective process that do not incur critical parameters or heavy work ups.

Crystallization and isolation of crystalline form of a compound takes the advantage of the fact that most crystal growth prefers incorporation of molecules of the same structure leaving other structures (impurities) out of the crystals. Moreover, isolation of compound in a crystalline form i.e. polymorphic form has an advantage over use of simple purified compound as polymorphs exhibits various physical properties, such as dissolution rate, shape, melting point, stability etc. which sometimes make them more suitable for formulating various compositions that are stable and having long shelf life and are more suitable for administering to the patients.
Based on the aforesaid, the instant application is focussed to develop an economical and simple process for preparation of nitrofurantoin macrocrystal and to develop a stable crystalline form of nitrofurantoin macrocrystal that can be used in various formulations and which is cost effective, environmental friendly and easy to develop at large scale production.
OBJECT OF THE INVENTION
The main object of the present invention is to develop a process for preparation of nitrofurantoin macrocrystal and purification thereof.
Another object of the present invention is to develop a stable crystalline form of nitrofurantoin macrocrystal.
One another object of the present invention is to develop stable nitrofurantoin macrocrystal that can be used for formulating various compositions.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of nitrofurantoin macrocrystal and isolation of crystalline form of nitrofurantoin macrocrystal that can easily be formulated.

Accordingly, the present invention provides a process for preparation of nitrofurantoin macrocrystal wherein said process comprising of:
a) suspending nitrofurantoin in aqueous solution of water miscible organic solvent to get a reaction mixture;
b) heating the reaction mixture to get a solution;
c) optionally filtering the solution to get a clear filtrate;
d) cooling the solution of step b) or filtrate of step c); and
e) isolating nitrofurantoin macrocrystal.
In another aspect, the present invention provides a stable nitrofurantoin macrocrystalline Form-I characterized by XRPD peaks at 14.35, 16.54, 18.76, 19.62, 22.67, 28.75 and 29.52 ±O.2°20.
DETAILED DESCRIPTION
Brief Description of Drawings
Fig. 1 depicts X-Ray Powder Diffraction (XRPD) of Form-I of crystalline
nitrofurantoin macrocrystal.
Fig. 2 depicts Differential Scanning Calorimetry (DSC) of Form-I of crystalline
nitrofurantoin macrocrystal.
The present invention will now be explained in details. 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 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.
In one embodiment, the present invention provides a process for the preparation of nitrofurantoin macrocrystal, wherein said process comprising of:
a) suspending nitrofurantoin in aqueous solution of water miscible organic solvent to get a reaction mixture;
b) heating the reaction mixture to get a solution;
c) optionally filtering the solution to get a clear filtrate;
d) cooling the solution of step b) or filtrate of step c); and
e) isolating nitrofurantoin macrocrystal.
In another embodiment, the water miscible organic solvent is selected from the group comprising of acetic acid, formic acid, orthophosphoric acid and/or mixture thereof.
In a preferred embodiment, the percentage of aqueous solution of water miscible organic solvent is in the range of 60-90%.
In another embodiment, the heating of the reaction mixture in step b) is carried out at a temperature range of 25-120°C.
The filtration of the solution in step c) can be performed by any convention method such as passing the solution through celite bed or through micron filter to get a filtrate.
In one another embodiment, the filtrate is cooled to a temperature in the range of room temperature to 0°C.

In yet another embodiment, the nitrofurantoin macrocrystal obtained in step e) is crystalline Form-I of nitrofurantoin macrocrystal wherein said crystalline form is anhydrous in nature.
In one more embodiment, the present invention provides a process for the preparation of crystalline Form-I of nitrofurantoin macrocrystal wherein said process comprising of:
a) suspending nitrofurantoin in 60-90% aqueous solution of acetic acid to get a reaction mixture;
b) heating the reaction mixture to get a clear solution (temperature);
c) filtering the solution to get a clear filtrate;
d) cooling the filtrate at 0°C; and
e) isolating the crystalline Form-I of nitrofurantoin macrocrystal.
In another embodiment, the nitrofurantoin compound that is used for the preparation of macrocrystals can either be procured from any commercial source or can be 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 VN. O- VNVH
o ^ .HCI xy*
Formula II Formula III Formula I
ii) optionally purifying crude nitrofurantoin to get pure nitrofurantoin of Formula I.
In one another embodiment, the present invention provides a stable nitrofurantoin macrocrystal crystalline Form-I characterized by XRPD having the peaks at 14.35, 16.54, 18.76, 19.62, 22.67, 28.75 and 29.52 ±O.2°20.

In another embodiment, the crystalline Form-I of nitrofurantoin macrocrystal is characterized by XRPD having the peaks at 9.35, 11.90, 14.35, 15.44, 16.54, 17.58, 18.14, 18.76, 19.62, 21.56, 22.24, 22.67, 23.27, 23.99, 25.39, 26.09, 26.51, 27.23, 27.76, 28.55, 28.75, 29.52, 30.98, 34.85, 35.78, 36.91, and 38.21 ±O.2°20.
In another embodiment, the crystalline Form-I of nitrofurantoin macrocrystal is characterized with peak endotherm at about 276.47°C and with peak onset at about
272.93°C.
In yet another embodiment, the crystalline Form-I of nitrofurantoin macrocrystal as prepared by the present invention is stable on storage when stored at a temperature of 25°C (± 2°C) and a relative humidity of about 60% ± 5% and at a temperature of 40°C (± 2°C) and a relative humidity of about 75% ± 5%, and can be used in formulating various compositions.
In yet another embodiment, the crystalline Form-I of nitrofurantoin macrocrystal as prepared by the present invention is anhydrous in nature with water content less than about 0.35% w/w.
Below given Table-1 shows the data related to water content and stability of anhydrous Form-I of nitrofurantoin macrocrystal.
Table-1

ND=Not detected,